| 30/09/2023 |
£388,606 |
PWC KENYA |
The Africa Climate Summit (ACS), co-hosted by Kenya and the African Union Commission, is set to take place in Nairobi from September 4th to 6th, 2023. The summit will convene leaders, development partners, intergovernmental organisations, the private sector, academia, civil society, and others to address climate change in Africa. The theme of the summit is "Green Growth and Climate Finance for Africa,''. The summit aims to present a visionary approach for a Green Growth agenda in Africa, which seeks to harness the continent’s rich human and natural resources in a climate-positive manner. It will focus on developing solutions that promote climate action, boost economic growth, and ensure that Africa is not marginalised in international markets due to high emissions. The ACS will spotlight five main areas of growth: energy transition and renewable energy, green minerals and manufacturing, sustainable agriculture, sustainable infrastructure and urbanisation, and natural capital. These growth areas will be supported by two critical cross-cutting aspects: adaptation and resilience to climate risks, and climate finance and carbon credits. The summit also seeks to address the challenges and opportunities of climate finance in Africa, emphasising the need for investments that can drive the Green Growth Agenda. |
| 30/09/2023 |
£80,830 |
AFRICAN POPULATION & HEALTH RESEARCH CENTRE, KENYA |
The potential of data science to revolutionize healthcare in Africa is vast, but persistent challenges hinder its progress. This project seeks to establish a benchmark assessing the current state of data science in African healthcare. This will provide invaluable insights for data scientists and health communities to evaluate their progress, emphasize the impact of data science, and foster its further development. The initiative aims to explore emerging trends, opportunities, and facilitate knowledge exchange to stimulate innovative thinking within the field. To achieve the project’s primary objective, 15 teams have been formed to produce 15 writeups. We reached out to the writing teams to identify key needs (time, location, staff support) and incorporated them into the proposal. We propose two writing retreats, one in Nairobi and one in Cape Town, to give teams protected time for individual writing and consensus building, facilitated sessions and engagement. The workshops will be led by experts selected by APHRC and co-chairs. The primary output will be fifteen draft manuscripts on advancing healthcare through data science in Africa. This work will contribute to the progress of data science in African healthcare, fostering innovation, and paving the way for improved health outcomes across the continent. |
| 30/09/2023 |
£15,070 |
UNIVERSITY OF OXFORD |
The second in-person meeting of the Wellcome-funded GALENOS project will be held in Oxford (UK) on November 14th-15th 2023. As part of our commitment to capacity building and global inclusion, we would like to invite all members of the leadership team, members of Global Lived Experience Advisory Board and the newly appointed research fellows from across Africa to attend the meeting. This will be a unique opportunity to foster the relationship within the team, accelerate learning across the multidisciplinary team and shape the future of the GALENOS project. We are asking Wellcome to contribute to the costs of this meeting. |
| 30/09/2023 |
£47,775 |
ONWARD |
Onward is a not-for-profit Westminster think tank that exists to to develop bold and practical ideas to boost economic opportunity, build national resilience, and strengthen communities across all parts of the United Kingdom. The Science Superpower programme explores how ministers can realise their ambitions for the UK to be a "science superpower". It fills a large gap in the current policy debate by bringing together some of the finest scientific minds with leading policymakers to explore the strategic challenges, opportunities and trade-offs that the government and scientific community face. Year 2 of Onward’s Science Superpower programme will deliver a number of ambitious and original research reports and impactful events with key policymakers, aimed at effecting positive change in how the UK Government approaches science. The programme has three overarching goals: Enhancing appreciation of the importance of science and technology to the UK’s economy and national interests Demonstrating what a whole-economy approach to science and technology looks like, and what a cross-government effort to support it needs to be. Helping to bridge the gap between science and policy to maximise the value science can offer to the world, and mitigate the harm of unfocussed policies on innovation. |
| 30/09/2023 |
£9,282,183 |
DIAMOND LIGHT SOURCE LTD |
Not available |
| 30/09/2023 |
£2,499,104 |
DIAMOND LIGHT SOURCE LTD |
Not available |
| 30/09/2023 |
£6,686 |
SUSTAIN OUR ABILITIES |
The purpose of this grant is to request funding for participation of Nicole Redvers, ND, a prominent Indigenous Persons and Climate Change Scholar to present on Best Practices related to including Indigenous Persons views and incorporating Indigenous Persons a partners into research related to Climate Change and Health. Climate Health 2023 is an inaugural meeting being launched on October 21 and 22 at Zucker School of Medicine in New York. This hybrid meeting posits to bring together health professionals from students, to senior researcher from around the world to begin the process of having a truly academic meeting that brings together people from around the world in Climate and Health. The inclusion of Dr. Redvers presentation will allow a focus on the importance of Indigenous Persons in the initiative. We will have Dr. Redvers presentation at the end of the first day of the meeting, after a session on Health Care Disparities and it will immediately be followed by a reception so that interaction and discussion about this important topic can continue into the evening. |
| 30/09/2023 |
£99,888 |
NHS CONFEDERATION |
Executive Summary The UK has the opportunity to formally participate in phase two of the EU Joint Action to develop the European Health Data Space (EHDS), a Europe-wide health data ecosystem. Participation would give the UK an opportunity to influence the development of the EHDS, and in turn the future direction of EU policy on data sharing for research, planning and policymaking. As a result of participation we aim to promote and protect UK interests in the development of common European standards, rules, governance, and legislation ensuring maximum interoperability for future UK-EU health data sharing for healthcare, innovation and research. |
| 30/09/2023 |
£5,000 |
FOUNDATION FOR THE FEDERAL UNIVERSITY OF SãO PAULO |
This proposal seeks support from Wellcome for the SciELO 25 Years Week event, themed Open Science with IDEIA - Impact, Diversity, Equity, Inclusion, and Accessibility. The week-long event will be held in São Paulo, Brazil, and online from September 25th to 29th, 2023. It consists of two meetings documented at https://25.scielo.org/en/. The first meeting is the SciELO Network Meeting on September 25th and 26th, with participants from 17 countries operating national collections of over 1300 open access journals. These journals publish approximately 65,000 documents annually, with a repository of over 1.1 million articles accessed by over 1 million unique visitors daily. The meeting aims to discuss collection development, challenges, and future prospects. The second meeting is the SciELO 25 Years International Conference, taking place from September 27th to 29th. It features national and international research and scientific communication authorities, 50 speakers, up to 300 in-person attendees, and an estimated 300 online participants. The conference aims to update SciELO and the research community on the latest advancements in scientific communication, focusing on open science. The budget for the SciELO 25 Years Week is £180,000, with a requested support of £5,000 from Wellcome. |
| 30/09/2023 |
£100,000 |
C40 CITIES |
This grant would support policy engagement and advocacy efforts across C40’s network of mayors and cities to build support both at mayoral level and in international fora for the phase out of fossil fuels, including activities leading up to and an event at COP28. It aims to distributing and amplify health, climate and economic arguments against fossil fossil use developed through research supported by Wellcome. City governments have a huge role to play in stopping investment in fossil fuels ($1 trillion in 2022) by enacting policies to reduce demand, and using their collective voice to shift the narrative globally. Proposed activities include: Ten-page fossil fuel phase out advocacy playbook for mayors including an overview of the coal, gas and stranded assets research accompanied with regionally specific messaging to support advocacy. Public letter from C40 mayors highlighting city solutions phasing out fossil fuels Engage cities and build momentum up to COP28 Event at COP28 to demonstrate that mayors are committed to the phasing out of fossil fuels, alongside other global voices that share this position (including health and financial experts, climate scientists, youth and climate movement voices). Support engagement with partners for the event Contribution to C40’s COP28 mayoral briefing |
| 30/09/2023 |
£150,000 |
FUTURE LEADERS NETWORK |
We are seeking £150,000 GBP to support ten young negotiators from low-income, small island developing states and/or global south countries (who are most vulnerable to the impacts of climate change, including the health implications) to participate in the Climate Youth Negotiator Programme 2023. We will prioritise your funding on young negotiators with a health background or focus. The Climate Youth Negotiator Programme (CYNP) is the first programme of the Youth Negotiators Academy (delivered by the Future Leaders Network), aimed at developing the next generation of climate change negotiators. The climate crisis is the biggest existential threat of our time - and yet current actions and commitments to reduce greenhouse gas emissions are insufficient to limit global warming to the goals of the Paris Agreement. The CYNP aims to tackle this by bringing the urgency, impatience and intergenerational lens of youth into international decision making. We do this by equipping young leaders - nominated by their country’s government and guaranteed a role in their UN climate negotiations team - with the skills, knowledge, networks and resources they need to effectively participate in climate negotiations and supporting them to drive systemic change within multilateral decision making. |
| 30/09/2023 |
£388,606 |
THE UNITED NATIONS FOUNDATION |
IMAGINE WINNING In 2023, we need determined players and champions. Leaders, businesses, campaigners and policy makers must come together for a critical halftime pep talk. That is why a ground-breaking partnership has come together to curate The Global Goals Campaign and the SDG Pavilion in 2023 led by the United Nations Office for Partnerships – breaking out of the UN bubble and setting the agenda for a week of decisive action. WE’RE DOWN AT HALFTIME In 2015, 193 world leaders agreed a game plan to build a fairer, greener, better world by 2030: The Sustainable Development Goals. In 2023, we’re at halftime, and these Goals are in jeopardy. The impact of COVID-19, cost of living, climate crisis, and conflict is being felt desperately around the world. And for the second year in a row, we are no longer making progress. But that is not a reason to give up. Any given match is won in the second half. |
| 30/09/2023 |
£151,785 |
UNITED FOR GLOBAL MENTAL HEALTH |
Using our expertise in advocacy, communications and convening we will ensure that climate change, the environment and mental health are put on the agenda for action by governments and decision-makers, and integrated into relevant national and global policies and financing mechanisms. Building the Field We will actively contribute to the Connecting Climate Minds project (our CEO is on the advisory board) and work with CCM and Wellcome to build networks of stakeholders, particularly CSOs and People With Lived Experience (PWLE) from LMICs, who are focused on addressing the mental health impacts of environment and climate change. Advocating for Change Working in coalition with partners, including the Climate and Health Alliance, CCM and Wellcome, we will advocate for the integration of mental health in health and climate related policy making. Our focus areas will be the COP, UN and WHO decision making processes and national policy making in a set of priority countries. We will develop advocacy briefs for use by CSOs, international organisations and governments to make the case for change for integrating mental health into government and international agencies’ environment and climate change plans and in relevant inter-governmental negotiations. |
| 30/09/2023 |
£178,768 |
PASTEUR NETWORK |
The Pasteur Network (PN) with members in 25 countries on five continents is a global leader in public health, science, innovation, and education. The PN holds an annual meeting to refine PN-wide research and public health priorities. This year’s meeting will focus on our four strategic pillars: (1) epidemic intelligence and preparedness with a clear focus on climate-sensitive infectious diseases; (2) R & D ecosystem reinforcement ; (3) capacity building, knowledge transfer, and technology; and (4) continue to modernize and update the Network. The PN aims to refine a strategy for climate-sensitive infectious diseases using different mechanisms, including climate health observatories, focusing on the global South, to link various climate data sources with human health and laboratory data. With support from the Rockefeller Foundation, the PN held a convening in June 2023 to discuss the implementation of this first pillar through discussions on strengths and weaknesses within the PN, including data sharing. A follow-up discussion concerning outstanding research needs is planned for the PN annual meeting in Tunis in November 2023. The meeting will bring together representatives of all member institutes as well as strategic thought leaders. This year we will also create a space for young scientists to showcase their research. |
| 30/09/2023 |
£221,101 |
UNIVERSITY OF KWAZULU NATAL |
Leveraging the existing wastewater surveillance infrastructure built for polio and COVID-19 in South Africa, and, using a metagenomic approach, the proposed Alternate Antimicrobial Resistance Monitoring System (AlARMS) will delineate the burden of AMR from the longitudinal surveillance of the microbiome, resistome and mobilome in multiple One Health settings, comparing and contrasting genomic data from three sources: gut microbiota of vulnerable/at-risk humans, gut microbiota of their major, intensively-produced food animal sources, and associated wastewater microbiota. AlARMS will ascertain whether AMR in wastewater is representative of AMR in the microbiota of vulnerable/at-risk human (adding a step to the sewage-clinical AMR correlation by linking population-level AMR data) and animal populations and compare this to AMR in contemporary bacterial isolates from clinical and veterinary laboratories. The project will additionally explore the correlation/association (if any) between antimicrobial use (AMU) and antimicrobial residues in wastewater. AlARMS also includes an ethnographic study to ascertain socio-behavioural drivers of AMR and uses mathematical modelling to elucidate transmission dynamics. AlARMS may serve as early-warning and a proxy for conventional AMR surveillance systems in humans, food animals and the water, sanitation and hygiene (WASH) sector. |
| 30/09/2023 |
£259,100 |
SCIENCE MEDIA CENTRE |
The Science Media Centre seeks funding of £200k for core activities over 4 years plus £50k to extend the Global Coordinator position for 18 months. Core funding will enable us to continue our mission of improving the quality and scientific accuracy of media reporting of the defining issues of our time, with the ultimate goal of serving the wider public. Public understanding of infectious disease, climate change, mental health and many more subjects depends on receiving an unbiased, accurate presentation of evidence from the very best experts. The SMC exists to ensure the most important issues in health and science are responsibly communicated through the mass media, and this funding will allow us to pursue our core goals. The SMC’s Global Coordinator facilitates coordinated working across the network of SMCs (now operating in seven countries), including sharing/translation of expert comment and making media briefings available to journalists on subjects of international importance. She identifies and advises people interested in setting up SMCs in other countries, coordinates global outreach and stakeholder engagement with key partners and collaborators worldwide, and investigates sources of funding for the network. Funding from Wellcome will allow us to maintain this important role until September 2025 |
| 30/09/2023 |
£378,071 |
AMREF HEALTH AFRICA |
Ostensibly, climate change is becoming a major driver of both communicable and non-communicable diseases, with an estimated 150,000 deaths and an expected 250,000 more deaths projected by the year 2030. The direct health costs will reach US$ 2-4 billion/year by 2030, posing major threats to the universal health coverage. The year 2023 presents a unique opportunity for the global community to position health as a major agenda within climate change conversations, including in significant events such as the upcoming Africa Climate Week, Africa Climate Summit, New York Climate Week, UNGA, and COP 28 in Dubai. Amref and its partners including AFIDEP and PACJA will be leading a pan African charge to build political momentum for the sustainable inclusion of health in formal processes and negotiations of the United Nations Framework Convention on Climate Change (UNFCCC). The specific objectives will include: Building a common position among key climate and health actors on submissions and statements during upcoming regional and global climate convenings. Engaging the Africa Group of Negotiators to advocate for health considerations at different UNFCCC negotiation tables. Strengthening the capacities and engagements of the Africa Ministries of Health, which will also involve organizing the first climate-health Ministerial meeting |
| 30/09/2023 |
£198,379 |
SOCIAL GOOD FUND |
GCHA proposes to implement a suite of activities to prepare health stakeholders to engage with UNFCCC policy-making; lead development of joint policy positions from the health community on key COP negotiating streams; and support strategic, effective, and coordinated lobbying and advocacy for climate policy that delivers for people’s health, in the run up to and during COP28; as well as to engage and build capacity among the broader climate community to support health goals and to effectively deliver the health argument for climate action. With the increased focus on health for COP28, GCHA will deliver dynamic mobilization and coordination of health stakeholder engagement with the UNFCCC process and related activities throughout the remainder of the year leading up to COP, and at COP28 itself, and will prepare partners in the climate space for effective engagement on the health focus that will be at play at this COP. Key goals include integrating the health argument for climate action, and policy positions that benefit health, into Party negotiating positions and talking points during the COP negotiations, to drive more ambitious and health-protective climate action. |
| 30/09/2023 |
£171,380 |
ACCESS TO MEDICINE FOUNDATION |
The Access to Medicine Foundation seeks to utilize an initial installment of €200,000 from Wellcome Trust to jumpstart the following work with their AMR programme. Finalise and publish the Foundation’s first ever deep-dive thematic study on responsible manufacturing of antibiotics, with an aim to shed light on critical issues relevant to G20 2023 discussions. Longitudinally assess and encourage further company progress through a publication on the opportunities identified in the 2021 AMR Benchmark. Deepen relationships and engagement work with antibiotic manufacturers, global health stakeholders, and governments in order to take steps towards creating a dependable accountability framework for manufacturing stewardship. Commence work on a thematic study on R & D for antibiotics, antifungals and diagnostic products as well as planning for related engagement activities to advance stakeholder alignment towards the 2024 high-level UNGA meeting on AMR. This generous funding will serve as a crucial seed for the AMR program work and empower the Foundation to continue leading the charge when it comes to holding industry accountability for curbing AMR. |
| 30/09/2023 |
£1,332,180 |
KING'S COLLEGE LONDON |
Commissioned by Wellcome, we landscaped the world for longitudinal datasets with the objective of finding the most promising opportunities for transformative research on depression, anxiety and psychosis. In the space of 9 months, we identified more than 3,000 international longitudinal datasets across different sectors and with a range of different foci. The list of datasets, posted on the Landscaping project’s website, generated great enthusiasm around the world on social media. Here, we propose to convert this list into an interactive platform for increasing the discoverability of longitudinal datasets, maximising the use of already collected data and generating new knowledge based on meta-data. We plan to review all identified datasets to extract information about their discoverability, the populations they cover and the data they collected. We propose to develop an automated updating system for ensuring the accuracy and relevance of this new platform in the years to come. We aim to offer a toolkit about Lived Experience Expert (LEEs) involvement in longitudinal mental health research. We envision to disseminate the platform to wide audience and targeted stakeholders. We intend to analyse meta-data to identify strengths and gaps of longitudinal datasets for mental health research. |
| 30/09/2023 |
£16,602 |
UNIVERSITY OF BIRMINGHAM |
The universities supported by the TPAs are keen to hold a in-person meeting with the intent of firming up those interactions that have been developed across the network since the beginning of the TPA program and share experiences and common practice. The University of Birmingham is currently managing the TPA partners network and is organising a in-person networking event for all Professional Services supporting the iTPA activities at the various institutions, ie the TPA Facilitators. The event is to be held on the 6th July 2023 at the Edgbaston Park Hotel, University of Birmingham. The budget requested aims to support the organisation of this networking event, looking to share experiences and best practices, and most importantly devise how best to continue working together for best use of resources to support common areas of need. The aim is to build on the excellent collaborative nature of the network, developed during these last 3 years and continue to work together towards upskilling our academics and support research culture change across the various institutions post TPA program, |
| 30/09/2023 |
£40,240 |
UNIVERSITY OF THE WESTERN CAPE |
In 2019, the Public Health Alliance for Genomic Epidemiology (www.pha4ge.org) was established as a global, community-driven effort to build consensus on technical solutions, establish and provide a forum to debate and develop new standards for data exchange in Public health. Over the past 3.5 years we have expanded to 200+ members in 68 organisations and have published data standards and analytical tools as guidance to, and with, Public health practitioners. This year we will launch the first of a biennial international conference on Public Health Genomics and Bioinformatics (www.pha4ge.org). This proposal requests 20 travel fellowships to support students who wish to attend the international PHA4GE conference. The first PHA4GE conference aims to bring the bioinformatics and public health practitioners together to review and strengthen public health bioinformatics and pathogen genomics surveillance solutions. The aforementioned aim will be explored through a series of goals as outlined in the themes of the different sessions within the conference namely: (1) Quality assurance in Public Health Laboratories, (2) Computational tools for pathogen surveillance, (3) Harmonising pathogen data collection, (4) Priority pathogens and (5) Training in public health bioinformatics. The conference and the preceding workshop will start 27th October till 1st November 2023. |
| 30/09/2023 |
£1,190,617 |
STICHTING EIFL.NET |
The proposal will develop and deliver a participatory funding approach with strong African governance that will support providers of African diamond open access (OA) publishing services to enhance their quality and sustainability while maintaining their diversity. It will also strengthen national and regional collaborations on diamond OA and solicit funding commitments from African institutions and governments (in national and institutional policies with permanent budget lines) in a multi-stakeholder forum framework. Two open grant funding calls for proposals co-designed with the diamond OA community will be issued and the funds provided will strengthen quality diamond OA publishing services across Africa. Costs and strategies for flipping APC-based journals to diamond OA will also be defined and sustainability models will be discussed with journals and institutions supporting them. Researchers will have more equal access to OA publishing services. Governments, funders and institutions will streamline policy and funding decisions on the national and continental levels. EIFL, AJOL and WACREN will collaborate to empower African diamond OA community of practice and offer cost-efficient, open, public, shared publishing infrastructures. |
| 30/09/2023 |
£38,031 |
WITS HEALTH CONSORTIUM (PTY) LTD |
This grant is intended to support the 7th meeting of the ANISE (African Network for Influenza Surveillance and Epidemiology) network, which will be the first ANISE gathering of influenza and respiratory disease-focused experts in the continent of Africa since the COVID-19 pandemic. The African Network for Influenza Surveillance and Epidemiology (ANISE) is a network of laboratorians, epidemiologists, public health officials, clinicians, veterinarians, researchers, and policy makers who work together to strengthen the capacity for surveillance and research related to influenza and other respiratory viruses in Africa. This will be an opportunity for these experts to share their experiences since 2018 and lessons learned which can be applied to both preparedness for seasonal influenza and respiratory disease pandemics. The meeting will cover a variety of topics including disease burden, cost burden, economic impact of vaccines, influenza and vaccine policy, epidemiology, virology, and preparedness. There will also be several workshops offered on topics such as genomic surveillance and annual influenza season severity assessment. This will be an important forum to discuss the future direction of respiratory disease prevention, control and preparedness.This grant would fund conference activities such as a poster presentation session (venue hire, prizes) and travel grants for youth researchers. |
| 30/09/2023 |
£2,724,735 |
EUROPEAN BIOINFORMATICS INSTITUTE |
Wellcome and EMBL-EBI seek to establish a partnership to deliver molecular biology open data resources that enable both basic research and translational innovation to improve human health. It is clear that in the future, the open data resources at EMBL-EBI - on which the world depends - need to be built even more fairly and inclusively to maximise the impact of research. The multifaceted challenge of improving human health on a global scale will need concurrence and collaboration among diverse stakeholders from multiple geographic regions, requiring a renewed approach to data resource development, capacity building and delivery. This proposal comes in two parts over two years starting 2 January 2024: Part 1. Preparatory phase. To enable EBI and Wellcome to explore together new ways to build life science data infrastructure that is truly global. This will combine agile resource development and networking to improve the global reach of data services. Part 2. Bridging. To maintain European Variation Archive (EVA) and ChEMBL, including pilot work for more global approaches to engagement and coordination. This will prototype a funding model for resource delivery in the future, allowing strategic adjustments across the EMBL-EBI portfolio to meet new operational opportunities globally. |
| 30/09/2023 |
£2,998,310 |
UNIVERSITY OF OXFORD |
The Global Health Bioethics Network (GHBN) is highly effective and resilient platform for the promotion of and support for LMIC-led research in bioethics. This research combines a contextually sensitive investigation of practical ethical problems on the front line of global health research, practice and policy, and a sophisticated engagement with macro-level ethical and political issues in global and social justice. GHBN is a partnership between the five Wellcome Africa and Asia Research Programmes (AAPs) in Kenya, Malawi, South Africa, Thailand, Vietnam, and the Ethox Centre at the University of Oxford. It aims to build the capacity of the AAPs to identify and address ethical issues arising in their research; promote and support research on practical ethical issues relating to global health research and practice, and, more broadly, to promote ethical reflection across the AAPs. The current proposal represents an exciting and ambitious moment of transition for the GHBN. At the heart of this development is the implementation of a new model of collaborative LMI leadership, an expansion of its activities to a broader and more inclusive LMIC membership, and the launch of a peer-reviewed funding scheme to support small scale LMIC-led collaborative projects for early career researchers. |
| 30/09/2023 |
£48,564 |
NATIONAL ACADEMY OF SCIENCES, AMERICA (NAS) |
In order to increase the contribution of open science to producing better science, the National Academies of Sciences, Engineering, and Medicine’s (NASEM) Roundtable on Aligning Incentives for Open Science was launched in 2019. The Roundtable convenes critical stakeholders to discuss the effectiveness of current incentives for adopting open science practices, current barriers of all types, and ways to move forward in order to align reward structures and institutional values in advancing open scholarship. During its initial three-year phase, the Roundtable has fostered the exchange of ideas and joint strategic planning among key stakeholders. Through its meetings, public workshops, and working group activities, the Roundtable has catalyzed the creation of new tools and initiatives aimed at helping research institutions, research sponsors, societies, and individual researchers to implement open practices and expand the reach and impact of open scholarship. In Phase Two, the Roundtable on Aligning Incentives for Open Scholarship will build on these accomplishments in order to further facilitate and promote the growth of sustainable, equitable open scholarship policies and practices. The Roundtable will convene two times per year and create a venue for exchange of ideas and a mechanism for joint strategic planning among key stakeholders. |
| 30/09/2023 |
£36,908 |
BROWN UNIVERSITY |
Proposal Summary We would like to host a Satellite Meeting to The Global Consortium for the Prevention of Depression: New designs. This event will focus on new problems and potential solutions for targeted prevention. This event will take place at Brown University (Providence, Rhode Island, USA) on Wednesday the 27th of September, 2023. Goal To deliver a stimulating and interesting one day meeting that provokes discussion among researchers with diverse backgrounds about the prevention of anxiety and depression. The underlying goal is to increase interest in the field of targeted prevention of mental health problems in vulnerable populations, to encourage the engagement and involvement of early career researchers and people with lived experience, and to address scientific issues around trial design and implementation ‘failure’. A report will be produced that aims to address prevention opportunities for funding. |
| 30/09/2023 |
£241,117 |
PANORAMA GLOBAL |
Over the years, there have been many recommendations for improving pandemic preparedness and health resilience — but few implemented because there was no concerted effort to build political will. With a collective advocacy model, Pandemic Action Network uniquely fills the policy and advocacy gap to advance progress on Pandemic PPR. Building on our successful partnership with Wellcome to support civil society engagement around the Pandemic Fund, Pandemic Action Network proposes to intensify our efforts to reduce the global risk of infectious disease and pandemic threats by aligning and mobilizing partners to advocate for policy and financial commitments around key political moments throughout 2023, including the UN Pandemic PPR High Level Meeting, Intergovernmental Negotiating Body (INB) on the Pandemic Accord, G7, G20, and African regional initiatives. Additional support from Wellcome at this time will enable Pandemic Action Network to continue to push for sustainable financing and effectiveness of the Pandemic Fund, along with other international finance and governance reforms that will benefit Pandemic PPR. We will also continue to grow and strengthen the depth and breadth of engagement with our global network of partners and champions — with particular focus in key markets and low- and middle-income countries (LMICs). |
| 30/09/2023 |
£1,002,593 |
RESEARCH ENGLAND |
This application outlines Wellcomes financial contribution to the National Co-ordinating Centre for Public Engagement (NCCPE) and how Research England will manage the award. Research England will administer the award and all other contributions from the Public Engagement Funders Group (PEFG), which co-manages NCCPE. Providing NCCPE funding from only one funder (Research England) reduces unnecessary reporting for all funders. It lessens the administrative and financial burden on the NCCPE to administer the award, allowing them to focus on supporting Wellcome, and the other funders in shifting sector-wide engagement operations and expectations. This application explains how Research England will manage the award, including governance, roles, and responsibilities. It will then briefly summarise the value of NCCPE to highlight why Wellcome and the other funders would fund the organisation. |
| 30/09/2023 |
£296,677 |
THE UNITED NATIONS FOUNDATION |
Recent global crises have demonstrated the importance of international cooperation to solve collective problems that impede health and wellbeing. Utilizing the UN Foundation's unique relationship with the UN System, we will build understanding and common ground across venues and geopolitical forums by increasing political salience for preventing and limiting the escalation of infectious threats among Member States in New York and Geneva. This will be achieved through key activities including: Tracking processes and Member State positions on pandemics, AMR, and Summit of the Future. Supporting mission champions' diplomatic leadership. Hosting engagements related to PPR and AMR processes. Amplifying the value of the pandemic accord to AMR policy solutions. Shaping debates; hosting discussions; and engaging with international leaders. Other key outcomes include: More Member States engaged in events related to escalating infectious threats, achieved via Materials published and amplified to increase awareness and political support. Policy analysis and solutions developed, including on escalating infectious threats. Stakeholder convenings and briefings to drive coordinated policy action. Increased stakeholder understanding of WHO’s PPPR processes, achieved via Tracking key multilateral processes, negotiations and policy debates. Sharing synthesis, analysis and observations of key processes and negotiations. Policy inputs, convenings, or consultations to increase understanding of PPPR. |
| 30/09/2023 |
£252,476 |
UNIVERSITY COLLEGE LONDON |
This application expands the Wellcome Trust Envisioning Environmental Equity project ("EEE-1", 224687/Z/21/Z). Climate change does not impact us equally. Due to racism and structural violence, those least responsible for climate change bear the greatest burden. For health, this means rising temperatures, extreme weather, and resulting environmental damages increase pre-existing health inequities along racial, ethnic, and economic lines. EEE-2 aims to address this by building agency with groups who are most impacted by this system of violence to support their pursuit for justice. We aim to work with the most affected people and areas (MAPA) from minoritised communities who already face the health issues imposed by climate change. The proposed work builds on EEE-1, taking a localised, focused approach on specific arenas of health that we know are impacting MAPA communities in Brazil, the Philippines, Sri Lanka (new) and Uganda. Working with young people, we will produce actionable community-led solutions that are locally and contextually relevant, and that stimulate networking between the most impacted communities and those with decision-making power. We hope to strengthen local networks committed to action on climate and health justice with an explicit anti-colonial perspective, and support shifts in discourse around the root cause of the issue. |
| 30/09/2023 |
£499,970 |
UNIVERSITY COLLEGE LONDON |
RoRI was founded in 2019 by a group of researchers, funders and data providers with a mission to accelerate transformative research on research systems, cultures and decision-making. RoRI translates ideas and evidence into practical, real world solutions. We gather evidence and data, undertake experiments and develop tools to improve how research is funded, practised, communicated and evaluated. Through five objectives, we are building a community of people who want to change research for the better: Research—We support and build capacity for transdisciplinary, international and mixed-method research on research. Translation—We connect academic research on research capabilities to the data and analytical resources of our partners. Innovation—With our partners, we experiment, co-produce and test new tools, indicators, methods and evaluation frameworks. Brokerage—We accelerate the translation and engagement with research on research data and evidence by research communities and decision-makers Facilitation—We create a supportive space for exchange, networking, co-design and collaboration between researchers, funders, policymakers, publishers, data and infrastructure providers As RoRI embarks on its second phase, we are requesting a discretionary award of £500,000 over three years in support of RoRI’s core operations. Specifically, the funds will go towards the salary costs of three members of RoRI’s core team. |
| 30/09/2023 |
£350,250 |
ADVANCE HE |
Advance HE wishes to deliver a further three years (2023-2026) of the programme ‘Success on the Board: Unlocking the power of underrepresented voices in research’ after an initial, successful two-year pilot funded, designed and run in collaboration with the Wellcome Trust (WT). This is a positive action programme designed to target underrepresented groups, where evidence shows they are currently not fairly included in the governance of higher education and other sectors (particularly, the membership of boards). This is in the context of calls to improve organisational culture, performance and outcomes delivered for society, including WT work on research culture. It is fully funded for 10 participants per year. The aims of the programme remain unchanged: Primary objective: Equipping participants with skills, knowledge, confidence, and guidance on how to access to opportunities, enabling effective board membership of research institutions, universities, and other organisations relevant to the sector, such as hospitals and funders. Secondary objective: Institutions that send participants on the programme embedding the learnings from the programme, and making an active commitment to addressing the board diversity of their own boards and governance structures. We are seeking £349,125 over three years to deliver the programme on a grant basis. |
| 30/09/2023 |
£10,000 |
IMPERIAL COLLEGE LONDON |
The Machine Learning and Global Health Network are hosting a workshop at the International Conference of Learning Representation (ICLR 2023). ICLR is recognised as the top conference in deep learning and its applications and this year will be hosted in Kigali Rwanda. This is the first time ICLR has been hosted in Africa and it presents a unique opportunity for knowledge exchange and co-production with a truly international group of researchers. Our workshop aims to encapsulate the diversity of Machine Learning in Global Health by inviting speakers, papers and poster talks from researchers working across LMIC’s as well as government, industry and academic representatives, in-person, during the week-long ICLR conference. We are requesting sponsorship to support the travel awards for: 6 paper submissions and 1 organiser from LMIC’s alongside 10 local students, a total amount of £10K. Without this generous support, the high entry cost of attending a conference such as ICLR will not be possible for all our community. Not only does this have an immediate detrimental effect on those individuals unable to participate, but also the network is at a loss for voices and perspectives which often represent the places where health challenges are being addressed. |
| 30/09/2023 |
£155,513 |
CITY, UNIVERSITY OF LONDON |
The SEDRIC (Surveillance and Epidemiology of Drug Resistant Infections) Board has a fixed term working group (WG) to accelerate learning and facilitate knowledge mobilisation to inform policy implementation trajectories in countries and regions. The objectives of the WG are to: Conduct analysis of AMR policy journeys within the larger health system and One Health context, to identify positive and negative outlier example countries and/or public health concerns/issues which offer learning for AMR (particularly in the LMIC policy field). Understand the relevance of AMR success to the wider agenda for Sustainable Development and Economic progress at the national level Identify generalisable mechanisms which lead to change in policy adoption, and impact on the ground, and advance the field of knowledge mobilisation Share this learning with specialists in AMR as well as wider stakeholders in public health, and global health policy development and implementation and evaluation To seek collaborations with academia, industry, civil society, think tanks and non-governmental organisations, to further the impact of the work by SEDRIC |
| 30/09/2023 |
£170,000 |
UNITED FOR GLOBAL MENTAL HEALTH |
The Global Mental Health Action Network Annual Meeting 2023 aims to organise the largest ever gathering of civil society stakeholders working on mental health around the world in order to network and collaborate and advance progress on mental health, among and beyond the mental health community. We will bring 150 participants together on the 28th and 29th of June in Cape Town Africa. Within these participants we will fund 50 from LMICs to attend the meeting and ensure the voices of poeple with lived experience of mental health conditions are at the forefront of discussions. Our objectives are to: Provide a unique opportunity for global mental health advocates to convene and build relationships on a scale like never before Engage with global stakeholders and decision makers outside of the membership base, who are crucial to the development of the field of mental health Build networks and relationships particularly within and among GMHAN members and GMHAN working groups to help achieve improved joint working and ensure deliverables for 2023/24 are met Leverage the collective voice of GMHAN members to engage influential stakeholders we will work to engage government officials and decision makers with the annual meeting |
| 30/09/2023 |
£4,487,365 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
The legacy of neglect of the issue of snakebite is clear. Up to one-third of annual global snakebite deaths occur in Sub-Saharan Africa. But the neglect includes uncounted deaths and incomplete assessment of morbidity due to snakebite. The 2019 WHO roadmap has a clearly stated goal of halving snakebite deaths and disability worldwide by 2030. However, achieving that goal is considerably hampered by the lack of high-quality research evidence to inform policy and practice. Aim: To improve health outcomes for people affected by snakebite envenoming by addressing evidence gaps in policy and practice in Africa. This bold and innovative approach will transform the snakebite field by linking the international scientific community with local policy and community actors in an Alliance that is anchored in Africa. This co-ordinated approach is crucial for ensuring that the WHO goal reducing morbidity and mortality will succeed. Objectives To undertake high-quality research relevant to improving health outcomes for people affected by snakebite in Africa To develop systems to support national and regional bodies in Africa to incorporate research evidence into decision making in policy and practice To develop and support a sustainable and cross-disciplinary capacity for snakebite research in Africa |
| 30/09/2023 |
£562,100 |
KING'S COLLEGE LONDON |
Lived Experience Involvement (LEI) in mental health research – including patient and public involvement, co-production, and survivor research – has increasingly become expected. Yet a thorough understanding of the forms, processes, challenges, and possibilities of LEI remains lacking. Using inclusive, values-driven, and survivor-led processes, we will collaboratively produce a global Lancet Psychiatry Commission that: reflects on the history and evolution of LEI; assesses existing knowledge, considering diverse knowledge and practice; establishes key principles; explores differences and debates; and provides recommendations and next steps. The project is a partnership between Traumascapes, the Service User Research Enterprise (King’s College London, KCL), the UKRI Centre for Society and Mental Health (KCL), The Lancet Psychiatry, and Wellcome. In years one and two, we will form a global lived experience advisory group to co-define working practices and potential Commission content and create a virtual hub for LEI resources. We will recruit around 20 international Commissioners to writing and/or editing roles. A newly formed Network of Global Lived Experience (aNGLE) will comment on updates and plans. Key learning on values and principles for co-working on LE will be captured by a survivor artist-researcher. In the third year, we will co-produce dissemination activities and various, targeted outputs. |
| 30/09/2023 |
£10,000 |
INSTITUT NATIONAL DE LA SANTE ET RECHERCHE MEDICALE (INSERM) |
After more than a year of hearings of various experts in the field of research involving Healthy Volunteers, in 2022, the French National Institute of Health and Medical Research (Inserm) set up an international initiative named VolREthics supported by several international partners. During a first meeting that took place on February 2022 at UNESCO Headquarters in Paris and remotely, more than 150 experts from over 40 countries presented their points of view and questions. These exchanges made it possible to identify situations in which the rights, well-being and safety of Healthy Volunteers may be endangered. A variety of possible solutions to address these issues were discussed. Following this first international event, the Inserm Ethics Committee initiated the organization of 5 regional workshops to further discuss these issues in light of regional specificities in Sub-Saharan Africa, Asia, North America, Latin America and Europe. All materials are posted on VolREthics website: www.inserm.fr/en/ethics/volrethics/ In April 2023, in collaboration with its international partners, the Inserm Ethics Committee is organizing a meeting to review all the information collected during these regional workshops, to summarize the state of play and to discuss the implementation of recommendations that will result from this initiative. |
| 30/09/2023 |
£14,891 |
CENTRE FOR GENOMIC REGULATION |
Cells are the fundamental units of life – underlying cooperative functions in multicellular organisms and complex temporal life cycles in microbial eukaryotes. In recent years, the rapid advance in single-cell genomics technologies, combined with the growing availability of whole-genome sequences, opened up the opportunity to systematically map cell types in diverse organisms. The goal of the Biodiversity Cell Atlas is to articulate a community effort to build whole-organism cell atlases across the diversity of life, working in a phylogenetically informed way, supported by high-quality genomes, and using shared standards that make comparisons across diversity possible. This coordinated effort should boost our understanding the evolution and diversity of life at cellular resolution: from gene regulatory programs, through cell type molecular profiles, to biological interactions between species. To make this possible, this first meeting will bring together leading experts in biodiversity genomics, in model organism cell atlas initiatives, and in comparative single-cell genomics. During two days, we will discuss the opportunities and challenges ahead for reconstructing the cell type tree of life. |
| 30/09/2023 |
£559,484 |
UNIVERSITY OF OXFORD |
Young Lives (YL) is the largest and most comprehensive mixed-methods longitudinal study in the Global South following the lives of 12,000 young people dispersed across more than 80 rural and urban sites in Ethiopia, India, Peru and Vietnam for the past two decades. The study offers a timely opportunity to examine risk and protective factors for mental health from infancy to young adulthood, something which is unique in a comparable multi-country setting. Identical assessments and measures in several domains (physical and mental health, cognitive, social-emotional) have been implemented over a 20-year period. This proposal will enhance the design and data collection of the seventh YL survey round to capture the mental health and subjective well-being of the 22- and 29-years old YL respondents; to include a cortisol measurement from individual hair samples to be used as an objective measure of stress and to collect information about young people’s experiences and responses to shocks, including climate-, covid-19- and conflict in the case of Ethiopia. We have the opportunity to contribute to the creation of unique open-access data providing an invaluable resource for our understanding of the lifetime and proximate risk and protective factors for young people’s mental health and well-being. |
| 30/09/2023 |
£903,663 |
GLOBAL IMPACT |
Digital Public Infrastructure (DPI) forms the backbone for public service delivery and a digital foundation for a range of functional applications including health care, economic recovery, and climate change. Co-Develop aims to accelerate the adoption of inclusive, save, and equitable DPI in 50 countries in the next five years. This research will focus particularly on strengthening the digital health components of digital public infrastructure and will fund five work packages: Health Sector Partnership Plan that summarizes the digital health strategies for the 10-15 major donors supporting global digital health efforts to increase coordination of funding and identify gaps. Research the key trends in digital health (including individual health records, AI, diagnostics, health worker empowerment, telemedicine, disease surveillance, etc.) and the underlying Digital Health Infrastructure Enablers that are required to support these services. Develop three to five Digital Health Investment Proposals for the Co-Develop Investment Committee to review, iterate these concepts with partners, refine the proposals, and shepherd the proposals through to grant completion. Seek out and engage expert voices across civil society, community research, and others to collaboratively develop a "playbook" for equitable, ethical and inclusive digital public infrastructure. Broadly share the above outputs through a deliberate communications strategy. |
| 30/09/2023 |
£20,541 |
BABRAHAM INSTITUTE |
Not available |
| 30/09/2023 |
£90,000 |
VIVLI (CENTRE FOR GLOBAL CLINICAL RESEARCH DATA) |
Vivli is seeking funding to launch a ‘Data Challenge’ with the key goals of a) promoting awareness and utilization of the Vivli AMR Register to more researchers; and b) driving technological advances in the field of Antimicrobial Resistance (AMR). We hope this event will attract data scientists and AMR experts to make use of the AMR Register to propose cutting-edge questions and analyses based on datasets hosted on the platform to advance scientific research in AMR. Hackathon-type events are well-established in data science and aligning fields, and therefore we believe the 'Vivli AMR Surveillance Open Data Re-use Challenge’ has the potential to draw AMR experts, data scientists/research software engineers, and researchers at the cutting-edge of machine-learning (ML) who could benefit from access to the 'big data’ on our platform. ATLAS antibiotics is the largest dataset available from the AMR Register which has over 100 columns and nearly 800,000 rows of data collected between 2004 and 2020. The AMR Register contains data from 960,000 isolates from 85 countries (including 40 LMICs) on over 500 organisms. |
| 30/09/2023 |
£82,600 |
POLICY CURES RESEARCH |
This project aims to assess the impact of past investments in global health research and development (R & D), as well as to co-create and co-design the framework and measures by which the health of the investment ecosystem can be tracked now and in the future. Specifically, the project will: Establish an impact measurement framework that reflects the range of outputs, outcomes, and impacts of the global health, product-related R & D ecosystem Create a foundational evidence base of approved poverty-related neglected disease (PRND) and emerging infectious disease (EID) products, pipeline candidates, and R & D priorities Analyze the health and economic impact and return on investment (ROI) of 20 years of investment in PRND and EID-related R & D Put this evidence in the hands of influential stakeholders to compel greater/sustained investment and positive change Through a collaborative and co-creation approach, this project will build the foundation and tools for continuous evaluation allowing stakeholders across the global health R & D eco-system to build cohesive and self-reinforcing impact narratives, better strategize and plan for their investments, improve coordination (both funding and research), as well as course-correct to achieve greater impact to improve the health of individuals and populations. |
| 30/09/2023 |
£125,955,160 |
GATES MEDICAL RESEARCH INSTITUTE |
A Phase 3, randomized, observer-blind, placebo-controlled, multicenter, clinical trial to assess the prophylactic efficacy, safety, and immunogenicity of the investigational M72/AS01E-4 Mycobacterium tuberculosis (Mtb) vaccine when administered intramuscularly on a 0-,1-month schedule to adolescents and adults. |
| 30/09/2023 |
£3,568,090 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
Pathfinder 2 aims to catalyse and support successful action on climate mitigation with a focus on measured co-benefits for health. The first phase of the Pathfinder Initiative synthesised evidence on actions with the largest potential co-benefits, including energy, transport and agriculture/ food sectors. The second phase of the project will focus on three key areas where progress is needed: evidence for action, monitoring and evaluating progress; and capacity strengthening. First, machine learning techniques will be used to bring together relevant evidence and make it accessible to actors using a living evidence map. Second, a Coalition of research, enabling and implementing partners will be set up to galvanise the implementation of informed actions and their evaluation. Third, a community of practice will be brought together for sharing of knowledge and tools. The key goals of the project are to identify and deliver context-specific evidence on health co-benefits, and to strengthen global capacity to implement and evaluate climate mitigation actions that will promote human health. Building on the successful Lancet Commission brought together for the first phase of Pathfinder, this work will be guided by a panel of experts from across disciplines and global regions, with major multilateral organisations represented. |
| 30/09/2023 |
£299,816 |
NHS CONFEDERATION |
The NHS Confederation is applying to host a new phase of Understanding Patient Data (UPD) which will support conversations with the public, patients and healthcare professionals on transformation and innovation in the use of health data. We aim to make the way patient data is used more visible, understandable, and trustworthy by working with patient groups, charities, NHS organisations and policymakers to: bring transparency, accountability and public involvement to the way patient data is used improve the use of patient data for research The new phase will be based around four work programmes: health data policy, data infrastructure transformation, population health and securing the long-term sustainability of the UPD initiative. The key deliverables will be to: Develop the health data community Commission attitudes research to understand people’s views, expectations, and concerns about data (re)use. Translate attitudes and engagement research into insights for policy and practice. Provide advice and commentary to those seeking to understand the key issues about data. Promote existing resources and produce engaging, accessible resources and guidance on how to talk about health data, freely available. Secure funding to sustain UDP beyond its 2-year funding cycle. The new phase will build on and advance existing UPD work. |
| 30/09/2023 |
£848,435 |
PROTAS |
Generating robust and reliable evidence from good randomised controlled trials (RCTs) is a critical component of good healthcare across the world. The Good Clinical Trials Collaborative’s Guidance for Good Randomized Clinical Trials describes five principles that lead to reliably informative, ethical and efficient trials.? This proposal brings together four research networks, based in Latin America, Singapore, South Africa, and Southeast Asia, to support locally-led uptake of the guidance and its principles in low- and middle-income countries (LMICs). By investing in and collaborating directly with these networks the Collaborative will enable and promote content development decision-making to be taken at the most relevant local level to design and direct appropriate learning opportunities for achieving sustainable change. Project goal: Strengthen the capability of individuals, institutions and systems to produce reliable evidence through RCTs that enables informed changes in healthcare practice. Project outcomes: High-quality, context appropriate, learning materials designed to improve the capabilities and competencies of key implementers and national/regional bodies that fund and regulate RCTs in LMICs. Stronger regional and national networks in LMICs that play a key role in the decision-making and implementation of clinical trials. |
| 30/09/2023 |
£4,744,892 |
UNIVERSITY OF OXFORD |
PLATCOV is an ongoing phase 2, open label, randomised, controlled adaptive platform trial. It is unique in providing a standardised quantitative comparative method for in vivo assessment of potential antiviral treatments in low-risk adults with early symptomatic COVID-19. The primary outcome is the rate of viral clearance measured as the slope of the log10 oropharyngeal viral clearance curve over the first 7 days following randomisation. The treatment effect is the multiplicative change in viral clearance rate relative to the no study drug arm. PLATCOV has recruited over 550 patients and provided definitive assessments of ivermectin (no effect), remdesivir (42% acceleration in viral clearance), casivirimab/imdevimab (60% acceleration in Delta, and approximately 20% acceleration in Omicron BA.2 and BA.5). This proposal is to continue PLATCOV in order to assess new antiviral drugs and monoclonal antibodies and combinations, to extend to five study sites across the world (continue in Thailand and Brazil, add Pakistan, Laos and an African site), and to conduct preliminary evaluations of a similar pharmacometric design to assess anti-influenza drugs. The final objective is definitive assessments of comparative antiviral effects in COVID-19, and initial establishment of a global platform for pharmacometric assessment of interventions in pandemic respiratory infections. |
| 30/09/2023 |
£493,634 |
AFRICAN POPULATION & HEALTH RESEARCH CENTRE, KENYA |
The INSPIRE network is building a platform for sharing and harmonising African population health data. This proposal brings together expertise on clinical and epidemiological research on mental health (MH) into the Big Data environment. INSPIRE will integrate MH expertise in the governance, vocabulary development, data programming and analysis of longitudinal African MH data. It will link international expertise with regional data repositories, population health data sources and other data science initiatives in Africa. The aims are: Discover new and existing data from population and clinical data sources on: (1) longitudinal African MH conditions; (2) MH signs, symptoms and biomarkers; (3) MH treatment interventions in the African context; and (4) MH risk factors in Africa Augment standard vocabularies used for FAIRly describing MH observations, African MH providers and assessment instruments used in East Africa Provide a dashboard for estimation and characterising these mental health observations Provide a central worldwide catalogue for discoverable and reusable MH data Identify cohorts that address current and future questions about causes and management of mental health in Africa Using these cohorts, conduct advanced causal inferential analyses on impact of community and household exposures on MH across a federated cloud-based environment on the East Africa data web |
| 30/09/2023 |
£1,595,207 |
NEWCASTLE UNIVERSITY |
The Human Developmental Biology Resource (HDBR) is a fetal biobanking partnership between Newcastle University and University College London. Human embryonic/fetal tissues (4-22 post-conception weeks) are collected, stored and distributed for human developmental research. Use of human fetal tissue is expanding, with single-cell gene expression analysis and novel cell lineage studies (e.g. barcoding in slice cultures). Human fetal material is needed to validate findings on cell/organ differentiation from human pluripotent stem cells and organoids. Building on feedback from a 2022 HDBR user survey (72 respondents), HDBR will: (i) continue to provide high-quality biobanking of human embryonic/fetal tissues; (ii) evolve its services to meet changing research needs. Specific aims are to: Develop ‘research clinics’ to future-proof HDBR’s collection of early-stage embryonic tissues against recent supply issues Extend biobanking into late fetal and early childhood periods – a hard-to-access period of human development Provide more specialist dissections of embryonic/fetal samples, as increasingly requested Expand collection of prenatally-diagnosed abnormal (TOPFA) samples for research into congenital defects Establish Spatial Transcriptomics as a fully cost-recovered HDBR service Enhance the HDBR Atlas of publicly available human gene expression patterns, annotated histological and 3D images as a research and educational resource. |
| 30/09/2023 |
£600,000 |
EUROPEAN BIOINFORMATICS INSTITUTE |
EMBL’s European Bioinformatics Institute (EMBL-EBI) has begun work on a new building, named the Thornton Building, located on the Wellcome Genome Campus. Funded by UKRI (£14 million) , BBSRC (£5.1million), and Wellcome (£10million). EMBL-EBI is the home of big data in biology and hosts open data resources for the life sciences. Millions of researchers from all over the world use EMBL-EBI’s freely available data resources to share and access research data, in order to find solutions to global challenges such as infectious disease, food security, and the biodiversity crisis. The Thornton building will be a space for cultivating the academic and pre-commercial collaborations required to translate the institute’s data management expertise into practical solutions to these global challenges. The Thornton Building is a timber CLT and concrete frame construction. The timber element was chosen due to the reduced environmental impacts this form of construction enables, aligning with all the investment parties’ sustainable pledges and adherence to the Wellcome Genome Campus Design Requirements. The timber frame design now requires a high specification sprinkler system the planned to meet the insurance requirements. This proposal seeks the additional £500K cost of this system, beyond the residual project contingency. |
| 30/09/2023 |
£1,486,451 |
BRITISH ACADEMY |
The British Academy is submitting a funding proposal to the Wellcome Trust which will provide support for researchers in the humanities and social sciences working in areas related to health and wellbeing. Taking a broad definition of health, the proposal will provide a portfolio of support for academics, at all stages of their careers, working in the humanities and social sciences by providing funding for Small Research Grants, academic conferences and policy workshops. The proposal follows discussions with the Trust over a number of months and is valued at £3.97 million including: funding of £2.76 million for Small Research grants; £1.12 million for conferences; and £84,000 for policy workshops (over 3 years). Funding is proposed to begin in early 2020 and to finish in 2026. The collaboration is designed to demonstrate the relevance of humanities and social science research in relation to health and wellbeing through the scale and breadth of funding options for researchers and the potential for long term impact. |
| 30/09/2023 |
£498,318 |
UNIVERSITY OF OXFORD |
Mesh Community Engagement Network (www.mesh-ce.org) is a collaborative open-access facility and networking project on The Global Health Network (tghn.org) to support optimum community and public engagement with global health research (CE). We have three aims: To ensure the value of CE is recognised by a diversity of global health stakeholders and is considered an integral part of research; to generate and strengthen leadership and capacity; and to increase outcomes-focussed, innovative CE. Mesh’s vision for the future is that all global health research incorporates high-quality CE built on evidence, good practice and strong networks. This two-year award will enable Mesh keep up with the demands of the community and research organisations, to grow with the wider expansion of The Global Health Network and to write a 5-year strategic development plan that will take Mesh to sustainability and to scale within a consortia funding model. We will have the strategic development plan in place by 2025, have secured a full time CE coordinator to work with the global operations team, and three new regional coordinators. All ensuring that Mesh is working to its maximum potential in guiding strong community engagement within research studies across the globe and sharing this excellence. |
| 30/09/2023 |
£846,064 |
EPICENTRE |
In 2019, Epicentre submitted a proposal to the Wellcome Trust for a research study which aims to fill an essential knowledge gap by assessing the impact of OCV mass preventative campaigns. The evidence generated from this project will be key to develop future strategies regarding cholera vaccine use in endemic settings. The project started in 2021 in Goma (urban) and Bukama (rural), Democratic Republic of the Congo, following Euvichol Plus mass campaigns. As it has been necessary to adjust study design and organisation since initial proposal, this revised proposal aims at pursuing activities to evaluate whether large vaccination campaigns in cholera hotspot in Africa allow sustained control of cholera for at least two years (including vaccine effectiveness and disease transmission level and patterns). The study comprises three different components: 1. Clinical surveillance of all cholera suspect cases to measure cholera diseases incidence according to vaccination status 2. Serial seroprevalence surveys to measure the prevalence of recent cholera infection in the community, and according to vaccination status across years (before and after vaccination) and cholera epidemics and seasons. 3. Home follow-up among household members of individuals with positive V. cholerae shedding (symptomatic or asymptomatic), including environmental bacteria presence in the household. |
| 30/09/2023 |
£3,048,043 |
UNIVERSITY OF OXFORD |
Vivax malaria remains a major global health problem. Because of the existence of a hypnozoite stage and the clinical relapses this causes, elimination strategies are more difficult to design and implement successfully than for falciparum malaria. Vaccines and new well-tolerated anti-relapse drugs are badly needed. To accelerate vaccine development, we will develop and assess the feasibility of conducting Plasmodium vivax volunteer infection studies in Thailand, recruiting semi-immune volunteers from endemic areas representative of target populations for vaccine deployment. We will draw on the participating institutions' expertise in clinical malaria, immunology, entomology, parasitology, volunteer infection studies, and vaccine development. We plan to develop vivax controlled human vivax malaria infection models able to test protective efficacy of the pre-erythocytic and blood stage vivax malaria vaccines currently in development. During this programme we plan to conduct six volunteer infection studies, determine immunological correlates of protection, and test four vaccine candidates. The programme will lay the groundwork for developing models to test future transmission blocking vaccines and new anti-relapse drugs for radical cure. The volunteer infection studies will be accompanied by a programme of social science and empirical ethics research to assess their acceptability and the understanding of volunteers, patients, researchers and policy-makers. |
| 30/09/2023 |
£49,958 |
UNIVERSITY OF CALIFORNIA, LOS ANGELES |
We propose to hold a workshop of thought leaders to advance the utility of digital devices for research and clinical assessments in mental health. Specifically, the goal of the workshop is to explore possible common frameworks for collecting, storing, analyzing, reporting on, and sharing data obtained remotely from the sensors in such devices. Achieving these overarching objectives will require the adoption of minimal standards for subsidiary goals. Common standards are essential for attaining reproducible results between studies using the derived variables from remote sensing. It is especially important given that studies may differ in factors such as the sensors themselves and methods for signal processing. We seek funding from Wellcome to cover the costs of specific participants including their registration fees, travel and accommodations. Funding will be used for those participants from institutions outside of the US as well as a few of those US-based participants included to increase inclusiveness (advocacy and lived experience).
|
| 30/09/2023 |
£15,400 |
PROGRESS EDUCATIONAL TRUST |
PET will convene a group of leading UK-based researchers in developmental and reproductive biology, together with relevant legal experts, to develop proposals for reform of the UK's Human Fertilisation and Embryology (HFE) Act. This follows the UK Government signalling that it is considering reforming this Act in the foreseeable future.
The project will involve assessing where the existing HFE Act – and regulation informed by it – does, and does not, work well for researchers. It will also involve identifying impediments to collaboration between fertility clinics and research centres, and to donation of embryos or gametes by fertility patients, so that ways of removing these impediments can be found.
Scientific advances in this area are fast-moving, and scientific categories do not always fit neatly with – or evolve in step with – legislative categories and concepts, which often lag behind. To some extent this is inevitable, but laws can be drafted in ways that make them more adaptable to change. While seeking to identify where the law needs to be brought up-to-date, the project will also develop proposals for 'futureproofing' legislation, inasmuch as this is possible.
|
| 30/09/2023 |
£66,110 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
The 2019 WHO roadmap aims to halve snakebite deaths and disability worldwide by 2030. Achieving that goal is hampered by the lack of high-quality research to inform policy and the absence of a coordinated approach to get evidence into policy. The applicants and core members have co-designed an alliance which will i) undertake high-quality research, ii) develop systems that support national and regional bodies in Africa to incorporate research evidence into into policy and iiii) develop and support a sustainable capacity for snakebite research in Africa. The full proposal will be submitted for evaluation in late January. This proposal requests support between Jan-July 2023 to maintain momentum during that evaluation. It will support critical activities and engagement with core members to facilitate production of outputs rapidly after instigation. Key goals are:
a) Development of the Theory of Change for the alliance
b) Discussion and agreement of the principles of equitable partnership for the alliance
c) Evaluation of existing clinical guidelines/evidence to enable rapid optimisation soon after alliance instigation
d) Engagement with community groups and setting up of community advisory panels
e) Development of detailed plans for the initial full Alliance start-up meeting and for the first three months of activities
|
| 30/09/2023 |
£151,313 |
SYDNEY CHILDREN'S HOSPITALS NETWORK |
The National Centre for Immunisation Research and Surveillance (NCIRS), working with Pacific Island Country (PIC) stakeholders, proposes to undertake a scoping and needs assessment of National Immunisation Technical Advisory Groups (NITAGs) or similar technical advisory bodies within PICs, and to explore options for a PIC sub-regional model that will support evidence-informed immunisation policy-making amongst PICs.
The project is guided by the vision of the World Health Organization (WHO) Pacific Strategic Framework for Immunization 2030 where all PICs can fully benefit from vaccines for good health and well-being, and aims to support the WHO recommendation for countries to establish and strengthen the functions of NITAGs.
The project will involve three phases commencing November 2022 to October 2023. Phase one will establish an advisory group with 1-2 representatives selected from PICs and key stakeholder groups and completion of a situation analysis. High level stakeholder engagement will also occur and include WHO Division of Pacific Technical Support (WHO-DPS), Pacific Community (SPC) and members of the Global NITAG Network (GNN). Phase two will involve extensive in-country and remote consultation and phase three will bring stakeholders together at a workshop to provide a report on consultation findings and seek feedback regarding potential proposed model(s).
|
| 30/09/2023 |
£85,250 |
TECHNICAL UNIVERSITY OF BERLIN |
Protein structure prediction has been revolutionised by AlphaFold2, an algorithm that uses deep learning and evolutionary information to predict accurate models from the primary sequence. However, proteins are dynamic entities that interact with other molecules, undergo conformational changes, and remain difficult to predict in some cases.
We have developed AlphaLink, a modified version of the AlphaFold2 algorithm that synergistically incorporates experimental distance restraint information into its network architecture (manuscript submitted, data presented below). By employing sparse experimental contacts as anchor points, AlphaLink improves on the performance of AlphaFold2 in predicting challenging targets. The noise-tolerant framework for integrating data in protein structure prediction presented here opens a path to accurate characterisation of protein structures from in-cell data.
Having addressed the challenge of predicting single proteins is encouraging also for predicting protein complexes. However, while AlphaFold2 and AlphaFold-multimer are closely related, they are different algorithms. Accordingly, AlphaLink can model the structure of single proteins but not the structure of protein complexes. The aim of the proposed project is to add experimental distance restraints to the AlphaFold-multimer framework for structure modelling of protein complexes.
|
| 30/09/2023 |
£42,496 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
Not available |
| 30/09/2023 |
£45,579 |
UNIVERSITY COLLEGE LONDON |
Not available |
| 30/09/2023 |
£80,000 |
UNIVERSITY OF OXFORD |
Not available |
| 30/09/2023 |
£105,000 |
UNIVERSITY OF OXFORD |
Not available |
| 30/09/2023 |
£110,000 |
UNIVERSITY OF OXFORD |
Not available |
| 30/09/2023 |
£50,000 |
SINGHEALTH |
The World One Health Congress (WOHC) is the world’s premier congress that takes place biennially for the worldwide One Health community. It aims to profile and advance trans-disciplinary efforts that further our collective understanding of animal-human disease transmission alongside their social and environmental determinants. This Congress is hosted by the SingHealth Duke-NUS Global Health Institute (SDGHI) with organisational support from the SingHealth International Collaboration Office (ICO). Other collaborating agencies include the Ministry of Health, Ministry of National Development, National University of Singapore, Nanyang Technological University, Singapore Management University, Saw Swee Hock School of Public Health, Duke-NUS Medical School and more. WOHC 2022 will serve to increase awareness and understanding of the drivers and global risks of a pandemic threat and ensure that these stay high on the agenda of governments and institutions in the region. The Congress will ultimately help countries to decrease risk by fomenting better surveillance and boost pandemic preparedness. The WOHC 2022 anticipates more than 1,500 professionals from international academic institutions, civil societies, national governments and multilateral organisations. At least 750 participants will attend the face-to-face Congress in Singapore, and another 750 will participate virtually.
|
| 30/09/2023 |
£210,712 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
Not available |
| 30/09/2023 |
£178,948 |
UNIVERSITY OF MANCHESTER |
Not available |
| 30/09/2023 |
£405,521 |
UNIVERSITY OF EDINBURGH |
Not available |
| 30/09/2023 |
£784,597 |
UNIVERSITY COLLEGE LONDON |
Not available |
| 30/09/2023 |
£958,831 |
UNIVERSITY OF OXFORD |
Not available |
| 30/09/2023 |
£184,846 |
UNIVERSITY OF BRISTOL |
Not available |
| 30/09/2023 |
£805,962 |
UNIVERSITY OF CAMBRIDGE |
Not available |
| 30/09/2023 |
£375,952 |
KING'S COLLEGE LONDON |
Not available |
| 30/09/2023 |
£87,313 |
UNIVERSITY OF BIRMINGHAM |
Not available |
| 30/09/2023 |
£317,198 |
IMPERIAL COLLEGE LONDON |
Not available |
| 30/09/2023 |
£7,289 |
UNIVERSITY OF DURHAM |
Not available |
| 30/09/2023 |
£30,712 |
UNIVERSITY OF SUSSEX |
Not available |
| 30/09/2023 |
£7,692 |
THE PIRBRIGHT INSTITUTE |
Not available |
| 30/09/2023 |
£6,601 |
UNIVERSITY OF ST ANDREWS |
Not available |
| 30/09/2023 |
£13,270 |
KEELE UNIVERSITY |
Not available |
| 30/09/2023 |
£15,500 |
UNIVERSITY OF ABERDEEN |
Not available |
| 30/09/2023 |
£24,125 |
BIRKBECK UNIVERSITY OF LONDON |
Not available |
| 30/09/2023 |
£4,264 |
UNIVERSITY OF STRATHCLYDE |
Not available |
| 30/09/2023 |
£15,692 |
UNIVERSITY OF EAST ANGLIA |
Not available |
| 30/09/2023 |
£40,271 |
INSTITUTE OF CANCER RESEARCH |
Not available |
| 30/09/2023 |
£17,830 |
QUEEN'S UNIVERSITY BELFAST |
Not available |
| 30/09/2023 |
£78,879 |
THE FRANCIS CRICK INSTITUTE |
Not available |
| 30/09/2023 |
£24,642 |
UNIVERSITY OF SOUTHAMPTON |
Not available |
| 30/09/2023 |
£44,859 |
UNIVERSITY OF LEICESTER |
Not available |
| 30/09/2023 |
£31,422 |
UNIVERSITY OF YORK |
Not available |
| 30/09/2023 |
£93,000 |
QUEEN MARY UNIVERSITY OF LONDON |
Not available |
| 30/09/2023 |
£32,131 |
UNIVERSITY OF WARWICK |
Not available |
| 30/09/2023 |
£55,878 |
UNIVERSITY OF EXETER |
Not available |
| 30/09/2023 |
£70,238 |
CARDIFF UNIVERSITY |
Not available |
| 30/09/2023 |
£48,989 |
UNIVERSITY OF NOTTINGHAM |
Not available |
| 30/09/2023 |
£76,866 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
Not available |
| 30/09/2023 |
£209,427 |
UNIVERSITY OF DUNDEE |
Not available |
| 30/09/2023 |
£52,909 |
UNIVERSITY OF LEEDS |
Not available |
| 30/09/2023 |
£99,474 |
UNIVERSITY OF LIVERPOOL |
Not available |
| 30/09/2023 |
£151,875 |
UNIVERSITY OF GLASGOW |
Not available |
| 30/09/2023 |
£103,695 |
NEWCASTLE UNIVERSITY |
Not available |
| 30/09/2023 |
£85,859 |
UNIVERSITY OF SHEFFIELD |
Not available |
| 30/09/2023 |
£3,000,000 |
TRINITY COLLEGE CAMBRIDGE |
We propose a partnership between The Trinity Challenge (TTC) and The Wellcome Trust, using a proven Challenge Methodology as a way to assist Low- and Middle-income countries (LMICs) develop tools to capture and interpret data relating to bacterial disease and antimicrobial resistance (AMR) in their own Communities, in order to drive local and National action.
Working together with an Expert Advisory Group (EAG) we would develop the challenge questions. This, and the application stage, would be supported by ‘sandbox / ideas collision’ workshops in LMICs for citizens, local community and experts, to engage local communities building engagement, knowledge, involvement, ideas, collaborations and action in bacterial diseases and AMR understanding including prevalence. They would be run by known Partners e.g. the UK Fleming Fund which works in the country. The Wellcome Trust would act as the ‘anchor funder’, funding the core secretariat and initial prize commitment, while helping to bring in other partner funders.
The inaugural TTC, in 2021 addressing pandemics, demonstrated the value of our Challenge approach in pulling through innovative tools that work for the global south, being relevant, equitable, new, and scalable solutions. The Winners (8) are now being supported to develop and scale.
|
| 30/08/2023 |
£2,595,290 |
JOHNS HOPKINS UNIVERSITY |
We will leverage a robust cholera research platform in the city of Uvira, Democratic Republic of Congo to estimate the effectiveness and impact of a cholera vaccination program, providing critical inputs for local and global policy decisions. Learning from cholera research in Uvira since 2016, we aim to improve vaccine research quality, by continuing systematic detection and recruitment of suspected cholera cases, establishing on-site PCR capacity and developing a vaccine register to ensure high-quality vaccination status ascertainment. We will estimate the direct effectiveness of killed oral cholera vaccines through a community-matched case control study, enrolling case and controls up to eight years after the initial vaccination campaigns in Uvira in 2020 and up to three years after the anticipated 2024 campaign. We expect to generate estimates by age group, number of doses, and previous vaccination/disease history. We will conduct two population-based surveys in Uvira to characterise population-level vaccine coverage and water, sanitation and hygiene conditions and will systematically collect data on water availability through the central piped water system. Using these data and the epidemiologic curve, we will build statistical and computational models to estimate the overall impact of the vaccination campaign on incidence and mortality in the community. |
| 31/07/2023 |
£781,389 |
UNIVERSITY OF GLASGOW |
Blocking Plasmodium parasite transmission is key to malaria elimination and eradication. A hidden transmission reservoir are asymptomatic individuals (i.e., carriers) that constantly transmit the parasite within the population. Carriers usually have low levels of transmission stages (gametocytes) in peripheral blood. However, these gametocytes efficiently infect mosquitoes, at rates that are higher than what modelling would predict. To explain how this is possible, I will i) determine Plasmodium gametocyte location, motility and interactions with the host dermal vasculature in vivo using a murine malaria model and intravital microscopy, and translating to humans I will ii) determine the motility and host-parasite interactions of Plasmodium falciparum gametocytes using an in vitro dermal vasculature microfluidic platform through a collaboration at EMBL Barcelona The process of malaria parasite uptake during a mosquito bite has also not been described. I hypothesise that when mosquitoes feed, they release signals that lead to the chemoattraction of gametocytes to the bite site, thereby improving transmission efficiency. To uncover the processes involved, and inform how transmission could be blocked, I will i) investigate the motile behaviour and uptake of gametocytes during mosquito biting, and ii) identify the factor(s) in mosquito saliva that facilitates improved transmission efficiency. |
| 31/07/2023 |
£730,440 |
UNIVERSITY OF BIRMINGHAM |
More effective immunotherapies are urgently needed for hepatocellular carcinoma (HCC). In previous work, I demonstrated for the first time the therapeutic potential of gamma-delta (ɣdelta)T-cells for HCC. I showed that ɣdeltaT-cells exhibit a tissue-resident memory(TRM) phenotype in human liver and HCC, with superior anti-tumour function. However a major subset, Vɣ9Vdelta2T-cells, were selectively depleted in HCC, which correlated with poorer prognosis. I subsequently demonstrated that a de-novo TRM phenotype can be recapitulated on expanded blood Vɣ9Vdelta2T-cells for adoptive cell-transfer, and combined with intratumoural delivery of the aminobisphosphonate Zoledronate, to enhance Vɣ9Vdelta2TRM-mediated lysis of HCC cell-lines (Zakeriet.al.Nat Comm.2022). In this project, I will study for the first time the mechanisms of Vɣ9Vdelta2T-cell recruitment across HCC endothelium and assess whether an induced TRM phenotype can confer improved tissue-retention and tumour-migration properties. I will utilise 3D preclinical models of HCC to examine whether intratumoural Zoledronate can enhance the local activation and anti-tumour function of Vɣ9Vdelta2TRM, whist minimising off-target effects. Furthermore, I will explore whether synergistic immune checkpoint blockade can further amplify Vɣ9Vdelta2TRM anti-HCC responses. This work will provide critical insights to inform a future trial comprising Vɣ9Vdelta2T-cell immunotherapy alongside targeted drug delivery, with the goal of developing a more universally effective immunotherapy for HCC. |
| 31/07/2023 |
£1,185,342 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
Essential hypertension is the leading preventable cause of cardiovascular disease and death, and has traditionally been associated with ageing. However, high prevalence of elevated blood pressure (BP) has increasingly been reported among youth in sub-Saharan Africa (SSA), posing challenges for clinical management. My fellowship will address critical evidence gaps on BP among youth in SSA. I will examine: population prevalence of hypertension in urban Zimbabwean youth and the agreement between routine brachial BP and the potentially more clinically-predictive central aortic BP. the population prevalence of early vascular ageing (EVA) and hypertension-mediated organ damage (HMOD), and the BP profiles at which they occur. the context-specific aetiological factors associated with elevated blood pressure, EVA and HMOD. I will conduct a detailed cross-sectional study of 650 individuals, randomly selected from a large population-based health survey of youth conducted in Zimbabwe in 2022 (N~17,000; 18-24y). This will provide population estimates of brachial and central hypertension, EVA and HMOD. I will examine risk factors and measure novel biomarkers (including immune markers, telomere length analyses and metabolomics) to conduct state-of-the-art causal inference studies. The fellowship will have clinically important implications for hypertension screening, prevention and treatment guidelines for youth in SSA. |
| 31/07/2023 |
£848,765 |
KING'S COLLEGE LONDON |
This transdiagnostic programme of work will examine the mechanisms underlying a reduced experience of pleasure (anhedonia) using novel methods which harness the latest developments in structural equation modelling, mobile health monitoring and virtual reality. Anhedonia is a significant barrier to recovery in mental health conditions in two conditions; psychosis and depression, with no effective interventions targeting anhedonia recommended by NICE. Similarities in the experience of anhedonia in these two groups have been proposed but not tested. This body of work will begin with qualitative interviews to understand the experience of these difficulties first-hand, for the first time. Machine learning techniques will be applied to identify maladaptive patterns in affect and detect vulnerable moments where intervention would be impactful. Experience sampling methodology (ESM) with a smartphone app will then examine the strongest candidate mechanisms from the depression literature: negative thinking patterns and reduced attention in positive experiences, across diagnostic boundaries. Candidate mechanisms will be tested in the final study using novel, ecologically valid virtual reality scenarios. This bold programme of research will advance the field with a transdiagnostic model of anhedonia, a step change in our understanding of an under-researched but critical area in recovery. |
| 31/07/2023 |
£678,172 |
UNIVERSITY OF OXFORD |
Most mental health problems onset between the ages of 10-24. At the same time, adolescence is a period of life characterised by an increased susceptibility to peer influence effects. Despite this, we have limited knowledge regarding the individual differences that increase susceptibility to peer influence effects on adolescent mental health. Adolescents spend a considerable amount of time at school, among peers, and knowing who is susceptible to peer influence effects on mental health will help identify those at risk, and highlight potential intervention targets. Indeed, peer influence effects on mental health might also underpin the success or failure of universal school-based interventions for mental health, which are delivered to adolescents in peer groups. Yet to date, peer influence effects have not been considered when examining the effectiveness of these interventions. This may explain why we see heterogenous outcomes, with some interventions succeeding, and others failing. This proposal, therefore, aims to reduce the discontent between our understanding of peer influence effects and adolescent mental health by (1) isolating the individual differences that increase susceptibility to peer influence effects on mental health problems, and by (2) examining whether these effects explain the success or failure of universal school-based interventions for mental health. |
| 31/07/2023 |
£542,777 |
UNIVERSITY COLLEGE LONDON |
Emerging evidence such as recent Lancet Commission (2020) shows that air pollution is a likely modifiable risk factor of cognitive decline and dementia. The Committee on the Medical Effects of Air Pollutants (2022) concluded that cardiovascular pathways are important. However, the contribution of cardiovascular pathways to dementia development has not been addressed systematically. Also, little is known about a vital next-step question, i.e., if there is an effect of air pollution on dementia, would it make an important difference to a benefit assessment of policies designed to reduce levels of air pollutants? This project aims to make a major novel scientific contribution to the science of air pollution and dementia, focusing on cardiovascular pathways, the impact of air pollution on dementia burden at population level, and estimating the potential benefits of air pollution control in dementia prevention in England and Wales. Identification of intermediate processes that lie on the casual pathways linking air pollution to dementia could guide appropriate policy and action, including behavioural change, to mitigate the effects of air pollution on health. This project will be a key step to guide policymakers in the development of strategy to protect populations from adverse impacts of air pollution on dementia. |
| 31/07/2023 |
£260,969 |
UNIVERSITY OF EXETER |
Responding to a recent "cultural wave" in the medical humanities calling for more creative responses to the "more than biomedical" cultural forces shaping human and environmental wellbeing, and extending the social science’s ongoing "chemical turn" into the arts and humanities, Molecular Dreamworlds: A Cultural History of Chemical Entanglement, 1945-1995 investigates the complex agentic capacities of four everyday synthetic materials—Paraquat, Lurex, Teflon, and AZT—through a multidisciplinary approach that utilises ethnographic studies, field trips, archival research, and various modes of close reading and cultural analysis. Foregrounding the complex agencies of synthetic chemicals through a multitude of voices—from farmers and sculptors; nurses and poets; toxicologists, IP lawyers, and avant-garde filmmakers—Molecular Dreamworlds brings a series of semi-structured interviews into dialogue with a remarkable archive of overlooked plays, novels, poems, and paintings pertaining to the post-modern period so as to help medical humanities scholars better understand the cultural forces shaping public and planetary wellbeing in the mid-to-late twentieth century. Expanding orthodox victim-exposure paradigms framing health-related research while rejuvenating a fledgling field of post-modernist studies, Molecular Dreamworlds promises a timely and epistemologically grounded investigation into post-modernism's chemical infrastructures that will be of lasting relevance to scholars across the arts and sciences. |
| 31/07/2023 |
£429,099 |
UKRI-MRC |
Mechanical instability of the nucleus due to mutation or dysregulation of NE proteins is linked to cancer, muscular dystrophies and both physiological and accelerated ageing. At the nuclear envelope (NE), interactions between the nucleus and the cytoskeleton, sustained by LINC complexes, allow force transduction from the environment to the nucleus and cellular adaptation. However, it is not clear how NE instability in disease affects the structure and activity of LINC complexes, or their ability to adapt to increased extracellular forces. In Aim 1, I will investigate the effect of severe disease-associated NE instability in LINC organisation, force-sensing and in situ interactions and structure. I will use a multidisciplinary approach, from super-resolution microscopy (STORM) to in situ structural biology (cryo-ET) under normal and increased extracellular forces. At regions of extreme instability, NE ruptures occur. Repair occurs through the recruitment ESCRT-III membrane remodelling complexes. In Aim 2, I will investigate how ESCRT-III oligomerisation occurs at the NE and how these complexes might adapt different geometries to fit membrane topologies and close ruptures. I will develop new tools and use a cryo-confocal and cryo-ET pipeline to solve the in situ ultrastructure of ESCRT-III complexes at NE ruptures, during different stages of repair. |
| 31/07/2023 |
£759,187 |
KING'S COLLEGE LONDON |
Neurons are polarised cells whose function critically depends on distinct sub-cellular compartments: axons and dendrites. In axons, a specialised region – the axon initial segment (AIS) – regulates neuronal excitability and polarity and is a focal site for developmental plasticity. Maturing dendrites also undergo significant plastic modifications that can include the pruning of entire branches. These processes of activity-dependent AIS and dendritic development are individually well understood, but their potential to influence each other remains critically understudied. Does dendritic pruning shape the developing AIS? And does AIS plasticity affect dendritic maturation? These are important questions because axo-dendritic interactions in mature neurons – and therefore the functional operation of neuronal circuits – depend on cells co-ordinating the development of the two compartments. Here, I will take advantage of a cell type that undergoes activity-dependent dendritic pruning at the time that its AIS experiences significant maturational changes, to ask how neurons co-ordinate these processes. By linking morphological, transcriptomic, and functional features of AIS maturation to dendritic pruning in the same cells, and by selectively manipulating either dendritic maturation or AIS development, I will uncover how each sub-cellular compartment influences each other’s development to build functional cells that contribute to healthy brain function. |
| 31/07/2023 |
£618,929 |
UNIVERSITY OF OXFORD |
Reinforcement learning (RL) is a dominant framework in neuroscience and artificial intelligence (AI) that formalises how agents learn from rewards. Nutrients, including fat and sugar, are critical, noninterchangeable reward components that must be separately processed by neural reward systems. Although direct neuronal implementations of key RL mechanisms, including reward prediction errors, have been discovered, how these mechanisms process biologically critical nutrient rewards remains unclear. Here, I combine monkey single-neuron recordings with recently developed nutrient-sensitive RL models to investigate how neurons in primate taste and reward systems process nutrients during RL. First, I will record single-neuron activity in orbitofrontal cortex, amygdala, anterior cingulate cortex, and insula while macaques learn and adapt their choices to changing visual-nutrient associations. These data will uncover how neurons encode learning and decision variables for nutrient rewards. Second, I will apply focused transcranial-ultrasound stimulation to these brain structures to test their causal roles in nutrient-sensitive RL. Third, I will determine how nutrients, as fundamental reward dimensions, shape the geometry of neural-population codes underlying nutrient-sensitive RL. The rare data and new concepts from this project have potential to deepen our understanding of neural reward systems, inspire AI innovations, and uncover vulnerabilities for maladaptive reward-processing in human mental disorders. |
| 31/07/2023 |
£703,232 |
THE FRANCIS CRICK INSTITUTE |
Tissue repair requires coordinated activation of resident stem and inflammatory cells achieved by secreted damage signals. Defects in the repair process can manifest in loss of tissue structure, prolonged inflammation or scarring and predispose for tumour formation. How the damage signal diffusion is regulated, to ensure stem cell activation while preventing excessive inflammation is not well understood. Moreover, it is unclear whether cancer cells can exploit tissue repair signals by altering their diffusion. Therefore, it is important to understand how secreted damage signals are regulated during tissue repair and tumorigenesis. In the proposed study, I will investigate how cell surface glypicans, which control extracellular gradients, interact with damage induced secreted proteins. By using state-of-the-art optogenetic tools I will dissect how glypican-interactions regulate the diffusion of secreted signals to promote tissue repair in vivo. Moreover, by using mouse and organoid models and spatial sequencing approaches, I will compare the roles of extracellular signal relay by glypicans in tumorigenesis and tissue repair. This work will identify how glypicans regulate damage signals and open avenues to generate treatments against the age-associated regenerative decline and tumorigenesis. |
| 31/07/2023 |
£733,391 |
UNIVERSITY OF OXFORD |
Receptor tyrosine kinases (RTKs) are molecular switches that are essential for cell signalling. Aberrant activation of RTKs has disastrous consequences, often leading to tumour growth. I propose a new framework to determine critical aspects of RTK signalling by investigating the contribution of receptor protein tyrosine phosphatases (RPTPs) and harnessing phosphatase activity in a controlled manner using engineered ligands. RTK activity is affected by phosphatases, including RPTPs. However, the specificity and activity of many RPTPs remain unexplored and their impact on RTK signalling is unknown. I developed a systematic screen to determine the specificity of RPTPs against a representative subset of 15 RTKs that, combined, are associated with a third of all tumours. I aim to identify which RPTPs suppress RTK activity and to develop a novel platform to explore this regulatory mechanism. I will generate synthetic bispecific proteins that recruit membrane phosphatases to RTKs, resulting in enforced kinase dephosphorylation and inhibition. These molecules will allow me to address critical questions on RTK regulation and to explore the interplay between RTKs and RPTPs at the cell surface. In addition, this approach will pave the way towards a new class of molecules for oncogene suppression with strong potential for therapeutic applications. |
| 31/07/2023 |
£1,164,283 |
UNIVERSITY OF CAMBRIDGE |
Over-exuberant inflammasome activation drives the pathogenesis of numerous diseases, although the molecular basis for hyperactivation in many cases is poorly understood. Recent studies into an autoimmunity risk gene (FAMIN) have highlighted the importance of intracellular purine metabolism in tuning immune responses. FAMIN, a multifunctional enzyme, balances flux through purine nucleotide interconversion cycles in immune cells such as macrophages. I will investigate the hypothesis that purine metabolites generated by FAMIN, and biochemically related enzymes, control inflammasome activation to tune inflammatory responses. I will delineate how intrinsic purine metabolism shapes inflammasome activation in macrophages and intestinal epithelial cells. Through functional assays and metabolic flux studies, I will dissect the biochemical mechanisms controlling inflammasome activation in the context of perturbed intracellular purine metabolism. This will be complemented with microscopy-based approaches to investigate differences in inflammasome spatiotemporal organisation. I will explore the hypothesis that endogenous purine metabolism controls pyroptotic cell death, a process closely intertwined with inflammasome activation, and utilise targeted and unbiased approaches to uncover responsible molecular mechanisms. I will uncover how purine-controlled inflammasome activation drives in vivo phenotypic differences in sepsis and infection models. This will advance our understanding of fundamental processes driving maladaptive inflammatory responses in disease. |
| 31/07/2023 |
£712,649 |
UNIVERSITY OF SHEFFIELD |
Streptococcus pneumoniae is the leading cause of deaths by pneumonia (~ 1M people annually) and is becoming resistant to antimicrobials. We urgently require emerging solutions. However, we need to understand the basic principles that underpin bacterial cell life. Peptidoglycan, a component of cell wall, is the target for crucial antibiotics like penicillin but we lack understanding of its architecture, synthesis and how this is undermined by antibiotics. My ground-breaking research in Atomic Force Microscopy (AFM) has opened a whole new approach for investigating the cell wall. In this fellowship, correlating AFM with Stochastic Optical Reconstruction Microscopy (STORM), STORMforce, I will produce quantitative images of peptidoglycan molecular architecture. Combining cutting-edge microscopies and developing image analysis software, I will answer the following questions: What is the peptidoglycan architecture of S. pneumoniae at ultra-resolution? How does different enzymes activity influence the peptidoglycan architecture and its growth over time? How does this dynamic macromolecule behave when antibiotics are present? This fellowship will launch my independent career and consolidate my leadership and project management skills. This will allow me to pursue my research interests and develop a key biophysical technique for the community (STORMforce in combination with software tools) that will answer pressing biological questions. |
| 31/07/2023 |
£271,067 |
UNIVERSITY OF SHEFFIELD |
Indigenous medical systems, often termed alternative medicine, continue to be hugely popular in Asian societies. This project investigates how Indian women, primarily from Muslim communities, interacted with Unani Tibb via print culture and professional practice in Bhopal, Punjab, and northern India c.1910-1970. Unani Tibb is a pluralist medical system with Greco-Arabic origins most popular amongst Muslim populations in South Asia. The project offers a sustained focus on women as targets of reform and practitioners in their homes through mass print whilst also investigating how women were trained in Unani in a semi-professional capacity to become hakimas/tabibas (female practitioners). For the first time, it will ask how and why female practitioners navigated the largely male-dominated terrain of Unani Tibb and how such innovations contributed to wider Unani discourse and national public health policies on maternal care, sanitation, and reproductive medicine. This research will radically alter perceptions about historical and contemporary public health regimes in postcolonial South Asia by demonstrating how women’s engagement with alternative medicine have dictated public health policy outcomes and markets. The research will result in two article publications, a second sole-authored monograph, and a collaborative special journal issue based on a conference organised as part of the project. |
| 31/07/2023 |
£789,871 |
INTERNATIONAL CENTRE FOR DIARRHOEAL DISEASE RESEARCH, BANGLADESH |
Bangladesh has achieved an 80% reduction in malaria cases over the last decade, but these gains are threatened by the rapid spread of Plasmodium falciparum resistance to the frontline artemisinin and partner drugs in the Greater Mekong Subregion (GMS). Over 90% of malaria cases occur in the Chittagong Hill Tracts (CHT) districts, bordering Myanmar. To date, there is no evidence of artemisinin resistance in the CHT; however, large influx of refugees fleeing Myanmar into Bangladesh warrants dedicated surveillance. The National Malarial Elimination Programme (NMEP) currently receives data on antimalarial drug efficacy from clinical surveys; however, the high financial cost and logistical complexities constrain their frequency and ability to detect emerging resistance. My proposed research aligns closely with and extends the activities of NMEP and leading malaria genomics researchers to establish amplicon-based sequencing as a sustainable, high-throughput molecular surveillance platform to monitor antimalarial drug resistance, transmission dynamics and provide early warning signals to prevent widespread resistance to artemisinin and partner drugs. The study will generate genomic data on antimalarial drug resistance and parasite genetic relatedness; and establish the capacity for processing the data to inform NMEP with clear intelligence on where to upscale interventions, conduct clinical surveys, and change drug policy. |
| 31/07/2023 |
£516,991 |
UNIVERSITY OF OXFORD |
SARS-CoV-2 is a novel human pathogen that emerged in late 2019 and caused a global pandemic. Despite the implementation of vaccinations and drugs to control the disease, SARS-CoV-2 continues to evolve and adapt to antiviral measures. Therefore, new approaches are needed to control the viral infection. The viral RNA polymerase complex is a conserved enzyme responsible for viral genome transcription and replication, making it an attractive target for drug development. The replication of the viral genome requires several cellular processes, and it is crucial to identify the host factors that directly participate in viral replication and to characterise their roles in regulating viral polymerase functions. My research will build upon previous studies on virus-host interactions and use state-of-the-art techniques to further analyse polymerase-host interactions. This project aims to gain mechanistic insight into SARS-CoV-2 genome replication, transcription and cellular machinery involved in viral replication. By gaining insights into the molecular and cellular biology of SARS-CoV-2, we hope to improve our understanding of host adaptation of SARS-CoV-2 and improve the antiviral preventive and therapeutic approaches. Keywords: SARS-CoV-2, viral RNA polymerase, replication, transcription, virus-host interactions |
| 31/07/2023 |
£660,053 |
UNIVERSITY OF CAMBRIDGE |
Research into the genetic basis of human diseases has led to powerful methods for polygenic risk scores (PRS) and the key challenge now shifts to application of these knowledge to improve patient care. We propose to develop methods and platforms to evaluate the clinical benefits of PRS. First, we will evaluate the clinical benefit of PRS by: (i) Evaluating early intervention benefits at population level. We plan to evaluate the benefits of PRS-guided intervention for common diseases using population-level EHR data (e.g. CVD-COVID-UK). (ii) Constructing polygenic scores for treatment responses. We propose a novel imputation method to construct more powerful pharmacogenomic PRS. (iii) Identifying disease subtypes with varying treatment responses. Second, we will integrate PRS with clinical data by: (i) Incorporating EHR data to improve prediction accuracy. We aim to construct better risk models through integrating PRS and diagnostic/prescription data. (ii) Leveraging PRS to construct metabolite/proteomics-based risk scores for complex diseases. Third, we will implement PRS computation infrastructure in NHS systems by: (i) Calibrating PRS to the NHS covered populations. We will develop PRS calibration and test them on routinely collected genotype data through NHS GLH. (ii) Implementing transferable PRS tools that are compatible with medical management systems. |
| 31/07/2023 |
£692,863 |
UNIVERSITY OF BIRMINGHAM |
Humans rely on information, but with so much available we must constantly choose to seek or avoid it. These decisions have critical importance for global issues and can be linked to precise neural and computational mechanisms. Existing research has focused on how we seek information about ourselves but overlooked a crucial aspect: information about other people. Here, I will quantify (i) the computational mechanisms, (ii) the spatiotemporal neural trajectory, and (iii) the causal neural modulators that drive information-seeking. For each, I will compare social and non-social information to characterise commonalities and mechanisms specific to information about other people. Across four experiments, I will combine novel tasks with state-of-the-art methods. Computational modelling quantifies how the nature of information (positive/negative, level of uncertainty) determines willingness to seek it, and whether the same computations underlie seeking information about other people. Bringing together diverse techniques establishes neural representations in space and time then tests causal mechanisms, through deep brain stimulation and dopamine manipulations in a unique sample of Parkinson’s disease patients. Together, these results will provide a shift in understanding of when and why people choose to find out or avoid information about themselves and others, with vital implications for physical and mental health. |
| 31/07/2023 |
£211,552 |
UNIVERSITY OF CAMBRIDGE |
This project will examine how the AIDS crisis reshaped the UK's border regime. It will argue that AIDS mobilised an expansive border apparatus - executed through international bureaucracy, health interventions, medical procedures and asylum protocols - all of which spoke to the exigencies posed by forms of Black African and South Asian mobilities in Britain.Through extensive archival research in Britain, Europe, India and Kenya, it will investigate the specific intersection of race, sexual health and migration posed by AIDS on Britain’s racialised minorities. Investigating the collective interventions made by the UK Foreign Office, Home Office and Health Department, the project will study how AIDS racialised and medicalised immigrant sexuality in new ways. Ultimately, it will advance an original argument about the significance of HIV/ AIDS in transforming UK’s migration and asylum governance, while fostering new languages of sexual health activism in racially minoritised groups. The project has three core objectives: To study the impact of HIV/AIDS on the UK’s border apparatus between 1985 and 2005. To analyse state and NGO health interventions targetting the UK's Black and Asian 'ethnic minority' populations. To examine new strands of Black and South Asian activism responding to AIDS-related health interventions and border exclusions |
| 31/07/2023 |
£527,381 |
KEMRI-WELLCOME TRUST RESEARCH PROGRAMME |
Electronic Health Record systems (EHRs) have the potential to improve health data collection and decision-making in sub-Saharan Africa (SSA) for monitoring health system performance, routine maternal, perinatal, and neonatal death surveillance and response (MPNDSR) and for integrated disease surveillance response (IDSR). However, existing EHRs audits reveal that they are challenging and expensive to sustainably implement in SSA. Therefore, in the short-to-medium term, paper-to-digital systems will continue to dominate. This study proposes to improve the quality, volume, and range of data collected through paper-to-digital systems in SSA while reducing the workload of information officers and improving data use culture. This will be achieved by (1) exploring the use of Artificial Intelligence and Machine Learning to develop an efficient, user-friendly clinical informatics pipeline that leverages paper-to-digital systems and (2) identifying how actionable patient-level data from the pipeline can be used for multiple surveillance needs (MPNDSR/IDSR) through optimising Audit and Feedback cycle and mechanisms targeting feedback, recipient and context variables. The initial focus will be on poorly performing neonatal conditions/outcomes exacerbated by global warming. This study aims to bridge the gap between data and information by developing a practical and sustainable solution for improving health data collection and use for decision-making in SSA. |
| 31/07/2023 |
£777,725 |
UNIVERSITY OF EXETER |
Host species vary markedly in their susceptibility to infection (e.g. for COVID-19, malaria, or tuberculosis). Variability in disease outcome is driven by differential induction of the immune system, especially for inflammatory diseases like COVID-19. This process depends on adaptive immunity, but also critically innate immunity: a conserved defence system built of recognition, signalling, and effector molecules. Immune genes evolve especially rapidly compared to the rest of the genome. However, little is known how immune evolution affects gene expression across species: we have yet to tie immune evolution to observable differences in the induced response. My research shows closely-related species can differ markedly in their induced immune response. Using a comparative approach, I will systematically characterise immune induction patterns of diverse species. Differences should rely on either i) alternate organisation of conserved immune pathways, or ii) gene duplications that evolve to promote novel pathway connections. Assessing gene expression, molecular evolution, and signalling organisation will reveal how these variables produce differences in immune activation. Ultimately, I will tie immune evolution to differences in the induced immune response. This proposal will greatly improve our ability to predict interactions between pathogens and novel host species, and to understand factors affecting the innate inflammatory response. |
| 31/07/2023 |
£990,915 |
UNIVERSITY OF SHEFFIELD |
Commercial involvement in public health has seen increased scrutiny in recent years, with many questioning whether capitalist interests and equitable public health praxis can align. This ethnographic project integrating clinical dental public health and medical sociology will analyse whether and how commercial involvement in sugar-related public health approaches serves to reproduce and reinforce social inequalities. Through the theoretical framing of racial capitalism, it will explore the racial, classed and gendered absences in public health’s conception of the ‘universal subject’, so as to contribute to more nuanced, equitable public health praxis. The project asks: How can sugar consumption amongst Britain’s racialised minorities be situated in a contemporary socio-political context? How does universal sugar-related public health policymaking and practice construct its subject, and what experiences are overlooked in this process? How do conflicting interests of actors within sugar-related public health mediate policymaking, actions and their constituent discourses? In what ways does better understandings of sugar consumption challenge any dominant public health approaches, and how might progress towards more equitable praxis be supported? As the first empirical exploration of how racial capitalism shapes public health policymaking and practice, the project will transform public health understandings of the relationships between racisms and health inequalities. |
| 31/07/2023 |
£864,192 |
UNIVERSITY OF BRISTOL |
Most healthy people in the UK visit a dentist for regular ‘check up’ appointments. This creates an opportunity to screen for systemic diseases alongside routine oral health checks, provided there are biomarkers which can be assessed easily and are predictive of both future oral and systemic health. I hypothesise that oral microbiota profile will associate with future oral and systemic health status and plan to test this using two complementary approaches. The key aims are a) To characterize the oral microbiota of 9,000 Swedish twins using nanopore sequencing of the 16s gene in existing biological samples, obtained when the twins were aged 21-47 years. b) To use polygenic scores for common complex disease outcomes as a proxy for pre-clinical disease events and test for association between the polygenic score and oral microbiota composition and function. This aims to identify oral microbiota signals of pre-clinical disease. c) To apply longitudinal modelling to test for association between baseline oral microbiota composition and subsequent disease diagnoses, leveraging around 20 years longitudinal follow-up data from disease registers. |
| 12/07/2023 |
£1,680,130 |
KING'S COLLEGE LONDON |
Problem statement: The effects of extreme heat events on mental health in vulnerable urban communities are under-investigated and unrecognised within current policies and practice. Strategic goals: improve evidence base for impacts of extreme hot weather on mental health in vulnerable urban communities using London as case-study; evaluate the mitigation of these impacts by different categories of urban green spaces based on The London Plan; elevate the voices of affected communities, bringing them into discussion with national, local and industry stakeholders; instigate the translation of the findings into policy and practice. Methods: (1) Leading-edge spatio-temporal analytics linking high-resolution environmental data with geo-tagged datasets including electronic medical records and smartphone-based data spanning over 15 years (2008-2023). Integration of satellite data, OpenStreetMap, Google StreetView to estimate exposure to urban green spaces. Microsimulation modelling to generate projections of temperature-related mental health changes under various climate scenarios. (2) Active participation of people with lived experience of mental illness, grassroots organisations, policy and practice experts and industry in all stages of the project. Success indicators: (i) amendments to Greater London Authority/Borough planning policies to empower local authorities; (ii) planners/developers using training and recommendations; (iii) community groups accessing and using co-developed resources to engage with change. |
| 12/07/2023 |
£486,704 |
ROYAL HOLLOWAY, UNIVERSITY OF LONDON |
As global temperatures rise, extreme temperatures claim more lives around the world than any other natural hazard, making heat stress a key priority under climate change. Nevertheless, a key obstacle to understanding heat stress is the complexity of measuring it. The thermal experience of climate change is shaped not only by a person's physical location, but also their social position. The jobs we do, the roles we play in society, the conditions we work in, and our freedom within those roles, all shape our exposure to the changing climate. Aiming to reframe the narrative of heat stress under climate change around the lived experience of labour regimes and working relations, OPPRESSIVE HEAT will assemble a novel, exploratory suite of conceptual and methodological tools to explore the dynamic workplace geography of thermal exposure under climate change. Incorporating CORE thermal sensors, Rapid Ethnographic Assessment, and multi-sited socioeconomic analysis to Cambodia, one of the world’s most climate vulnerable countries and also a key site of labour exploitation and modern slavery, it will generate vital context-specific data directed towards UK and Cambodian OSH policy, whilst also opening up a vital high-impact field of scholarship on the health dimensions of labour exploitation under climate change. |
| 30/06/2023 |
£5,360,744 |
UNIVERSITY COLLEGE LONDON |
AHRI’s vision is optimal health and well-being of under-resourced populations. We conduct research on important, intractable and intersecting health problems which impact well-being and mortality in South Africa and globally. The highest prevalence of HIV and TB, globally, is in our province; our research on these infections will therefore continue, with new strategic directions. We will introduce research on emerging and neglected infections, building on extraordinary impact of our Covid-19 science. We will build a new research programme in adolescent common mental health disorders, which is a very significant local – and global – health challenge. AHRI is uniquely placed to address these challenges: we focus on research questions for which we have a competitive advantage and exploit our integrated research value chain of basic, translational, clinical, population and social sciences. We will introduce innovation in all these areas, while fostering a research culture of well-being and scientific success. We regard training of the next generation of African scientists as a priority. We cannot achieve success alone – we will nurture academic partnerships and optimise public engagement, particularly with our research communities. Our ultimate goal is impact on scientific knowledge, practice and policy, in South Africa and beyond. |
| 30/06/2023 |
£2,766,658 |
UNIVERSITY COLLEGE LONDON |
AHRI’s vision is optimal health and well-being of under-resourced populations. We conduct research on important, intractable and intersecting health problems which impact well-being and mortality in South Africa and globally. The highest prevalence of HIV and TB, globally, is in our province; our research on these infections will therefore continue, with new strategic directions. We will introduce research on emerging and neglected infections, building on extraordinary impact of our Covid-19 science. We will build a new research programme in adolescent common mental health disorders, which is a very significant local – and global – health challenge. AHRI is uniquely placed to address these challenges: we focus on research questions for which we have a competitive advantage and exploit our integrated research value chain of basic, translational, clinical, population and social sciences. We will introduce innovation in all these areas, while fostering a research culture of well-being and scientific success. We regard training of the next generation of African scientists as a priority. We cannot achieve success alone – we will nurture academic partnerships and optimise public engagement, particularly with our research communities. Our ultimate goal is impact on scientific knowledge, practice and policy, in South Africa and beyond. |
| 30/06/2023 |
£200,000 |
UNIVERSITY COLLEGE LONDON |
AHRI’s vision is optimal health and well-being of under-resourced populations. We conduct research on important, intractable and intersecting health problems which impact well-being and mortality in South Africa and globally. The highest prevalence of HIV and TB, globally, is in our province; our research on these infections will therefore continue, with new strategic directions. We will introduce research on emerging and neglected infections, building on extraordinary impact of our Covid-19 science. We will build a new research programme in adolescent common mental health disorders, which is a very significant local – and global – health challenge. AHRI is uniquely placed to address these challenges: we focus on research questions for which we have a competitive advantage and exploit our integrated research value chain of basic, translational, clinical, population and social sciences. We will introduce innovation in all these areas, while fostering a research culture of well-being and scientific success. We regard training of the next generation of African scientists as a priority. We cannot achieve success alone – we will nurture academic partnerships and optimise public engagement, particularly with our research communities. Our ultimate goal is impact on scientific knowledge, practice and policy, in South Africa and beyond. |
| 30/06/2023 |
£65,134,256 |
UNIVERSITY COLLEGE LONDON |
AHRI’s vision is optimal health and well-being of under-resourced populations. We conduct research on important, intractable and intersecting health problems which impact well-being and mortality in South Africa and globally. The highest prevalence of HIV and TB, globally, is in our province; our research on these infections will therefore continue, with new strategic directions. We will introduce research on emerging and neglected infections, building on extraordinary impact of our Covid-19 science. We will build a new research programme in adolescent common mental health disorders, which is a very significant local – and global – health challenge. AHRI is uniquely placed to address these challenges: we focus on research questions for which we have a competitive advantage and exploit our integrated research value chain of basic, translational, clinical, population and social sciences. We will introduce innovation in all these areas, while fostering a research culture of well-being and scientific success. We regard training of the next generation of African scientists as a priority. We cannot achieve success alone – we will nurture academic partnerships and optimise public engagement, particularly with our research communities. Our ultimate goal is impact on scientific knowledge, practice and policy, in South Africa and beyond. |
| 23/05/2023 |
£5,844,961 |
KING'S COLLEGE LONDON |
Neuronal gene regulation is spatiotemporally controlled in a highly context-dependent manner through combinatorial interactions of RNA binding proteins (RBPs). These interactions are typically mediated by the intrinsically disordered domains (IDRs) of RBPs and their multivalent binding to RNA. A key goal of biomedical research is to determine how multivalent assemblies of RBPs on primary transcripts enable selective and developmentally dynamic regulatory programmes, and how these programmes are disrupted in pathological contexts. A closely related goal is to exploit knowledge of these mechanisms to establish improved therapeutics for brain disorders that currently lack effective treatments. We will draw on our collective extensive expertise in the areas of RNA biology, genomics, and brain disorders, to: (a) understand mechanisms underlying the formation of ribonucleoprotein (RNP) assemblies that are critical for the spatiotemporal regulation of RNA processing and translation in cortical neurons; (b) systematically dissect mechanisms whereby mutations in brain disorder-relevant RBPs selectively perturb RNP assembly and function, and define the underlying sequence codes mediating this selectivity; and (c) develop combined transcriptional, RNA processing and localization modules for autonomously-gated gene therapeutic applications. Thus, through a new understanding of post-transcriptional gene regulation, we will develop context-dependent therapeutic strategies for brain disorders. |
| 23/05/2023 |
£3,506,267 |
UNIVERSITY OF WARWICK |
The goal of this proposal is to determine the molecular, mechanistic and biophysical principles by which proteins build and close the bacterial cell division septum, using Gram-positive Bacillus subtilis as a principal model organism. This project will reveal how bacteria spatially coordinate cell envelope remodelling to build and close their division septum, will identify novel functional and regulatory roles of highly conserved bacterial cell division proteins and aims to identify new proteins with major roles in septal closure. This will be achieved by exploiting multi-disciplinary approaches including super-resolution microscopy, electron cryo-tomography, cellular scale coarse-grained molecular simulation, bacterial genetics and molecular microbiology. We will realise these goals via four linked aims: Aim 1. How is the nanoscale activity of individual divisome synthesis complexes regulated? Aim 2. How does the cytoskeleton coordinate septum building on the microscale? Aim 3. What are the key mechanistic principles of septal closure? Aim 4. Which proteins specifically mediate septal closure? By providing crucial mechanistic information our work will, we believe, support ongoing world-wide efforts to find new antibiotic inhibitors of bacterial cell division. |
| 23/05/2023 |
£2,169,838 |
THE FRANCIS CRICK INSTITUTE |
How do organs reach their appropriate size during animal development? Unravelling organ size control is key to understanding growth pathologies such as cancer and fulfilling the potential of regenerative medicine. Although we know many signals that can modulate developmental growth, we lack a coherent model of how growth ceases at the correct time. Furthermore, although differences in body size and proportions across species are among the most striking aspects of animal evolution, the cellular and molecular bases for these differences remain little explored. Here, we exploit the unique live-imaging and genetic tractability of the fruit fly Drosophila melanogaster abdominal epidermis to ask how growth is terminated at the appropriate size in a developing system. We will combine rigorous quantitative biology with temporal genomics and a candidate approach to identify the signals that ensure the robust control of tissue size during development (Aim 1). We will take advantage of the broad variation in abdomen sizes across the Drosophila genus and the precision of our quantitative approach to developmental growth in the abdominal epidermis to explore tissue size control in differently sized Drosophila species. We will ask what cellular behaviours and molecular mechanisms underpin the evolution of organ size (Aim 2). |
| 23/05/2023 |
£3,334,028 |
UKRI-MRC |
Microtubule-based motors are critical for cell organization and function. In neuronal axons, inbound (dynein) and outbound (kinesin) motors are coordinated to direct the correct delivery of organelles, RNAs and proteins, and can be hijacked by pathogens such as herpes viruses. These cargos recruit motors by different, but incompletely defined, networks of interactions involving several families of adaptor proteins. Surprisingly, both cargos and individual adaptors can simultaneously recruit dynein and kinesins. This leads to the question of how direction, distance of travel and other behaviours are controlled to achieve the desired cargo distribution. Our work aims to 1) identify the network of connections linking motors to specific cargos and 2) understand how the connections control motor activity. We will develop crosslinking mass spectrometry methods to identify motor:cargo interactions in neurons. This will complement detailed mechanistic studies using live-cell imaging, cryo-EM and reconstitution approaches. Our discovery-based research will uncover the molecular principles underlying cargo delivery in cells. |
| 23/05/2023 |
£4,486,918 |
UNIVERSITY COLLEGE LONDON |
Dystonia is a common movement disorder, but its pathophysiological mechanisms are poorly understood. Currently, there is no cure, with treatments focussed on symptom management. The development of novel, targeted treatment strategies will require new foundational knowledge of the pathophysiology of this neural circuit disorder. By using mouse genetics, we recently showed that spinal cord circuit dysfunction underlies the pathophysiology of the most common genetic dystonia. In this ambitious proposal, we will leverage this new knowledge, proposing to dissect the pathological neural substrates to determine how their specific dysfunction - from cells to synapses - contributes to the movement disorder. We will confine the genetic manipulations to four key components of motor control: motoneurons, sensory afferents, spinal inhibitory circuits, and myelin, with the goal of dissecting the mechanisms by which each of these elements contribute to dystonic phenotypes. We will then generate a new mouse with the human Tor1a gene (and conditional dystonia mutation), in order to match more closely the human condition. By the completion of the eight year term of this programme, we will have a solid understanding of the cellular and circuit pathophysiology of dystonia, paving the way for new treatment possibilities. |
| 23/05/2023 |
£3,909,569 |
UNIVERSITY OF CAMBRIDGE |
Our understanding of how complex immune responses are guided by signalling pathways is incomplete. We study Hedgehog signalling - a classical cell-cell communication system that controls embryonic development and adult tissue maintenance in vertebrates. Interestingly, we found that T cells have adapted morphogenic Hedgehog signalling towards a cell-autonomous pathway downstream of the T cell receptor. Which immune cells utilise the pathway and elemental signalling characteristics remain elusive. Our research programme has two key objectives: Use a dynamic in vivo reporter of Hedgehog signalling activity and spatial transcriptomics to determine the cohort of immune cells that are dependent on the Hedgehog pathway in homeostasis and during infection and cancer challenge. A series of immune cell-specific knockout models we have generated will dissect individual roles of Hedgehog signalling in immune cell subsets. Define the unique mechanistic pathway adaptations of Hedgehog signalling in T cells. Bespoke transgenic mouse models and molecular, proteomics and imaging approaches using nanobodies will be used to understand Hedgehog ligand processing and signal transduction and the immune specific target genes of the pathway that interface biological output. Taken together, the proposed work will reveal fundamental new biology and detail unique therapeutic entry points against infection and cancer. |
| 23/05/2023 |
£2,645,534 |
UNIVERSITY OF BIRMINGHAM |
Reading is an essential human skill relying on coordinating saccades and visual attention while translating text to meaning. Yet the neuronal mechanisms supporting natural reading are poorly understood. We will develop a new research field exploiting insight into spatial attention to uncover the neuronal dynamics supporting natural reading – and investigate how the mechanism matures in children with learning. The research is anchored in a pipelining mechanism providing a hypothesis for how brain oscillations guide the flow of information and control saccades during reading. The mechanism will be made explicit in a computational model implemented as a dynamical deep neural network. We will test the mechanism in children and adults using magnetoencephalography (MEG) combined with eye-tracking. Hypothesis testing will rely on novel methodology including rapid invisible frequency tagging, multivariate analyses and natural language processing. Brain stimulation, perturbing neuronal oscillations, allows for causally testing the pipelining mechanism. We will develop a paediatric Optically Pumped Magnetometer (OPM) system to understand the mechanisms that must develop in children learning to read. My proposal will catalyze a new research field in which state-of-the-art electrophysiological imaging approaches are used to translate fundamental research on spatial attention to uncover the mechanism of reading and reading acquisition. |
| 23/05/2023 |
£3,693,674 |
UNIVERSITY OF CAMBRIDGE |
All life forms defend their genome against nucleic acid invasion, yet RNA-derived retroelements make up > 40% of our DNA. Retrotransposition, the predominant route by which our genome acquires new genetic material, is therefore tolerated but must be tightly regulated. We discovered the HUSH epigenetic repressor complex and characterized its central role in genome defence through repression of RNA-derived retroelements (retroviruses/retrotransposons). How HUSH distinguishes retroelements from endogenous genes was unclear. We showed how cellular introns provide a novel means for self-nonself discrimination, with HUSH specifically silencing intronless (RNA-derived) transgenes. HUSH therefore regulates the reverse flow of genetic information (RNA-DNA) in the genome, providing a means of post-integration immunity. Here we will elucidate the signals which trigger HUSH recruitment and chromatin-dependent silencing. In particular, the molecular features of intronless genes that recruit HUSH, how introns protect against HUSH and how transcription initiates HUSH-dependent silencing. We will determine how RNA-mediated (canonical) HUSH silencing differs from DNA-mediated (non-canonical) HUSH-dependent silencing and ascertain the importance of HUSH-dependent repression in specialised cells, including hiPSC and the germline. Understanding the different modes of recruitment, and how specialised intronless genes and viruses evolved to evade HUSH-mediated silencing, will provide an integrated understanding of HUSH’s role in genome defence. |
| 23/05/2023 |
£5,778,159 |
UNIVERSITY OF OXFORD |
Our vision is that First Referral Hospitals (FRH) deliver quality care as part of Universal Health Coverage (UHC). Expectations of FRH service delivery are growing rapidly driven by research. However, expectations often confront the reality of insufficient resources, workforce numbers or skill-mix resulting in preventable mortality and morbidity, especially in ‘hardship’ areas that face increasing climate and disease risks. Technologies and task-sharing may help improve access to services but care must be high quality and safe. Our research will discover how best to align FRH roles, workforce requirements, skill-mix and use of technologies to achieve UHC. Our work addresses decades of research neglect of FRH as a key component of primary healthcare systems. Our research will: i) embrace complexity, ii) assemble a new multi-disciplinary, multi-country team, iii) employ novel methods including longitudinal studies of ‘sentinel hospitals’, iv) deliberately include diverse contexts and advance use of realist methods, and v) embed learning within the policy and practice community. Over 6 years we will learn how place, people, technologies, and task-sharing will reshape the future of FRH. We will build capacity and global and national networks so that quality essential hospital care is available to all everywhere, even in hardship areas. |
| 23/05/2023 |
£1,696,710 |
UNIVERSITY OF NOTTINGHAM |
Sports sponsorship by the addictive industries of tobacco, alcohol, and gambling pressurises health services and damages lives. While tobacco sponsorship is no longer legal, sports fans are nevertheless still routinely exposed to sponsorship by the alcohol and gambling industries. The health dangers of this involvement are pressing. Marketing is shown to directly impact the behaviours of those vulnerable to health harms, prompting unplanned betting in nine out of ten people experiencing gambling problems. Similar impacts have been recorded for tobacco and alcohol use. This important project will be the first to systematically map and analyse professional sport sponsorship from a historical perspective. As such, it works towards Wellcome’s strategic goals by uncovering historical precedents as a means to mobilise better health outcomes. Stimulated by the 2021-22 UK governmental gambling review (that includes an examination of sponsorship), three leading experts within history and the social sciences analyse the tobacco, alcohol, and gambling industries’ relationships with five professional sports (football, rugby, cricket, formula one, tennis). From the first sports sponsorship deals of the mid-1960s to 2025, we scrutinise the involvement of sport and industry in sponsorship and interrogate what the production of health-harming behaviours means for sport, industry, and the interested public. |
| 23/05/2023 |
£1,976,772 |
UNIVERSITY OF OXFORD |
T-cell based immunotherapies targeting MHC-Ia-restricted peptides are often compromised by MHC-Ia down-regulation or by mutations within peptides. Although originally reported to present conserved MHC-Ia leader sequences to convey cellular health to NK cells, recent evidence from simian immunodeficiency virus /rhesus macaque CMV-driven vaccines showcase the protective role of MHC-E-restricted T cells targeting remarkably sequence-diverse peptides. Pathogen-specific HLA-E-restricted CD8+ T cells have also been identified in humans. As near monomorphic and resistant to down-regulation, MHC-E (HLA-E In humans) offers a promising "universal" target. HLA-E displays many unusual qualities that require interrogation prior to immunotherapeutic targeting. Through a highly collaborative and multi-disciplinary approach involving structural, biochemical/physical, immunopeptidomic and functional studies, we aim to (a) interrogate how atypical peptides that do not register as MHC-E binders in vitro elicit T cell responses in vivo -how do they bind MHC-E – could unknown compounds facilitate their binding (b) explore how modest binding peptides that generate unusual MHC-E conformations impact T cell recognition (b) interrogate the co-stimulatory requirements of MHC-E-restricted T cells which likely differ to MHC-Ia-restricted T cells and (d) develop new antigen discovery strategies to capture weak MHC-E binding epitope that are under-represented using current methods. The answers provided should inform therapeutic design. |
| 23/05/2023 |
£3,587,180 |
UNIVERSITY COLLEGE LONDON |
The CD28-CTLA-4 pathway controls T cell immune responses to both foreign and self-antigens, where loss of CD28 compromises adaptive immunity and loss of CTLA-4 causes fatal autoimmunity. The system is regulated by two distinct ligands CD80 and CD86, which bind with different affinity, avidity and valency characteristics to CD28 and CTLA-4. The binding of another ligand (PD-L1) to CD80, alters these characteristics and directly connects CD28, CTLA-4 and CD80 to the PD-1 pathway. Despite this critical position in controlling immunity, the fundamental mechanisms underpinning these pathways remain poorly understood. In this proposal we hypothesise that the integrated CD28-CTLA-4-PD-1 pathway represents a tunable thermostat that is regulated by a series of ligand-receptor interactions, competitions and feedbacks that control T cell outcomes. We propose to: a) Understand how biophysical characteristics of ligand-receptor interactions control pathway behaviour, by acting in concert. b) Determine how natural and engineered changes in these biophysical characteristics alter T cell responses in vitro and in vivo. c) Generate mathematical models to predict outcomes and look for emergent behaviours. We therefore aim to provide a fully integrated view of how this essential immune regulatory system works, from molecular detail through to immune function. |
| 23/05/2023 |
£3,019,351 |
UNIVERSITY OF DUNDEE |
The ability of T-lymphocytes to rapidly activate following infection and to curtail effector function following pathogen clearance is fundamental for adaptive immunity. CD8-T-cells, essential for immune responses to viruses and tumours, have highly dynamic pathways of selective protein degradation that drive rapid remodelling of their proteomes in response to pathogens, cytokines, and environmental signals. This is a fundamental mechanism that allows rapid reprogramming for acquisition of effector function or return to quiescence. Pathways important for protein degradation in T-cells include autophagy and the ubiquitin-proteosome system controlled by E3 ubiquitin ligases. However, there are substantial knowledge gaps in our understanding of the molecular mechanisms that control the selectivity of T-cell protein degradation. We will exploit mass spectrometry, chemical biology, and genetic engineering to systematically uncover key regulators of protein degradation in CD8-T-cells in response to changes in their immune and nutrient environment. This project will identify control switches for autophagy in T-cells and deliver a systems level identification of active E3 ligases and their substrates in naïve, effector and memory CD8-T-cell populations. It will transform understanding of how T-cells control exit and entry to quiescence and pinpoint molecules that can be targeted for therapeutic immune interventions to treat autoimmunity and cancer. |
| 23/05/2023 |
£4,817,214 |
JOHN INNES CENTRE |
Plants make a vast array of chemicals that have been honed by evolution to be bioactives. If the instruction manual needed to make this chemical diversity could be decoded, this would unlock unprecedented opportunities to understand plant natural product biosynthesis, function, and mechanisms of metabolic diversification, and to harness this biosynthetic capability for medicinal applications. We have developed a powerful computational platform and rapid transient plant expression technology that now uniquely position us to address this challenge. We will focus on a large and structurally complex groups of plant natural products, the pharmaceutically important triterpenoids, as our exemplar. By decoding the genetic potential of the Plant Kingdom to make and diversify these compounds, we will gain a comprehensive understanding of enzyme specificity and function, and of the rules governing sequential modification of scaffolds by tailoring enzymes, enabling us to control and direct biosynthesis. We will develop machine learning-based approaches for predicting bioactivity that will enable hypotheses about structure-activity relationships to be iteratively refined and tested, and design molecules with optimised bioactive properties using engineering biology approaches. This project will deliver a step-change in our ability to access, harness and engineer new enzymes, pathways and chemistries with potential therapeutic applications. |
| 23/05/2023 |
£3,613,518 |
UNIVERSITY OF EDINBURGH |
Nearly a billion people are at risk of infectious diseases caused by kinetoplastid parasites. Kinetoplastids are a group of eukaryotes that are evolutionarily highly divergent from commonly studied eukaryotes. Our overall objective is to reveal how unconventional machinery and regulatory networks drive proliferation of kinetoplastid parasites using Trypanosoma brucei as a model. Centromeres and their associated intricate kinetochore machinery (~60 proteins) are essential for mediating accurate chromosome segregation in all eukaryotes. Since the identification of the first kinetochore proteins ~40 years ago, it appeared that kinetochore structure and their regulation would be broadly similar across all eukaryotes. It was therefore surprising when we discovered that kinetochores in Trypanosoma brucei are composed of unique proteins, KKT1-to-KKT25. These highly divergent kinetochores provide an attractive drug target for combating kinetoplastid diseases. Our goal is to understand how the unique components and underlying centromeres are organized to carry out conserved kinetochore functions. We will also dissect the nature of noncanonical cell cycle control executed by conserved mitotic regulators. Identification of novel mechanisms will not only provide opportunities for drug development against kinetoplastid parasites but also deepen our understanding of intricate chromosome segregation machinery in all eukaryotes. |
| 23/05/2023 |
£5,990,700 |
UNIVERSITY OF SHEFFIELD |
Antimicrobial resistance (AMR) threatens human healthcare. Our international team will integrate microbial physiology, biochemistry and genetics with biophysics, mathematical modelling and world-leading imaging capabilities, to gain a transformative understanding of the important human pathogen Staphylococcus aureus. We will focus on Methicillin Resistant S. aureus (MRSA) which is responsible for 100,000 deaths annually, building on our foundation of recent discoveries. AMR provides a powerful tool to understand processes critical to life, which we will use to unlock the interwoven pathways linking growth, division and cellular physiology. Our key goals are: to determine the molecular and biophysical basis for high-level resistance in MRSA; to unravel the mechanisms underpinning bacterial cell wall homeostasis during growth and division; and to understand the coordination of cell wall dynamics with cellular physiology, providing a route to novel therapies. Utilising cutting-edge imaging technologies and predictive, quantitative mathematical models, we aim to link genetics, through protein dynamics, to cell wall architecture, mechanical function and growth in the context of the adaptations in whole cell physiology required to accommodate the components necessary for AMR. By spanning disciplines and length scales, we will generate a comprehensive understanding of growth, resistance and new paradigms for developing control regimes. |
| 16/05/2023 |
£5,204,139 |
UNIVERSITY COLLEGE LONDON |
In hearing, spatial information must be computed from interaural cues, from which the brain reconstructs a 3D scene. We are readily able to switch between describing a sound’s position relative to ourselves ("head-centered"), or relative to external landmarks ("world centered"). Here we test the hypothesis that mapping sounds into a world-centered reference frame is a key function of auditory cortex (AC). In Aim 1, we will train animals in a world-centered localisation task before making key manipulations to test how world-centered receptive fields are constructed and anchored by visual cues, and how tuning is established in novel environments. In Aims 2 and 3 we will employ a sensory-guided navigation task in which animals ‘hunt’ sounds (Aim 2) or audiovisual stimuli (Aim 3) in a large arena. By preserving the natural timing relationships between perception and action and measuring head and eye movements, we will define the active sensing strategies employed by animals and how sensory and motor components shape AC activity. Using optogenetics we will establish which elements of sound-guided action are supported by AC. In Aim 4 we will combine neural recordings and pathway-specific manipulation of activity to determine what brain regions support AC in mapping sounds into space. |
| 16/05/2023 |
£2,085,584 |
UNIVERSITY OF EXETER |
A fundamental challenge in study of cell function and disease is understanding how cis-regulatory regions control gene expression. These regions are often denoted non-coding as they do not encode protein, yet a sequence code read by transcription factors underlies these regions. Our understanding of the code is insufficient to predict how changes in sequence impact function. This is a significant limitation in our understanding of disease as it impairs our ability to interpret genetic variants within cis-regulatory regions. This interdisciplinary research programme will significantly advance our understanding of the sequence basis of cis-regulatory control of gene expression. It will use rare and common glucose regulatory disorders studied in pancreas development and function as a model to understand the cis-regulatory code. I will use the novel technology of single-molecule footprinting to measure base-pair level activity of cis-regulatory regions. Pairing this with my expertise in data science and machine learning, I will build predictive algorithms to understand how the cis-regulatory code integrates information allowing the interpretation of cis-regulatory variants in disease. This proposal will make fundamental insights into the study of gene regulation and the genetic causes of disease. It will act as a model to understand cis-regulatory variation in human disease. |
| 16/05/2023 |
£2,123,593 |
ROYAL COLLEGE OF SURGEONS IN IRELAND |
Medications provide important therapeutic options to prevent and manage disease and prolong life. As people age, the number of medicines prescribed tends to rise, leading to increased risk of medication-related harm. Even effective medications are often continued beyond the point of providing benefit. The WHO recognise this significant risk, designating the current Global Patient Safety Challenge ‘Medication Without Harm’. Deprescribing, the process of stopping or reducing such unnecessary medications is one critical solution to this contemporary challenge. We propose a 21st century solution, using big data to develop novel methods to identify, quantify, and address medication burden and harm as a critical public health issue. DIAMOND aims to develop and advance novel methods to research deprescribing using big data, and to apply these to generate knowledge on benefits and harms of stopping medications. The research will significantly progress methods to evaluate effects of deprescribing medications through examining optimal definitions for deprescribing and confounding control, and then emulating target trials with health record data. It will develop a novel tool to predict harm from selective serotonin reuptake inhibitors, to inform risk stratification for deprescribing. Last, it will explore prescribing cascades and how deprescribing may produce downstream benefits in reducing medication burden. |
| 16/05/2023 |
£2,052,013 |
BIRKBECK UNIVERSITY OF LONDON |
How infants learn to interpret and respond to their surrounding sensory environment is a fundamental developmental process. Alterations in this process may have wide-reaching consequences; atypical sensory responsivity is present from early infancy in a range of neurodevelopmental conditions. However, the neurobiological mechanisms that contribute to individual differences in sensory responsivity early in child, and the longer-term impacts of alterations in these mechanisms on key developmental outcomes, are not well understood. This project will combine large-scale existing datasets of infants followed from early infancy to toddlerhood with data collection using novel integrated neuroimaging-virtual reality (VR) methodologies. This innovative approach will allow me to establish the cortical features associated with atypical sensory responsivity in both controlled presentations of isolated stimuli and complex real-world sensory environments. This project will advance current understanding of brain-based risk (sensitivity) and resilience (regulation) features that underpin sensory responsivity in toddlerhood, and map the cascading consequences of individual differences in these neurobiological mechanisms on child development. This project will elucidate the factors that may explain why some children respond very differently to sensory inputs, and may lead to important insights as to where to best target support for children with atypical sensory responsivity to promote positive outcomes. |
| 16/05/2023 |
£1,892,130 |
UNIVERSITY COLLEGE LONDON |
This project redefines the spectrum of neurodegenerative conditions via a new understanding of mixed pathologies provided by novel computational modelling approaches. Mixed pathology affects most individuals with neurodegenerative diseases and is a key confounder in clinical trials yet is not widely considered or quantified in research studies as several pathologies lack specific biomarkers. This project builds new computational tools that learn the contributions of mixed pathology to non-specific biomarkers such as structural magnetic resonance imaging by accounting for major confounding factors including disease progression and within-pathology subtypes. This will enable individuals to be given a pathology profile describing the different pathologies they have and the quantity of each. These pathology profiles will then be used to improve patient stratification and prediction of clinical outcomes, to understand the links between pathologies and symptoms, to generate hypotheses on treatment strategies, and to shed new light on the shared mechanisms of concurrent pathologies. Whilst the project focusses on neurodegenerative diseases, the aim is to develop tools that will ultimately have broader applications across a wide range of complex long-term health conditions. |
| 16/05/2023 |
£3,443,729 |
KING'S COLLEGE LONDON |
In order to survive, animals must flexibly update their behaviour in response to changes in the environment. This ability to adapt ongoing behaviour is one of the most fundamental of cognitive processes, yet its underlying neural mechanisms remain poorly understood. The framework of predictive processing provides a simple yet powerful way of describing flexible behaviour. While this account has widespread support across species, the neural circuit basis of this process is largely unknown. In this project, I will address the following question: What brain-wide neural circuits enable animals to compute cognitive prediction-errors, and use these to flexibly adapt their behaviour? My lab’s recent work has identified prediction-error encoding neurons in mouse anterior cingulate cortex (ACC) which provide a substrate for the computations underlying flexible behaviour. Building on these results, I hypothesise that ACC is part of a network of brain areas that utilise inhibitory microcircuits to compute prediction-errors. These prediction-error signals drive task switching behaviours by engaging neuromodulatory circuits.­­­­­ I will test this hypothesis by 1) Establishing a causal map of prediction-error signalling across cortex. 2) Identifying the comparator circuit which computes the prediction-error. 3) Identify the specific output route through which the prediction-error signal influences the animal’s behaviour. |
| 16/05/2023 |
£3,564,781 |
UNIVERSITY COLLEGE LONDON |
During development cells choose between alternative cell fates, each characterised by specific gene expression. Cis-regulatory elements (CREs) are responsible for directing cell-type-specific gene expression with spatial and temporal precision. Our understanding of CRE function remains limited. Most studies have focused on activating transcription factors (TFs). However, many crucial TFs are repressors, which also have essential roles dictating fate decisions. The mechanisms by which repressors regulate cell-type-specific gene expression during development are not well understood. In contrast to models where inaccessible chromatin enforces silencing, I have identified a chromatin regulatory strategy where CREs acting as silencers remain accessible across alternative cell fates, in mouse neural progenitors. These CREs would act as cell-type-specific enhancers and silencers, switching function without chromatin remodelling, with potential implications for cell plasticity. To understand the molecular regulation of silencer elements, and their developmental phenotype, we will (1) identify the cis-regulatory logic of these CREs, (2) the cell-type specific protein composition of CREs and their silencing mechanisms and (3) how the dynamics of TFs control CRE function. The regulatory principles uncovered here will bridge primary DNA sequence to cell fate choice, with broad applicability across developmental systems and for regenerative medicine. |
| 16/05/2023 |
£2,728,253 |
UNIVERSITY OF CAMBRIDGE |
Cardiac form and function are inextricably linked. In the heart, disease is associated with changes in both physiology and morphology, although mechanistic insight into this relationship is complicated. Early heart development provides a unique model to explore how the onset of function impacts form. My research programme will use heart development to identify how cellular physiology influences gene expression and cell fate decisions, in order to identify mechanisms with therapeutic potential. To address my research vision, I will temporally define the transcriptional and physiological characteristics of cardiac progenitors as they generate distinct cardiac lineages during the onset of function. I will explore how disrupting function influences form in vivo. Furthermore, and aiming to translate my findings, I will develop in vitro human models, focusing on the generation of distinct cardiac progenitor types identified in the human embryo, enabling me to connect descriptive genomic insight with functional relevance. Functional perturbation experiments will identify pathways which integrate different components of contraction with gene expression, regulating heart development and disease states. My work will enhance models of human heart development and provide insight into the relationship between form and function, aiding in the development of cell-based approaches for cardiac regeneration and heart disease. |
| 16/05/2023 |
£2,038,400 |
UNIVERSITY OF CAMBRIDGE |
To turn a fertilised egg into an adult organism, intricate patterns of cell differentiation must emerge from an initially simple and uniform state. This process, embryo patterning, is robust (withstands perturbation), scalable (adapts proportionally to embryo size), and flexible (produces different outputs in different species). Prevailing mathematical theories of patterning struggle to account for these properties, indicating a serious mismatch with biological reality. What is lacking, in my view, is an understanding of how the sophisticated gene regulatory networks inside cells exploit information exchange between cells to generate pattern regulation at the level of the whole tissue. I will study this question by interrogating anteroposterior (head-tail) patterning networks in model organisms, first the relatively simple Drosophila embryo, and later the more complicated embryos of Tribolium (a beetle) and zebrafish. For each species, I aim to (1) resolve the structure of the gene regulatory network responsible for patterning, (2) explain the mechanistic basis for its robustness, and (3) determine its control parameters and constraints. My research approach will combine quantitative imaging, genetic perturbations, and computational modelling. This work will advance our basic understanding of embryonic development, which facilitates progress in the treatment of developmental disease and the development of regenerative technologies. |
| 16/05/2023 |
£1,257,056 |
UNIVERSITY OF OXFORD |
To understand how enzymes bind and activate O2 is of both basic scientific and, given the important roles of oxygenases in human biology, medicinal interest. Advances in X-ray sources have opened the door to room temperature investigation of reactions in microcrystals, i.e. time-resolved (tr) serial crystallography (SX). However, the current sample delivery systems available at synchrotron/XFEL endstations (fixed target chips, mixing jets, or drop on demand methods) are not suited for homogeneous and rapid initiation of in crystallo reactions by mixing with gases, including O2. I propose to develop an innovative fixed-target device that enables initiation of reactions with O2 for individual chip-mounted crystals in which a key element is in situ O2 generation. The bioluminescent luciferases that convert the chemical energy of O2 into light will be used as models to validate application of the new methods for tr-SX studies. The results will inform on how luciferases and related enzymes react with O2 and on dynamic structural changes and the nature of intermediates during luciferase catalysis. The pioneering new methodologies will lay the ground for a new generation of mixing possibilities in fixed-target devices and will be of general use in tr-S(S/F)X studies on O2-utilising enzymes and far beyond. |
| 16/05/2023 |
£3,054,783 |
UNIVERSITY OF CAMBRIDGE |
Regeneration in the mature brain is limited. An understanding of the molecular mechanisms that regulate self-renewal, proliferation, differentiation, and importantly, the lineage plasticity of neural stem/progenitor cells during development and homeostasis is crucial for discovering how to stimulate brain repair upon injury. My previous work shows that the neonatal mouse cerebellum has remarkable regenerative potential as it can recover from injury at birth by various mechanisms, one of which involves lineage plasticity. However, the adult cerebellum has lost this regenerative ability, despite the existence of stem-like cells. Using comparative approaches in this powerful system, we will identify the signalling pathways and gene regulatory networks that control the developmental and regenerative responses of cerebellar progenitors in neonates and determine how they differ in adults. Candidate stimulators of neonatal regeneration will be tested through in vitro and in vivo stem cell assays, and then pro-regenerative pathways will be assessed for their ability to stimulate stem cells. Finally, we will develop models to translate our findings from mouse to human. This work will provide fundamental knowledge on the regulatory mechanisms that govern neural progenitors and harnessing new findings will provide a basis for in vivo manipulation of stem cells to facilitate brain repair. |
| 16/05/2023 |
£1,689,461 |
UNIVERSITY OF LIVERPOOL |
Pregnancy is a unique window during which the health and wellbeing of future generations are established. To maintain optimal maternal and fetal health, many women require at least one drug during pregnancy. For most drugs, the associated risks are poorly understood because the rodent and rabbit models used during drug development do not recapitulate human physiology. My research programme aims to transform the assessment of drug safety during pregnancy by developing a platform to generate human-pregnancy-relevant safety information early in development. I will deliver this through a transdisciplinary team supported by robust scientific collaborations. First, we will develop an open access pregnancy pharmacokinetics database to qualify maternofetal pharmacokinetic models for granular prediction of drug exposure across gestation. Second, we will develop a placenta-on-chip model to characterise drug disposition for pharmacokinetic model improvement and to investigate drug-induced perturbations. Lastly, integrated analysis of multi-omics data from placenta-on-chip will be used to uncover molecular signatures of drug-induced perturbations, which will form the basis for risk assessments. This work will underpin future addition of fetal organs-on-chip to the platform to characterise drug-induced perturbations in developing fetal organs. This programme will benefit from a comprehensive portfolio of stakeholders’ engagement for early input and policy influence. |
| 16/05/2023 |
£2,126,783 |
UNIVERSITY OF EDINBURGH |
Astrocytes are a highly abundant cell type in the central nervous system. They perform critical homeostatic functions but respond to insults by undergoing a ‘reactive transformation’. By applying integrative single cell RNA-seq and genome-wide spatial transcriptomics I have recently discovered that astrocytes fall into discrete subtypes that occupy distinct spaces in the brain, and that each subtype undergoes a subtype-specific reactive transformation during brain inflammation. Key goals of my project are understanding how homeostatic, regionally-restricted astrocyte subtypes turn into specialized reactive subtypes in neuroinflammation and chronic neurodegeneration, particularly Alzheimer’s disease (AD). I have already identified two subtypes relevant to neurodegeneration: 1 – An astrocyte ‘super-responder’ subtype that is induced by type-I-interferons and is selectively present around amyloid plaque depositions. 2 – I identified the transcriptomic identity of glia limitans superficialis astrocytes that cover the entire brain and spinal cord surface and can be described by a single gene, Myoc. Using scRNA-seq, spatial transcriptomics, advanced bioinformatic analyses as well as novel and established astrocyte-specific transgenic mice combined with functional in vitro assays, I will uncover the upstream-inducers and downstream functions of specialized astrocyte subtypes in order to identify novel therapeutic targets in neurodegeneration and neuroinflammation. |
| 16/05/2023 |
£1,616,579 |
TRINITY COLLEGE DUBLIN |
A major question in neuroscience is to understand how sensory information and memory influence behaviour. Dopaminergic neurons are candidates of special interest in this context: dopamine is implicated in learning and dopaminergic neurons innervate the brain widely, including regions controlling sensory perception, circadian rhythms, motivation... Memory acquisition and modulation of memory strength are independent processes, both controlled by the dopaminergic system: some neurons impart valence, whereas others impart motivational salience. The physiological mechanism by which dopamine modulates cognitive processes through salience is not known in any circuit or organism. Drosophila is a pioneer model organism at the cutting edge of the study of neural circuits: a relatively simple nervous system confers sophisticated behavioural complexity while maintaining principles of information coding and molecular conservation with other systems. This proposal aims to dissect compartmentalized contributions of dopamine to the cognitive process, specifically in the modulation of memory strength, using imaging and behavioural approaches to identify the neural circuits involved in motivational salience and how they interact with the circuits that dictate behavioural responses. |
| 16/05/2023 |
£3,254,644 |
UNIVERSITY OF SHEFFIELD |
The human bacterial pathogen Streptococcus pyogenes is responsible for a substantial global infection burden, with > 300,000 deaths annually due to the post-infection condition of rheumatic heart disease (RHD) alone. Infection burden is highest in low- and middle-income countries (LMICs) and a vaccine is urgently needed, particularly to prevent primary throat or skin infections which may lead to RHD. Currently there are significant barriers to vaccine success in the form of 1) the lack of knowledge regarding S. pyogenes:host interactions at primary infection sites, and 2) extremely limited information on streptococcal molecular epidemiology and biology in LMICs; available data shows much higher diversity in these countries. We will address these barriers with our unique tissue-engineered human tonsil and human skin infection models for comprehensive study of S. pyogenes:host interactions. We will perform extensive functional genomic analysis of skin and throat isolates collected in the UK (a high-income country) and in The Gambia (a low-income country), alongside bacterial genome-wide transcriptomics and mutagenesis in the context of our human-relevant infection models. This innovative combination of research approaches will elucidate infection determinants and tissue-tropisms of high-income and low-income country isolates, transforming our understanding of global streptococcal biology and directly supporting vaccine development. |
| 16/05/2023 |
£1,903,191 |
IMPERIAL COLLEGE LONDON |
Chronic lung diseases such as asthma and COPD are a major health problem in the UK with an estimated 1/5 people impacted by one form of lung disease and this number is predicted to increase in the next decade. One underestimated impact of respiratory disease is the effect of chronic inflammation on the crucial network of blood vessels in the lungs. During my previous projects and fellowship, I discovered that mast cells (MCs), a type of immune cell, play a vital role during vascular inflammation and can modulate function of pericytes, the structural components of the vascular wall. The importance of this interaction in the lungs, where MCs and pericytes are abundant, remains to be investigated. My proposed project, combining mouse models, human samples, spatial transcriptomics, and 3D analysis of blood vessels will shed new light on this important question. I will investigate how the hyperactivation of MCs leads to pericyte loss, and how this impacts lung vascular function. Furthermore, this transdisciplinary proposal will identify MC-derived factors such as proteases as potential therapeutic targets. In summary, my project will develop strategies to prevent pericyte dysfunction and further prevent respiratory and vascular disorders during chronic lung diseases. |
| 16/05/2023 |
£1,989,593 |
UNIVERSITY OF EDINBURGH |
Circular RNAs (circRNAs) play key co- and post-transcriptional roles in many human diseases, including cancer and neurological disorders. I was one of the first to discover that circRNAs regulate virus infection. I also identified virus-encoded circRNAs. The low immunogenicity of circRNAs presents them as ideal viral tools to manipulate gene expression. My research revealed a host circRNA (circRELL1) that is induced by many herpesviruses, promotes the survival of latently infected cells, and suppress the lytic cycle of an oncogenic Kaposi sarcoma herpesvirus. While the significance of circRNAs on latency establishment is well documented, an understanding of the regulatory mechanisms is lacking. Further, effects of viral and host circRNAs on immunity and oncogenesis needs investigation since they are critical aspects for herpesviruses. As a first step, I employed high-throughput approaches including a CRISPR-based method, to identify circRNA-associated proteins and RNAs. These data led me to the hypothesis that herpesviruses exploit circRNAs to control mRNA stability and modulate signaling pathways. By integrating biochemical and phenotypic analyses, I aim to obtain mechanistic insights into how human and herpesvirus circRNAs regulate the viral life cycle, antiviral immunity, and tumor microenvironment. This research will lead to a fundamental understanding of how circRNAs impact virus infection. |
| 16/05/2023 |
£1,723,633 |
UNIVERSITY OF OXFORD |
Adenovirus vector and mRNA vaccines have proven their real-world efficacy as rapidly deployable modular vaccine platforms. However, major differences exist between the two systems, particularly with respect to immunogenicity where mRNA vaccines induce markedly stronger antibody responses. The reason for these differences remains unknown. Furthermore, my preliminary data has revealed important qualitative differences in the B cell responses induced by these two vaccines, particularly around the role of the germinal center response. Thus, there are key quantitative and qualitative differences in the B cell immunity induced by these vectors, but a mechanistic understanding of the cause is lacking. My project will address this major gap in knowledge using a combination of human and mouse immunology techniques involving bioinformatic and experimental approaches. Specifically, my project will (1) define the dynamics of the B cell responses induced by these vaccine technologies, (2) identify critical regulators of these B cell responses, and (3) define how T follicular helper cells are regulated and regulate the subsequent B cell response. Through synthesis of these data, this project will enhance our fundamental knowledge of how these vaccines induce B cell immunity and allow for rational improvements in their design and deployment. |
| 16/05/2023 |
£2,516,746 |
KING'S COLLEGE LONDON |
Phosphotyrosine-based signal transduction is fundamental to cell growth, migration and communication. Aberrant phosphotyrosine signalling, by dysregulation of pathways or subversion by pathogens, is implicated in a variety of human diseases. While such signalling requires a balance between kinase and phosphatase activities, research in this area has thus far heavily focused on tyrosine kinases. Tyrosine phosphatases, a large and heterogenous superfamily of proteins, are relatively understudied and our knowledge of their in vivo functions, interactors and mechanisms of action is highly limited. Using Vaccinia virus that hijacks host phosphotyrosine signalling to the cytoskeleton, I have identified three tyrosine phosphatases that regulate actin polymerisation. Here I propose to deeply characterise these model phosphatases using a combination of quantitative microscopy, protein interaction analyses and powerful C. elegans genetics. I will identify their binding partners and substrate-interaction motifs in healthy and virus-infected mammalian cells. I will measure the quantitative impact of these phosphatases on signalling dynamics using Vaccinia virus as a platform. Finally, I will determine their roles and localisation in a live organism. My research will generate fresh knowledge on how cellular tyrosine phosphatases perform their functions, paving roads for new therapeutic approaches in viral infections, cancers and more. |
| 28/03/2023 |
£1,212,058 |
IMPERIAL COLLEGE LONDON |
Neonatal bacterial infections are an important cause of morbidity and mortality in low-resource settings (LRS). Accurate identification of those needing treatment while avoiding unnecessary antibiotics in those who do not is crucial. Features used to identify neonates with risk factors for, or clinical features of possible serious bacterial infections (PSBI) in international guidelines merit re-evaluation, due to a massive shift to facility-based deliveries in LRS and a changing spectrum of pathogens. I plan to reassess methods for identifying neonates with, and at risk of PSBI in LRS, to derive a patient-centred, contextually appropriate decision-support tool. I will assess contextual influences on clinician decision-making e.g. resource availability, and seek families’ opinions of risk trade-offs in clinical decision-making about PSBI in Zimbabwe. I will use national neonatal electronic healthcare records to prospectively evaluate features and risk factors for PSBI across a Zimbabwean province, with senior clinician diagnosis of PSBI and/or positive microbiology as the primary outcome. I will use machine learning to develop and externally validate a clinical prediction model. Qualitative data be incorporated into the model to develop a clinical decision-support tool to triage neonates into high/moderate/low risk. I will pilot the tool in preparation for large-scale evaluation after this Fellowship. |
| 28/03/2023 |
£799,814 |
UNIVERSITY OF EXETER |
Optimisation of glucose-lowering treatment in type 2 diabetes is important to reduce the risk of patients developing microvascular and macrovascular complications. Despite the known heterogeneity of type 2 diabetes, and the multiple drug classes available with different mechanisms of action, treatment decisions do not take into account the clinical characteristics of individual patients. The aim of this study is to improve clinical outcomes in type 2 diabetes by developing a universal approach to optimise therapy choice for individual patients based on their characteristics. To achieve this, I will apply a novel outcomes-based data science approach to conduct studies using routine clinical data (discovery) and individual-level data from clinical trials (validation). This will allow the discovery of patient characteristics that alter clinical outcomes (cardiovascular and renal disease, glycaemic response, weight, and tolerability) on all major type 2 diabetes therapies after metformin, and the development and validation of treatment selection algorithms to provide individualised estimates of risk/benefit with each medication. Reproducibility will be tested in people of different ethnicities to assess generalisability. Studies will prioritise routine clinical features meaning the approach developed is low-cost, with the potential to lead to the development of a practical universal approach to treatment individualisation applicable worldwide. |
| 28/03/2023 |
£428,452 |
UNIVERSITY OF LEEDS |
When, how, and why did babies come to be seen as moral agents? Constructing Moral Babies investigates this phenomenon among so-called "experts" of babyhood: pedagogues, theologians, physicians, scientists, and childrearing matrons of the nineteenth century. The moral life of babies - their interior lives - has increasingly intrigued modern society, evident in the emergence of so-called "baby labs" in universities and greater awareness of infants' mental health worldwide. Babies are frequently framed as active agents who learn to manage their emotions in conjunction with their main carers. However, we know little about the origins, and therefore significance, of these trends. Drawing on history and philosophy of science and medicine, feminist theology, sociology, childhood studies, and material culture, this study will develop the first comprehensive history of infants that generates new historical and philosophical narratives of infancy. Infancy itself remains neglected, despite influential scholarship examining other life stages: childbirth, childhood, teenagehood, and older age. This project places infants at the center of analysis, rather than as dependents. By interrogating archives, published texts, and objects associated with the "science" of infancy the project will fundamentally shift our understanding of infants and consequently, our treatment of them in both public and private spaces. |
| 28/03/2023 |
£744,620 |
UNIVERSITY COLLEGE LONDON |
To external observers, animal behaviour has a puzzling yet ubiquitous property: its variability. Because animals adjust their decisions not only based on external inputs, but also on their internal state, similar situations can lead to different behavioural outcomes. How does such behavioural variability arise in the brain? In mice, correlative evidence points to a key role of frontal cortex, although its computations, networks, and causal mechanisms are unknown. Current challenges are that internal states are complex and hidden to experimentalists, and reliably observing large populations of neurons across states and brain regions is difficult. To solve these issues, I propose to combine behaviour, large-scale chronic recordings, and optogenetics to test the hypothesis that frontal cortex underlies behavioural variability. First, using high-throughput Neuropixels recordings, I will uncover the computations frontal cortex deploys to integrate external and internal signals and drive behaviour. Second, using functional ultrasound imaging and multi-area Neuropixels recordings, I will characterize how variability-related information flows in the networks supporting frontal cortex. Finally, using optogenetics, I will causally test the role of frontal cortex in driving behavioural variability. The results will provide fundamental advances in our understanding of the neural basis of behavioural variability, opening new avenues for future research. |
| 28/03/2023 |
£748,017 |
UNIVERSITY OF EDINBURGH |
Depression during adolescence and early adulthood is associated with a range of psychological, social and behavioural impairments. Worryingly, depression is rising in young people, with the reasons and repercussions not yet understood. My research will accelerate understanding of the nature, causes and consequences of depression in young people, and transform findings into knowledge that informs future intervention and prevention strategies that are person and time specific. During this award, I will use high quality datasets, causal inference methods and longitudinal models to stratify individuals into different youth depression trajectories that may each have more circumscribed characteristics, aetiologies and outcomes. I will examine what risk factors are causal for poorer depression trajectories and identify sensitive periods of youth depression that lead to poorer downstream consequences, thereby highlighting timely opportunities for future interventions and preventions. Finally, I will use intensive longitudinal data to identify potentially modifiable risk factors for depression trajectories in real-time, that could highlight novel pathways informing more personalised and timely treatments. Upon the conclusion of this award, I will have completed a series of interlinking studies that triangulate evidence to deliver improved understanding of youth depression trajectories and provide a platform to implement these findings to future treatment strategies. |
| 28/03/2023 |
£535,941 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
Whereas we are aware of the roles genetics play in the development of major depressive disorder (MDD) (mainly from research among Caucasian populations), there remains a dearth in literature about specific genes affecting susceptibility among continental Africans. Moreover, African ancestry individuals harbour marked genetic diversity compared to persons from the rest of the world. To address this gap, I propose to investigate the genetic risk factors for MDD among continental Africans by (i) performing a genome-wide association study of MDD among pooled data from three ethnically diverse African cohorts (GPC, NeuroGAP and DepGenAfrica cohorts, n~23,776), (ii) replicate findings in an African/African-admixed PGC Cohort (n=198,497), (iii) meta-analyse findings from these combined cohorts (n~23,776 + n=198,497) and (iv) combine these results with the rest of the MDD PGC dataset (n~23,776, n=198,497 and n=1,622,192) in a final meta-analysis. Transferability of variants and MDD polygenic risk scores between the continental African cohort and PGC cohorts will also be determined. In the continental Africans dataset, causal relations for MDD will be investigated and a machine learning model for prediction of MDD will be built. This study has potential to identify mechanistic pathways and ultimately lead to development of new molecules or drug targets for MDD. |
| 28/03/2023 |
£705,708 |
UNIVERSITY OF BRISTOL |
The pandemic potential of avian influenza considering life-long influenza infection histories, both in animal and human populations, is an unresolved question. The age distributions of influenza cases in pandemics and avian influenza spillover events suggest prior infection as an important factor. In this fellowship, I will develop an immuno-epidemiological framework to understand the interplay between life-histories of influenza infection in birds, humans and at the animal-human interface to predict pandemic conditions. Using transmission models for wild birds and humans I will investigate the hypothesis that subtype-specific infection in early life influences future susceptibility and disease dynamics of influenza A. High-throughput multiplex immunoglobulin and surrogate neutralisation assays will be developed and deployed to longitudinal birth cohorts of humans and wild birds of long-life spans. Serological profiles will be used to reconstruct subtype-specific infection histories. From this, I will calculate the frequency of influenza infections in the host population and evaluate cross-reactivity. Sero-epidemiological findings will be integrated back into mathematical models to determine conditions for pandemic potential. This work will deepen our understanding of the influenza immunity landscape for zoonotic disease control and pandemic prediction. |
| 28/03/2023 |
£1,013,209 |
UNIVERSITY COLLEGE LONDON |
The work in my proposal aims to transform our understanding of hyperkinetic movement disorders (chorea, dystonia, myoclonus, tics and tremor). I will apply an innovative combination of computational methods to leverage meaning from current clinical classification of phenotype. I will then flip the perspective to analytically challenge traditional approaches and probe existing assumptions for novel insight. Key goals are: 1) Define the feature space and boundaries of each phenotype 2) Model the behavioural signatures for each phenotype 3) Evaluate which behavioural tasks have the most ‘signal’ for each phenotype 4) Reveal how a data-led clustering of hyperkinetic movement compares to current clinical classification. An early-career award would be based at the Gatsby Computational Neuroscience Centre, an opportunity to acquire an exceptional training in state-of-the art pattern recognition and machine learning and apply computational methods to ambitious and carefully curated behavioural datasets. All datasets and analysis will be published online as resources for the international movement disorders community. |
| 28/03/2023 |
£666,336 |
UNIVERSITY OF CAMBRIDGE |
I will conduct in-depth investigations into the mutagenic impacts of resection around DNA double-strand breaks (DSBs). I will use a combined approach to first quantify the lengths of the different types of DSB resection and follow this with siRNA mediated depletion and chemical inhibition of all major resection enzymes to comprehensively elucidate the mechanisms of resection. Little is known about resection lengths at DSBs, and the overlapping roles of the long-range resection enzymes BLM, DNA2, EXO1 and EXD2 are poorly characterised. What determines recruitment of one long-range enzyme over another to a particular DSB and how the lengths of resection vary between them is unknown. Given that resection appears to be the major mutagenic process of DSB repair, a detailed understanding of these processes and their regulation is crucial for understanding DSB-induced mutagenesis. Finally, I will take various approaches to investigate the mutagenic impacts of these processes, identifying all mutations from rare point mutations to large-scale chromosome rearrangements, and crucially defining how these various enzymes are associated with this mutagenesis. The findings from this project will yield new insights into the mutagenic mechanisms of DSB-repair, significantly advancing our understanding of carcinogenesis and cancer progression, as well as other DSB-related diseases. |
| 28/03/2023 |
£746,745 |
UNIVERSITY COLLEGE LONDON |
My research will combine my expertise in live-cell, high-content microscopy to develop and advance imaging and analysis platforms to investigate the spatiotemporal regulation of the intracellular lifecycle of individual viral particles. I will use this to provide key mechanistic insights into HIV infection of human primary CD4+ T-cells and determine how the virus hijacks the host cell machinery to drive successful infection. Key goals are: Advance high-content, super-resolution, live-cell imaging and deep learning analysis to track the molecular phenotypes associated with successful virus infection of cells at a population scale. Dissect the cell biology of key stages of the HIV viral life cycle at single-particle resolution (entry, uncoating, nuclear import) in primary T-cells, mapping the kinetics and contributions of molecular interactions between virus and host cell cofactors. Determine the cell biology dynamics that underpin heterogeneity in infection outcome and molecular determinants of host cell permissivity. By pioneering the use of super-resolution microscopy and machine learning to investigate the cell biology of virus infection at the single-virion and single-cell level I will deliver an integrated mechanistic model of the relationship between molecular virus-host interactions and infection outcomes. Exploiting HIV as a paradigm virus, I will innovate approaches transferable to other viruses. |
| 28/03/2023 |
£1,143,309 |
UNIVERSITY OF OXFORD |
Background Tumour cells evolve by acquiring a diverse repertoire of copy number variants, large chromosomal rearrangements and DNA mutations, leading to clonal diversity. Tumour-infiltrating T-cells, a critical component of the tumour microenvironment, control the growth of clonal cells naturally and in response to treatments such as immunotherapy. Despite its importance, an integrated view of the phenotypic and spatial co-evolution of clonal and tumour infiltrating T-cells has been unexplored. Slide-seq is a novel foundational platform for multi-omic spatial tissue analysis. The resolution, sensitivity and flexibility of the platform now allows for an integrated spatial map of DNA, RNA and now T-cell receptor sequences (TCRs) in human tissue. Chronic lymphocytic leukaemia (CLL), a common and incurable haematological malignancy, is an excellent model for the study of the spatial co-evolution of tumour clones and the microenvironment. Aims 1. Develop-tumour-specific mutation profiling with Slide-seq. 2. Generate a computational platform for spatial-omic data integration. 3. Determine the co-localisation patterns of tumour clones and T-cells in lymph node biopsies in CLL and Richter’s transformation. Outcome Completion of these objectives should advance our understanding of the interactions between tumour and host immunity. This will inform our understanding of cancer progression and potentially on novel microenvironment-directed therapies. |
| 28/03/2023 |
£613,630 |
DIAMOND LIGHT SOURCE LTD |
The family Bornaviridae within the order Mononegavirales comprises enveloped negative sense single-stranded RNA viruses that cause encephalopathies with an often-fatal outcome in mammals, birds, and reptiles. In recent years, bornaviruses have emerged as zoonotic pathogens and have caused human fatalities on multiple occasions. In the absence of curative treatment, there is an urgent requirement for anti-bornaviral therapeutic strategies. As the sole viral surface antigen, the bornavirus glycoprotein (BorV-G) is responsible for receptor recognition and membrane fusion, thus constitutes the primary determinant of cell, tissue, and host tropism. BorV-G is genetically distinct from other characterised viral fusogens encoded by related virus families (e.g., Rhabdoviridae, Filoviridae) and its detailed structural information is lacking. The proposed research aims to utilise an integrative approach to provide a holistic understanding of BorV-G architecture and functionality. X-ray crystallography and single-particle cryo-EM will be employed to study BorV-G assemblies. Characterisation of G-receptor and G-antibody interactions will define the molecular determinants of tropism and the minimal components required for immunogen design. Cryo-ET and subtomogram averaging of cell surface-displayed BorV-G will assess the native G architecture in the context of vaccine-derived BorV-G processing. This work will provide a molecular-level blueprint that may guide the development of anti-bornaviral prophylactics. |
| 28/03/2023 |
£1,104,010 |
UNIVERSITY OF OXFORD |
Transplantation is the gold standard treatment of choice for many end-stage organ diseases. However, immunosuppressants can result in life-threatening infection and cancer, which are leading causes of death after the 1st year post-transplant. There is little improvement in long-term graft attrition compared to previous eras. The consequences of potent immunosuppression extend to autoimmune diseases: 30% of sufferers remain refractory to immunosuppressive therapy. Novel therapeutic strategies are urgently required to improve outcomes. Regulatory B cells (Breg) can control immune responses in animal models of transplantation and autoimmunity; Breg deficiencies are associated with poor clinical outcomes. I have developed novel methods to expand human Breg (expBreg) with in vivo function, as a precursor to cell therapy. In this new proposal, I will build on this work, using transcriptomics, proteomics, gene editing and humanised mouse models to: i) clarify human expBreg phenotype and ontogeny; ii) identify immunoregulatory signalling pathways and Breg-specific drug targets iii) assess and improve function of kidney transplant recipient-(KTR)-derived Breg of patients with poor clinical outcomes in vivo, as personalised therapy; iv) interrogate stability and specificity of antigen-specific expBreg cell therapy in vivo. My findings will have translational value for autoimmune disorders, bringing Breg cell therapy closer to the clinic. |
| 28/03/2023 |
£750,300 |
UNIVERSITY OF EDINBURGH |
This ethnographic study examines the booming ‘FemTech’ industry as a window onto menstrual health in the UK and US, against the backdrop of increased public attention to periods, endometriosis, hormones, abortion, and inequities in women’s health provision. Attending to menstruation-adjacent issues challenges conventional framings of disease, illuminates whose pain is considered ‘normal,’ and de-centres fertility by foregrounding women's and gender minorities’ lived experience. However, using new and ‘data-driven’ technologies to mediate this transformative potential introduces issues of privacy, profit, and control. Private companies are leveraging mass aggregate data to shed light on under-researched menstrual issues; they are providing services and information to consumers, recruiting healthcare professionals’ expertise, and partnering with universities, while clinical research itself increasingly involves ‘big data’ technologies. This study investigates transformations in public and private institutions of knowledge production and care provision by engaging with menstruating people who might use FemTech, tech workers and entrepreneurs, scientists, clinicians, and period activists. By grappling with the tension in critical scholarship between the emancipatory possibilities of valorising periods, and dystopian aspects of surveillance, this project will reshape conversations in medical and cultural anthropology, STS, and gender studies, with implications for the development of responsible FemTech itself. |
| 28/03/2023 |
£859,090 |
UNIVERSITY OF DUNDEE |
Activation of mitophagy signalling is an emerging therapeutic concept in Parkinson’s disease, supported by mutations in upstream components (e.g. PINK1/Parkin) in patient sub-groups. We will develop novel methodology to discover molecules that stabilise a master regulator of mitophagy and boost signalling. This will deliver two transformative advances: 1. Provide specific chemical tools that can validate pharmacological activation of mitophagy in cells and in vivo as a therapeutic concept to treat Parkinson’s disease and 2. Validate new methodology that can be readily transferred to other concepts reliant on effecting target protein stability. We will use the concept of inducing proximity of proteins with small molecules to achieve targeted protein stabilisation (TPS). Induced proximity methods have been used with success for targeted protein degradation (TPD), but TPS offers a unique strategy for directly restoring downregulated biological pathways. Despite the potential benefits, TPS methodology is currently limited and has not been applied in the context of rescuing neuronal function. Firstly, a chemical genetics approach will be developed to validate target proteins that activate mitophagy in neurons when stabilised. We will then aim to discover targeted protein stabilisers that can demonstrate selective mitophagy activation in vivo and that penetrate the blood brain barrier. |
| 28/03/2023 |
£768,560 |
UNIVERSITY OF OXFORD |
Early human B cell response, including the extrafollicular (EF) response, are poorly characterised but have a vital role in rapid antibody production. I propose that this pathway has longer-term consequences in the lymph node (LN) microenvironment and metabolite availability affecting cell fate. This project will integrate human in vivo fine-needle aspirant samples with ex vivo LN culture slice models to characterise and validate differentiating human early B cell trajectories. Spatial transcriptomics, complemented by multiplex imaging, will spatially verify a transcriptomic EF B cell gene signature. Early B cells in human LNs responding to a primary antigen encounter from a xenogenic protein challenge study will be characterised by scRNAseq and clonal analysis. The recall memory response and prediction potential of early human B cells will be evaluated by an intradermal re-challenge using in situ hybridization. Computational metabolism analysis with ex vivo LN slice functional validation will determine metabolic differences distinguishing early B cell fates and how they can be altered. Together, I will address a fundamental immunological question about early human B cells and their impact on long-lived antibodies. Findings may facilitate tailored next-generation vaccination and adjuvant strategies to enhance long-term memory responses. |
| 28/03/2023 |
£648,444 |
UNIVERSITY OF EDINBURGH |
My post-doctoral fellowship proposes a bold and ambitious programme of work to address the urgent health and social challenge presented by lesbian, gay, bisexual, trans and queer (LGBTQ+) suicide. Whilst it is well established that LGBTQ+ people are more likely than heterosexual, cisgender (non-trans) people to think about and attempt suicide globally, there is a lack of research seeking to understand why this health inequality exists or how to prevent it from the perspectives of LGBTQ+ people with lived experience of suicidal distress. My post-doctoral fellowship will address this tragic health inequality, working in interdisciplinary and cross-sectoral ways to enhance understandings of LGBTQ+ suicide and demonstrate the transformative potential of tailoring suicide prevention approaches when working with marginalised or oppressed groups. This ambitious aim will be achieved through four inter-related work packages, which have been co-designed and will be co-produced with community and practitioner partners. WP1 will map service provision for LGBTQ+ people experiencing suicidal distress; WP2 will explore lived experiences of LGBTQ+ suicide; WP3 will learn from deaths by suicide, working with people bereaved by LGBTQ+ suicide; whilst WP4 will draw together learning from WP1-3, co-producing a toolkit tailoring suicide prevention practices for LGBTQ+ communities in the UK. |
| 28/03/2023 |
£1,091,988 |
UNIVERSITY OF CAMBRIDGE |
A major challenge for early cancer detection is predicting which pre-cancerous clones will progress to cancer. In blood, pre-leukemic mutation acquisition is increasingly common with age. In most, this so-called ‘clonal haematopoiesis’ does not progress to cancer, but if clonal expansion and further mutation acquisition occurs, acute myeloid leukaemia (AML) can develop. Clonal haematopoiesis can also progress to AML via myelodysplastic syndrome (MDS), a course associated with particularly poor prognosis. Approximately 30% of individuals with MDS will progress to AML and so, not only is a better understanding of MDS important, but its high rate of transformation, compared to clonal haematopoiesis, makes MDS a model system to better understand factors that drive clonal evolution towards or away from AML. Harnessing the power of longitudinal samples and multi-omics, this project aims to answer: How does clonal evolution differ in individuals with MDS who progress to AML? What effect do health and lifestyle factors have on driving/ impeding clonal evolution? Can longitudinal multi-omic profiling in MDS patients improve AML early detection and reveal clinically relevant molecular pathways and potential therapeutic targets? Answering these questions will be invaluable for accelerating development of AML early detection tools and therapies to prevent progression to AML. |
| 28/03/2023 |
£595,441 |
UNIVERSITY OF OXFORD |
How does the human brain orchestrate information processing to enable cognition? Disentangling qualitatively different kinds of information has revealed that the brain regions supporting complex cognition interact synergistically: the information they provide together goes beyond the sum of their individual contributions. Humans also exhibit greater brain synergy than non-human primates, raising the prospect of harnessing synergy to understand human intelligence, and guide the development of AI systems. To realise this potential, we must understand how synergy emerges from the brain’s complex organisation, and its computational advantages and drawbacks. Does synergy come at a cost of increased vulnerability to injury or disease? To fill these gaps, I will design AI architectures optimised to exhibit high synergy, and assess their computational capacity and limitations. Leveraging large-scale neuroimaging datasets, I will investigate how brain synergy is reshaped across health and disease, obtaining an information-specific characterisation of human cognition. I will develop an innovative combination of biophysical modelling and "neuromorphic" neural networks constrained by the brain’s empirical wiring: systematically perturbing this joint model with disease-realistic lesions will dissect which features of brain organisation shape the resulting patterns of synergy. Overall, this project aims to establish an information-theoretic lens to illuminate biological and artificial intelligence. |
| 28/03/2023 |
£729,706 |
UNIVERSITY OF SHEFFIELD |
Breast cancer is the most commonly diagnosed cancer worldwide, with an estimated 2.3 million new cases globally and an incidence of 50.4 per 100,000 in Southern Africa in 2020. Breast cancer incidence rates in sub-Saharan Africa increased rapidly. This study will use a discrete event simulation approach to determine and explore the impact of health systems constraints on breast cancer care in South Africa. We will estimate the costs from a payer’s perspective and the cost-effectiveness of constraints relaxation required to reduce health system delays in diagnosing and treating breast cancer. We will use 2 breast care clinics, a public and private clinic in Johannesburg, South Africa, as case studies. In light of the rollout of universal health coverage through the National Health Insurance (NHI), the study will also test how a collaborative community approach (where public and private sector providers work together to achieve common objectives and outcomes and improve health system performance) can result in technical efficiency through resource and risk pooling. |
| 28/03/2023 |
£580,549 |
UNIVERSITY OF MANCHESTER |
A criticism of economic evaluations conducted to determine if a new heath intervention is a good use of resources is that they assume that every eligible patient will receive the intervention and it will be delivered in an optimal way. However, many barriers exist in the health system which may reduce the benefits of a new intervention or increase its costs. This means that the cost-effectiveness of an intervention depends on the way it is implemented in practice, and that it may not be cost-effective to implement an intervention unless investment is provided alongside the intervention to address these barriers. This fellowship will explore how implementation barriers can be identified, incorporated into health economic evaluations of interventions in cancer screening, and their impact on costs, outcomes for patients, and cost-effectiveness quantified. Examples of interventions currently under development in cervical screening and risk-stratified breast cancer screening will be used as case studies. The outputs of this research programme will aid decision makers in determining if investments in the health system or further research are required, or will be beneficial, in ensuring that health benefits to patients are maximised while the cost of the intervention is minimised. |
| 28/03/2023 |
£689,786 |
QUEEN'S UNIVERSITY BELFAST |
Financial toxicity (FT) refers to the objective financial burden and subjective financial distress that occurs as a result of cancer treatment. In the United Kingdom (UK) which has a publicly funded health system, evidence suggests that objective financial burden comes mostly from direct non-medical costs (e.g., fuel for transportation, heating, special foods) and indirect non-medical costs (e.g., loss of income). People living with cancer and faced with FT may experience worse financial well-being (e.g., loss of savings, increased dependency on borrowing, and failure to make mortgage payments), lower health-related quality of life, and additional mental health problems (e.g., psychological stress and anxiety). The ongoing rapid rise in energy costs and increased likelihood of a recession are likely to make the situation critical in the short to medium term as household budgets generally come under increased pressure. Therefore, there is an urgent need to examine FT, understand its effects and potential mitigations within a changing economic environment. This research aims to investigate the situation, causes and consequences of FT for UK cancer patients, survivors, and their families during a cost-of-living crisis as well as potential solutions. The analysis and improved understanding will inform measures that may mitigate the impact of FT. |
| 28/03/2023 |
£626,692 |
UNIVERSITY OF CAMBRIDGE |
Myelination of neuronal axons is fundamental for rapid and efficient signal conduction, yet a detailed understanding of how the molecular contacts between the myelin sheath and axon are established remains poorly characterised. This septate-like junction, known as the paranode, forms a diffusion barrier that prevents aberrant protein translocation between the myelinated axon and the nodes of Ranvier and limits short-circuiting of the action potential. The importance of this junction is highlighted by the severe and devastating diseases that arise as a consequence of its disruption. In the nervous system, this cell-cell contact is mediated by the myelin-specific protein NF155, axon-specific proteins CNTN1 and Caspr, and interactions with specific glycosphingolipids in the plasma membrane outer leaflet. However, a molecular understanding of this multifaceted contact site, and therefore how the paranode stabilises myelination, is currently lacking. My preliminary data suggests a complex and intriguing mechanism with the potential to shift the way in which we investigate membrane-protein contacts. This proposal seeks to advance our understanding of how the healthy nervous system is myelinated through in-depth molecular characterisation of the paranodal complex and gain insight into the pathophysiology of demyelinating autoimmune neuropathies, laying the foundations for the development of new targeted treatment strategies. |
| 01/02/2023 |
£1,970,587 |
QUEEN MARY UNIVERSITY OF LONDON |
Preterm birth is the leading cause of under-5 mortality. There is emerging evidence that heat stress in pregnancy is associated with preterm birth; however, the underlying mechanisms are uncertain. Our hypothesis is that extreme heat propagates induction and amplification of inflammation, and reduced integrity of fetal membranes, leading to premature rupture and preterm birth. An interdisciplinary team of UK and Zimbabwean scientists will: Determine the relationship between extreme heat and prematurity in rural Zimbabwe. Explore associations between extreme heat and inflammatory mechanisms underlying preterm birth. Evaluate the effects of extreme heat, inflammation and mechanical stimulation on structural integrity and function of fetal membranes using a human fetal chip model. First, we will leverage a well-characterised cohort of pregnant women in a rural district of Zimbabwe affected by climate change, to collect longitudinal biological samples, map household locations, and deploy high-resolution sensors to measure temperature and humidity. Second, we will explore associations between extreme heat and preterm birth, and define underlying inflammatory pathways in the maternal systemic circulation and at the materno-fetal interface. Finally, we will use human explant and 3D co-culture models to study the mechanical properties and cellular responses of fetal membranes to extreme heat. |
| 01/02/2023 |
£319,301 |
IMPERIAL COLLEGE LONDON |
Pregnant women from socioeconomically disadvantaged populations living in tropical climates are most vulnerable to the effects of climate change. Extreme heat has been linked to preterm birth, fetal growth restriction, stillbirth and preeclampsia. We aim to describe how extreme heat leads to these outcomes by studying in detail heat exposure and physiological responses in women across India. Our study involves three linked activities. We will use the Garbh-Ini retrospective cohort (10 000 mother-baby pairs) to identify biomarkers and clinical factors associated with heat exposure and adverse outcomes. We will also describe how the fetal heart rate changes with heat exposure by studying a large database of 110 000 antenatal fetal heart traces recorded across India. These findings will inform a prospective, matched cohort study of 600 women vulnerable to heat stress across three different climate zones. Using state-of-the-art climate, imaging and laboratory diagnostics, we will study how heat exposures affect maternal, placental, fetal and lactational function. We will capture women’s lived experiences with heat, identifying opportunities for local heat adaptation. As findings emerge, we will bring together policymakers, researchers, clinicians and people living with heat to develop practical policies and actions that will protect women and their babies. |
| 01/02/2023 |
£1,833,067 |
TRANSLATIONAL HEALTH SCIENCE AND TECHNOLOGY INSTITUTE |
Pregnant women from socioeconomically disadvantaged populations living in tropical climates are most vulnerable to the effects of climate change. Extreme heat has been linked to preterm birth, fetal growth restriction, stillbirth and preeclampsia. We aim to describe how extreme heat leads to these outcomes by studying in detail heat exposure and physiological responses in women across India. Our study involves three linked activities. We will use the Garbh-Ini retrospective cohort (10 000 mother-baby pairs) to identify biomarkers and clinical factors associated with heat exposure and adverse outcomes. We will also describe how the fetal heart rate changes with heat exposure by studying a large database of 110 000 antenatal fetal heart traces recorded across India. These findings will inform a prospective, matched cohort study of 600 women vulnerable to heat stress across three different climate zones. Using state-of-the-art climate, imaging and laboratory diagnostics, we will study how heat exposures affect maternal, placental, fetal and lactational function. We will capture women’s lived experiences with heat, identifying opportunities for local heat adaptation. As findings emerge, we will bring together policymakers, researchers, clinicians and people living with heat to develop practical policies and actions that will protect women and their babies. |
| 01/02/2023 |
£1,946,070 |
THE AGA KHAN UNIVERSITY, PAKISTAN |
Extreme heat adversely affects pregnant women and babies, and is associated with hypertension, miscarriages, stillbirths, and low-birthweight. An in-depth study is needed on pathways and the direct and indirect effects of extreme heat during pregnancy and early life, especially in developing countries where there is a dearth of existing evidence. We aim to assess the impact of extreme heat stress on maternal, fetal, and newborn health and how it interacts with confounding effects of social determinants, nutrition, and seasonal drivers. To understand the biological mechanisms of increased vulnerability to extreme heat exposure, we plan two work packages: (1) capitalisation of available large datasets and bio-banked laboratory specimens from previous large trials/studies of pregnancy outcomes: (2) prospective, population-based, birth cohort (n=6000 pregnant women) from peri-urban and rural settings in Pakistan, linking environmental heat measurements at household/individual level with serial physiological measurements in a subset (n=3000) linked to pregnancy, fetal and birth outcomes. We will also assess the processes and pathways of these effects in the subset by measuring clinical variables (including Echo, ultrasound, ECG), and urine and blood biomarkers related to adverse effects of extreme heat on maternal, fetal and newborn health. |
| 01/02/2023 |
£2,050,809 |
UNIVERSITY OF SYDNEY |
The rising threat of extreme heat due to climate change is set to disproportionately affect disadvantaged and vulnerable populations, including pregnant women. Clinicians, Researchers, and Policy Makers working in maternal health are uniquely positioned to better understand and educate about the impact of climate change to ensure healthy future generations. There are significant gaps in our understanding of which period of pregnancy is the most vulnerable, how thermoregulatory capacity changes throughout pregnancy, and what underlying mechanisms are responsible for increased risks of observed adverse outcomes following extreme heat exposure. This proposed project co-led by Professors Adrienne Gordon and Ollie Jay will build on existing successful partnerships between the University of Sydney, International Centre for Diarrhoeal Disease Research, Bangladesh, and the Sitaram Bhartia Institute of Science and Research, New Delhi. Specifically, we will perform a pregnancy cohort study in 2 countries, and a climate chamber study in Sydney Australia, which will collectively contribute to the creation of a pregnancy-specific thermo-physiological model to determine heat-health risk for women throughout pregnancy. Our model will: 1) Improve future health outcomes by determining heat-health risks for women throughout pregnancy 2) Be accessible and applicable to clinicians, researchers and policy makers in low- and middle-income communities. |
| 01/02/2023 |
£815,737 |
UNIVERSITY COLLEGE LONDON |
Extreme heat events (EHE) increase risk of hyperthermia. Maternal hyperthermia is associated with a range of birth defects, particularly neural tube defects (NTDs). Maternal exposure to EHE during the critical period of pregnancy, when the embryo undergoes neurulation, may increase susceptibility to NTDs through additive interactions with nutritional and genetic risk factors. Highest rates of NTDs occur in low- and middle-income countries (LMIC), many of which are prone to EHE, and have a disproportionately higher prevalence of nutritional risk factors, including inadequate folate intake. The effect of increasingly frequent and severity of EHE on NTD frequency are likely to manifest most profoundly in LMIC. Improved understanding of the mechanisms underlying heat-induced NTDs and identification of potential protective interventions is crucial to mitigate effects of extreme climate. This project will use mouse genetic models of NTDs, in embryo culture and in vivo, to identify heat-sensitive components of neurulation and determine whether folate metabolism is impaired in heat-exposed embryos. We will interrogate three-way heat, genotype, maternal diet interactions and test whether supplemental nutrients, such as folic acid, can prevent hyperthermia-related NTDs. Identification of protective nutrients, as a modifiable variable in heat-induced NTDs, may be applicable to NTD prevention in ‘at-risk’ human populations |
| 01/02/2023 |
£2,056,943 |
UNIVERSITY OF LEEDS |
Exposure of the mother to extreme heat events while pregnant are reflected in the life course health of the offspring. A critical time of exposure is during the peri-implantation period of pregnancy when: 1) epigenetic determination of cell fate occurs, 2) cues to establish organ systems are established, and 3) molecular and biophysical interactions between the mother and the embryo are also established. There are unknown mechanisms by which acute extreme heat causes peri-implantation pregnancy loss and affects life course health. Mitigation of this is critical if we are to ensure life-course health of babies. We aim to: Identify how acute extreme heat alters health of the offspring Determine how heat stress alters life-course development of organ systems Establish intervention strategies to mitigate against heat-exposed changes to life-course health in offspring Taking an interdisciplinary approach by harnessing our expertise in 1) bioengineered embryo-maternal interaction models, 2) comparative developmental biology of the pig and mammal systems, 3) computational evolutionary biology, we will determine conserved mitigation pathways for intervention in humans to understand the mechanistic biology of heat stress and to identify intervention strategies. |
| 01/02/2023 |
£2,049,397 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
Maternal exposure to acute and chronic heat stress predicts multiple adverse birth outcomes with long-term impacts, but pathophysiological pathways remain undefined. West Africa is particularly affected by extreme heat. This project seeks to describe the physiological, biochemical and structural changes in pregnancy due to heat stress. Five integrated work packages are proposed. WP1 will synthesise global evidence for human and non-human primate maternal responses to heat exposure in pregnancy. WP2a will employ environmental chamber studies (FAME Lab Athens) to determine heat stress thresholds for acute maternal, fetal, and materno-placental physiological stress accompanied by a simplified heat-chamber protocol in The Gambia (WP2b). WP3 will be a longitudinal cohort study of 762 pregnant women conducted across 3 heat gradient environments in The Gambia. Outcome measures include maternal physiology & sleep quality (wearable device), materno-placental interface (placental blood flow), pregnancy outcomes and newborn neurobehaviour. WP4 will use placenta samples collected in WP3 to assess the impact of heat stress on placental structure, function and molecular changes. WP5 will use Gambian community workshops to co-design adaptation strategies building on evidence from WPs1-4. This project will build local research capacity, foster international collaborative links and engage communities, key stakeholders and policy makers. |
| 01/02/2023 |
£1,914,745 |
UNIVERSITY OF WESTERN AUSTRALIA |
Australia has a diverse climate and population. This context provides a unique opportunity to define the health implications of extreme heat exposure during pregnancy and extrapolate findings to a global context. This multidimensional proposal encompasses individual, population, and discovery science data. Three key aims encompass our proposal: 1) Lived Experience which includes Indigenous and recent migrant knowledge, 2) Environmental Epidemiology across the breadth of Australian climate zones, and 3) Biological Mechanisms utilising our established sheep model of pregnancy in environmentally controlled housing and human samples. These aims, along with community co-design and consultation, will lead to the development of approaches to minimise the adverse effects of extreme heat in pregnancy. The deliverables will include health education approaches for individuals and health care workers, identification of clinical applications for health management of pregnant patients in the heat, and development of new public health and policy approaches to preparedness, responsiveness, and secondary prevention for pregnant women in extreme heat. Key words: pregnancy, heatwave, physiology, epidemiology, at-risk populations. |
| 31/01/2023 |
£2,605,888 |
UNIVERSITY OF CAPE TOWN |
Adolescence is characterised by profound changes in brain development, sleep and circadian biology making this age group vulnerable to a variety of mental health challenges, which have the potential to persist into adulthood. We propose a longitudinal study using a range of complimentary techniques to identify sleep- and circadian-related mechanisms through which adolescents may either develop, or demonstrate resilience to, depression and anxiety. We will work with lived-experience experts from the design to implementation and dissemination phases to strengthen our approaches. Critically, we will examine how the trajectory from sleep- and circadian-related changes to depression and anxiety during adolescence differs in lower, medium and higher income communities from a country in the global North (United Kingdom) and one in the global South (South Africa) so that the research findings are applicable across geographical, societal and cultural contexts. The goals are to identify how (mechanisms) and when (during adolescent development) symptoms emerge, to guide future interventions that both prevent and provide early treatment of adolescent depression and anxiety, thereby reducing chronic adult depression and anxiety and reducing future burden of care on health services. |
| 31/01/2023 |
£1,754,127 |
UNIVERSITY OF KENT |
This project addresses the unmet challenge of the role of sleep and circadian health in precipitating and perpetuating adverse mental health outcomes in healthy and clinical populations. We will a) use a multidimensional approach to index sleep and circadian health; b) explore the dynamic interplay between sleep, circadian rhythm, and cognitive and emotional processing in healthy and clinical populations; c) examine a model of sequential comorbidity, from sleep disturbances to mental health disorders, through assessing the perturbation from variable work schedules using shift work as a naturalistic manipulation of the impacts on sleep, cognition, psychotic-like and emotional symptoms; and d) explore the role of cognitive control mediating the impacts of sleep/circadian disturbances on mental health. We will study the following 3 groups with increasing potential for sleep/circadian disturbance and adverse mental health consequences: healthy participants with regular work schedules, shift workers with variable work schedules and patients with depression & psychosis who have disturbed sleep/circadian disturbance. Understanding the dynamic relationship between circadian biomarkers, sleep, cognition and mental health outcomes is critical in order to be able to develop interventions to meet the outstanding challenge of normalising sleep/circadian rhythm related behaviour in the early stages of psychotic and depressive illness. |
| 31/01/2023 |
£3,154,554 |
UNIVERSITY OF OXFORD |
In this proposal we hypothesise that there is a bidirectional relationship between sleep and circadian rhythms and functional brain networks that play a key role in mental health. In particular, the salience network – a network of brain regions that directs attention – has been implicated in both sleep disorders and a range of mental illnesses including depression, anxiety and psychosis. This common mechanism provides a novel hypothesis for exploring the bidirectional links between sleep and circadian rhythm disruption (SCRD) and mental illness. We will explore these mechanistic links using both human participants and mouse models. Firstly, we will explore how effective sleep interventions modify disease-relevant functional networks. Secondly, we will interrogate existing large datasets to investigate associations between functional networks, sleep and mental health traits. Thirdly, we will use mouse models to characterise the neural circuits underlying the bidirectional links between SCRD and functional networks - such as the salience network - that are known to play a role in mental health. Together, our proposed studies will provide the first evidence for common neural mechanisms underlying the links between SCRD and mental illness, providing new biomarkers and opportunities for therapeutic intervention. |
| 31/01/2023 |
£1,839,699 |
MONASH UNIVERSITY |
Despite being among the most commonly prescribed medications, the mechanism of action for antidepressants remains unknown. Our hypothesis is that selective serotonin reuptake inhibitors (SSRIs), the most commonly prescribed class of antidepressants, are effective due to effects on circadian function. We have shown that SSRIs amplify the non-visual effects of light. This potentially results in increased mood-elevating effect of light, but also an increased vulnerability to sleep and circadian disruption by light at night. We propose to investigate how SSRI efficacy may be due to an individual's balance of these positive and negative effects. Our comprehensive sleep and circadian phenotyping study will address the following aims: What is the effect of chronic SSRI use on multiple measures of non-visual light sensitivity (including melatonin suppression, phase shifting, fMRI-measured responses to light, pupillary light responses), and common markers of circadian function (circadian phase, amplitude)? Test the hypothesis that increased light sensitivity is predictive of better SSRI treatment efficacy for depression. Test the hypothesis that sleep regularity and light-dark patterns interact with changes in light sensitivity to predict SSRI treatment efficacy for depression. Are there baseline circadian characteristics (circadian phase, amplitude, markers of light sensitivity, genetics) that can predict better SSRI treatment efficacy? |
| 31/01/2023 |
£3,058,318 |
UNIVERSITY OF SYDNEY |
We hypothesise that sleep and circadian rhythm disturbance (SCRD) is a pathophysiological mechanism underpinning a significant subset of youth-onset mood disorders called "circadian depression". To test this hypothesis, and to evaluate the effectiveness of SCRD-targeted interventions for youth with circadian depression, our five key goals are: To explore in an early intervention youth cohort the dynamic, prospective relationships among mental health, SCRDs, biological/environmental factors (e.g., light sensitivity, light exposure), and treatment-associated changes over time. To disentangle the genetic, environmental, and phenotypic links among SCRDs and youth-onset mood disorders in our longitudinal twin, family, and case-cohort studies. To test in a multi-site randomised controlled trial, whether melatonin plus dCBT-I is a more effective early intervention for youth-onset mood disorders than placebo plus dCBT-I, and whether treatment-associated changes in SCRDs causally mediate changes in depressive symptoms. To develop and evaluate novel, multiplex, blood-based biosensors to track SCRD biomarkers at in vivo state ("Circadian Chip") and trait ("Red Blood Cell Signature Sensor") timescales. To integrate data with clinical and lived experience expertise in a computational model of youth-onset mood disorders, and to release an interactive dashboard so users can explore links among SCRDs and mental health and test novel hypotheses via computer simulation. |
| 31/01/2023 |
£2,994,698 |
UNIVERSITY OF CALIFORNIA, BERKELEY |
Extensive research indicates that sleep and biological rhythms are often disrupted among those with bipolar disorder (BD) and among their relatives, and that these biological rhythms are tied to severity of illness, to cognitive dysfunction, and to metabolic syndromes. Accordingly, there is a profound need for interventions that can stabilize biological rhythms in BD. Time-restricted eating (TRE) is an intervention shown to improve circadian rhythms in animals and humans, but it has not been tested in BD. We aim to conduct two studies to examine TRE in BD. First, we will conduct a randomized controlled trial (RCT) to examine efficacy as compared to a control intervention of the Mediterranean diet, and to test the hypothesis that the intervention will be particularly powerful early in the course of BD. Second, to understand mechanisms, we will measure how TRE adherence predicts the diurnal amplitude of core circadian clock gene expression and phase and amplitude of melatonin secretion changes after 1 month, and how amplitude of clock gene expression predicts changes in symptoms and QOL. If successful, this work will provide a novel, easily implemented and highly acceptable intervention for BD, and a critically needed test of the circadian rhythm hypothesis of BD. |
| 31/01/2023 |
£3,103,849 |
UNIVERSITY OF EDINBURGH |
Bipolar disorder is defined by extreme variability in mood, activity, sleep and circadian timing recurring over weeks and months. To date, studies of sleep/circadian rhythms in bipolar disorder have been cross-sectional and based on only 1-2 weeks of monitoring: we urgently need new approaches that can assess longer-term individual-level changes in sleep, activity and mood, to better understand symptom trajectories and mechanisms of relapse. We will optimize innovative ambient and passive data collection methods over long time periods and test their feasibility and performance against gold standards. A lived experience advisory panel will help us to identify and prioritize clinical and functional outcome measures and develop ‘low intensity’ methods for collecting these outcomes. In parallel, we will develop a data collection and management system to support data collection and optimize data sharing with patients, clinicians and the research community. The core of this project is an 18-month prospective follow-up study of sleep, circadian rhythms and clinical/functional outcomes in people with bipolar disorder that primarily makes use of low intensity ambient and passive data collection methods. We will also work with Bipolar Scotland to co-produce an innovative programme of knowledge exchange on the theme of ‘Sleep, circadian rhythms and bipolar disorder'. |
| 24/01/2023 |
£4,988,099 |
IMPERIAL COLLEGE LONDON |
The global burden of malaria remains unacceptable with > 200 million cases and > 600,000 deaths annually. Vaccines are the most effective and cost-effective public health interventions against infectious diseases, but the only one licensed for malaria has limited efficacy that wanes rapidly. The fact immunity can be acquired and passively transferred through immunoglobulins strongly motivates research to understand the immune responses that underpin protection. New data from the Osier laboratory challenge the long-held view that the inhibition of erythrocyte invasion is the main correlate of protection. We found that IgG Fc-dependent mechanisms targeting merozoites and involving complement, monocytes, neutrophils, and natural killer cells strongly predicted clinical outcome following intravenous challenge with Plasmodium falciparum parasites in humans. Invasion-inhibition did not. We will now partner with a renown structural biologist, B-cell immunologist, and experts in glycobiology and Fcgamma receptor pathways to map out the precise structural and fine molecular characteristics that lead to the successful control of malaria. We will use this knowledge to design and test new vaccine constructs and monoclonal antibody therapies. These data will transform our understanding of acquired immunity, provide urgently needed candidates for new vaccines and immuno-therapeutics, and create new benchmarks against which these can be assessed. |
| 24/01/2023 |
£3,042,794 |
UNIVERSITY OF OXFORD |
Transcription is vital for the lifestyle of bacteria. To achieve adaptation in a host, or survive under hostile conditions, bacteria employ a complex network of responses centred around transcriptional control of related genes, some of which give rise to virulence and antibiotic resistance. However, despite progress in structural and single-molecule biophysical studies of transcription, we are far from understanding how transcription operates inside a bacterial cell, which features an enormously complex and fluctuating environment impossible to reconstitute in vitro. We will address this complexity using cutting-edge single-molecule methodologies we have been pioneering over the past decade. We will perform direct, real-time monitoring of single molecules of RNA polymerase and transcription factors as they go through the transcription cycle inside living cells, as well as high-resolution multiplexed imaging of large transcriptional clusters that may represent biomolecular condensates forming via liquid-liquid phase separation. Using our advanced toolbox and complementary approaches, we will elucidate controversial kinetic aspects of the transcription cycle, resolve the structure, composition, and physical nature of the large transcriptional clusters, and identify functions of these clusters in promoter search and transcription re-initiation. Our work will revolutionise the understanding of bacterial transcription, while enabling applications in biotechnology, therapeutics and synthetic biology. |
| 24/01/2023 |
£3,616,262 |
BABRAHAM INSTITUTE |
CD8 T cell activation sets in motion waves of gene expression accompanied by metabolic changes that promote proliferation and alternative differentiation fates. The ZFP36-family of RNA binding proteins (RBP) regulate this by limiting the tempo of differentiation and potency of CTL. Through interactions with the multiprotein CCR4NOT complex ZFP36-family bound mRNAs are translationally repressed and degraded. This complex and its regulation remains uncharacterised in mature T cells and we propose it acts in activated T cells as a regulatory hub to interconnect and coordinate epigenetic, transcriptional and metabolic reprogramming. We will address how the components of this complex are regulated by TCR and costimulatory signals and their role in negative feedback and inhibitory receptor signalling. We will establish how RBP affect the formation and function of memory cells and test the hypothesis that they promote T cell exhaustion. By developing tools and approaches to define the dynamics of protein and RNA interactions, coupled with analysis of mRNA fate, we will distinguish how target transcripts are regulated. Working in a largely unexplored field these studies will reveal new functions of RBP in metabolism, epigenetic remodelling and RNA localization/trafficking providing insight into a deeper layer of molecular regulation of the immune system. |
| 24/01/2023 |
£4,376,805 |
UNIVERSITY OF CAMBRIDGE |
Mitochondria play a central role in the homeostasis of nucleated cells, but mitochondrial insults preferentially affect some cell-types and not others. The reasons for this are not clear. Our over-arching aim is to define the principal mechanisms underpinning cell-type-specific mitochondrial vulnerability. We will take a reductionist approach, focussed on genetic disorders of intra-mitochondrial translation caused by mutations affecting mitochondrial DNA (mtDNA) transfer RNA genes and their corresponding nuclear-encoded mitochondrial aminoacyl tRNA synthetases (mt-aaRS). Our five specific inter-related aims are: Aim-1: To discover the key nuclear genes regulating mtDNA-heteroplasmy and mtDNA-levels in different cell types using single-cell functional genomic screens. Aim-2: To define cell-type-specific nuclear transcriptional signatures that modulate mitochondrial function throughout life in health and disease. Aim-3: To determine the role of canonical and non-canonical functions of mt-aaRS in cell-type-specific vulnerability. Aim-4: To characterise cell-type-specific downstream consequences of disrupting mitochondrial protein synthesis, focussing on the integrated stress response (ISR). Aim-5: To discover new mtDNA-nuclear DNA interactions in undiagnosed patients with tissue-specific mitochondrial disorders using genomics. Given emerging evidence that mitochondria contribute to many common late-onset diseases, our findings will have broader relevance for understanding tissue and cell vulnerability in many human disorders, potentially identifying new cell-type-specific therapeutic targets. |
| 24/01/2023 |
£4,230,617 |
UNIVERSITY OF OXFORD |
The development of a layered cortex requires tightly regulated cell migration events. These are controlled by context-dependent interactions of cell guidance receptors and their ligands, which occur between migrating cells and their environment. In this project, we focus on Unc5 guidance receptors and their FLRT ligands, which together with further binding partners, form combinatorial interactions that instruct the radial migration of neurons in early cortical development. We will assemble a detailed spatiotemporal map of when/where different protein complexes form during radial migration, determine their atomic structures to obtain mechanistic insight, and design structure-based mutants to specifically target combinatorial ligand binding in vitro and in vivo using mouse models. These results will establish a molecular-level understanding of how radial migration is determined by these guidance receptors. Research questions: Where are different receptor interactions established during cortical migration? What are the structural principles that control their interactions? How do these interactions direct specific cellular behaviours during radial migration? The proposal presents an integrated work package using structural biology, protein engineering, proteomics, cell biology, advanced imaging and mouse in vivo technology. The project creates an outstanding interdisciplinary and international training environment for early career researchers to develop independent academic careers. |
| 24/01/2023 |
£5,576,341 |
UNIVERSITY OF OXFORD |
Motivation is a crucial feature of mental health, wellbeing and success. Yet we understand very little about the brain mechanisms underpinning it. Pathological loss of motivation manifest as the syndrome of apathy is a common symptom in many brain disorders but it has no established treatment. Here we test a new conceptual framework to provide an ambitious, transformational step change in this field. By bringing together the expertise of a diverse, multidisciplinary collaboration we seek to: Understand variability of motivation in healthy people across different domains –behavioural, cognitive, social and emotional – at the level of behavioural and brain mechanisms. Using a transdiagnostic approach, establish mechanisms underlying pathological apathy in patients with Parkinson’s disease (PD), small vessel cerebrovascular disease (SVD) and Alzheimer’s disease (AD). Investigate modulation of motivation in healthy people and PD using drugs that target different neurotransmitter systems, and deep brain stimulation (DBS) in PD. We will deploy a common set of behavioural measures, computational modelling and neuroimaging analyses to provide a unifying platform for data integration, across studies. This will provide a comprehensive understanding of human motivation and apathy, new behavioural tools and potential novel treatment approaches for loss of motivation and apathy in health and disease. |
| 24/01/2023 |
£5,542,513 |
NEWCASTLE UNIVERSITY |
The mycobacterial cell envelope is a complex structure critical for interactions with the host and other bacteria. An important class of cell wall molecules are the D-arabinan containing polysaccharides arabinogalactan and lipoarabinomannan. Decades of research has focused on the biosynthesis of these molecules, with little understanding of how bacteria modify or degrade these structures post-synthesis. We recently discovered a new family of enzymes with endo-D-arabinanase activity and we provide evidence that these enzymes fall into three functional classes: cell maintenance, inter-bacterial competition, and immune modulation. The diversity of functions ascribed to these enzymes underscores the importance of their activity to mycobacterial biology, and yet we know almost nothing about their specificity, how they are regulated, how they contribute to cell fitness or how they enable survival in the host. Our research team has been assembled to draw on crucial expertise to address these questions using cutting-edge approaches and technologies. Together this research program will provide a transformative view of mycobacterial cell surface variation, and revolutionise our understanding of mycobacterial interactions with other bacteria and host cells. It could also lead to new diagnostics, therapeutics or vaccines against mycobacterial diseases such as tuberculosis. |
| 24/01/2023 |
£5,792,362 |
SOUTH AFRICAN MEDICAL RESEARCH COUNCIL |
Severe intimate partner violence (IPV) has an enduring impact on affected women and children: for some, it is fatal, and among exposed children, it fuels intergenerational cycles of violence. South Africa has one of the highest rates of intimate partner femicide (IPF) globally and large numbers of children are exposed annually. We aim to understand the pathways and mechanisms of impact of severe IPV on the social and economic circumstances, relationships and health of affected women and their children, with a special focus on risk factors for intimate partner femicide and the processes of intergenerational cycling of violence. We will recruit women approaching the Courts for Protection Orders (POs) for IPV and study their social and economic circumstances, the trajectory of contact with their abusive partner, further IPV exposure, physical and mental health, and the drivers of poor outcomes. We will investigate mortality by linking the cohort to the national death database, and use verbal social autopsies. A vital element is deepening understanding of intergenerational cycling of violence, and we will study IPV-exposed children of the women participants to understand the impact of IPV on their health and lives at home, among peers and in their relationships. |
| 24/01/2023 |
£2,498,399 |
THE FRANCIS CRICK INSTITUTE |
Do we have sufficient understanding to engineer bespoke neural tissue? To test this, we will use the developing neural tissue to establish a synthetic approach to form robust patterns of cellular organisation. This will test and extend our understanding of neural tube development and create tools to control and engineer tissue for use in synthetic applications and disease modelling. Previously we: Developed quantitative understanding of the genomic, molecular and cellular mechanisms of neural tube development. Established methods for the biomimetic generation of neural tissue from Embryonic Stem Cells (ESCs). Established collaborations with physicists and computer scientists to develop data driven dynamical models. On these foundations we will develop a system for precision tissue engineering based on ESCs, re-engineered neural tube components, and multiscale models. We will: Establish optogenetic control of extracellular signals to instruct spatial-temporal pattern formation in synthetic ESC derived neural tissue. Generate a suite of synthetic gene regulatory elements with defined regulatory function and use these to produce novel circuits that elicit predictable responses. Combine extracellular and intracellular modules to produce precision programmable synthetic developmental patterns of gene expression and cell fate. To guide experiments and interpret data, we will use computational simulations constrained by quantitative experimental measurements. |
| 24/01/2023 |
£6,426,819 |
UNIVERSITY OF CAMBRIDGE |
The PIWI-interacting RNA (piRNA) pathway is a small RNA-based innate immune system that guards the germ cell genomes of animals from the potentially deleterious consequences of the unfettered activity of mobile genetic elements. The integrity of this pathway is important for maintaining germ cell function and reproductive fitness throughout the animal kingdom. We propose to use Drosophila as a model system to deepen our mechanistic understanding of piRNA biology, drawing upon genetics, biochemistry, molecular and structural biology, high resolution and live-cell imaging, and computational and evolutionary biology. We seek to understand how piRNA clusters are defined and expressed, how their long non-coding RNA products are fated for biogenesis, how they are processed on the surface of mitochondria, and how the resultant piRNAs elicit co-transcriptional silencing, as well as the timelines and dynamics of the underlying processes. Finally, we will draw upon the expertise built in other areas of focus within our group to study the spatial and temporal interactions between transposons and host defence, as the relationship between mobile elements and their host are likely much more nuanced than can be reveal by bulk analyses which collapse multiple developmental stages into a single averaged measurement. |
| 24/01/2023 |
£5,148,322 |
UNIVERSITY OF BRISTOL |
Despite international efforts to eliminate HIV/AIDS, infection levels remain high among key populations (KPs). Although effective interventions exist, evolving evidence suggests structural factors limit their impact and increase HIV transmission among KPs. Initiatives to reduce these factors (societal enablers) are a focus of new global HIV elimination strategies, but little evidence exists on the contribution of structural factors to HIV transmission or the potential impact of societal enablers. The proposed research will develop a novel evidence-based statistical and modelling framework to improve this evidence base. We will conduct epidemiological analyses to improve our quantitative understanding of the causal pathways between structural factors and HIV-risk, utilising global longitudinal datasets. We will then develop new mathematical models that include these causal pathways to robustly estimate the contribution of structural factors to HIV transmission and evaluate the impact and cost-effectiveness of societal enablers across diverse KPs and countries. The project will transform the evidence and methodologies used to evaluate the effect of structural factors and interventions to mitigate their effects. It will result in a step change through enabling evidence-based planning for including societal enablers in HIV programming for KPs, with insights being crucial for national/global policymakers aiming to eliminate HIV/AIDS by 2030. |
| 24/01/2023 |
£1,976,186 |
CARDIFF UNIVERSITY |
Studies of antiviral humoral immunity are dominated by neutralization. However, within a host viruses spread cell-to-cell, which avoids this activity. Thus, antibodies that bind cell-surface viral antigens and activate antibody-dependent cellular cytotoxicity (ADCC), become critical. Entry glycoproteins are assumed to be optimal targets for both neutralizing and ADCC activity. However, when we developed novel techniques to measure proteome-wide ADCC, we found that entry glycoproteins are poor ADCC targets. Instead, non-structural proteins are dominant targets. Thus, the induction of neutralisation and ADCC requires different strategies; by focusing on entry glycoproteins, current vaccines fail to provide maximal protection against certain viruses. By focusing on non-structural antigens, we generated the first antibodies capable of promoting immunological control of HCMV. We therefore propose that non-structural ADCC is an important component of protection, and provides a novel route to enhance antiviral strategies. However, it also reveals fundamental gaps in our understanding - we do not know what determines ADCC potency. We therefore seek to understand the protective capacity of non-structural ADCC in disease, how it can be exploited to enhance next-generation therapeutics, and what determines the induction of robust ADCC, as the basis to systematically exploit ADCC against other and future virus threats. |
| 24/01/2023 |
£2,645,277 |
UNIVERSITY OF BRISTOL |
The concept of epistemic injustice (EI) in healthcare identifies epistemically unjust ways of conceiving of illness, treating ill persons, and allocating healthcare. This application to healthcare, initiated by Carel and Kidd, has inaugurated a new research area, with it's own significant and growing literature. However, much work remains to be done. There are understudied forms of EI in healthcare; there is a need for detailed empirical study of EI cases in healthcare and for empirical testing and validation of the concept; there is little research on how EI could be ameliorated; and the conceptual resources of EI need to be integrated into wider discourses about healthcare. Epistemic Injustice in Health Care (EPIC) is a bold six-year research project which will address these issues. EPIC will create a step-change in EI research by addressing these four problems. The project will fill lacunae in existing EI theory; test the validity of the concept via six case studies of EI in ill health; develop strategies of amelioration; and introduce academic and clinical researchers and patient groups to EI to develop its theoretical and practical possibilities. EPIC will offer a new healthcare paradigm, that will benefit patients, increase health equality, and improve healthcare. |
| 24/01/2023 |
£4,013,436 |
UNIVERSITY OF CAMBRIDGE |
Mycobacterium abscessus is an intrinsically multidrug-resistant species of nontuberculous mycobacteria (NTM) that has recently emerged as a major threat to individuals with Cystic Fibrosis (CF) and other chronic lung conditions, including non-CF bronchiectasis. In CF, M.abscessus drives accelerated inflammatory lung damage, is frequently impossible to treat, and usually prevents safe lung transplantation. Infection rates are increasing globally, which we have shown are driven (at least in part) by indirect person-to-person transmission of M. abscessus, probably through the generation of long-lived infectious aerosols and via fomite spread. We currently do not understand how M. abscessus interacts with macrophages and epithelial cells to cause lung infection, or the reasons why some individuals are susceptible to infection. There is therefore a critical unmet need to better understand the pathophysiology of this organism and the mechanisms of human susceptibility to M. abscessus, to thereby identify therapeutic targets and discover strategies to mitigate infection risk. Our aims are therefore to: 1) Explain how horizontal gene transfer and within-host evolution have shaped M. abscessus virulence; 2) Define key pathways involved in pathogenesis through transcriptional analysis of bacteria and host; and 3) Understand the mechanisms causing susceptibility to M. abscessus infection in CF and non- CF individuals. |
| 24/01/2023 |
£2,003,072 |
UNIVERSITY OF OXFORD |
Inferring the phylogenetic relationships between biological sequences (orthology inference) is fundamental to biological and biomedical research. It provides the framework for transfer of biological knowledge between species, and enables the use of model organisms for studying health and disease. However, orthology inference methods are not perfect. The best methods are only ~80% accurate on benchmark tests and also fail to make inferences for thousands of genes in a typical analysis. In addition to these limitations, orthology inference methods are poorly scalable and are unable to analyze the current (or future) quantities of genome data. Finally, the methods themselves are poorly accessible to researchers lacking expertise in command line environments. This project aims to address each of these limitations and challenges by improving the accuracy, enhancing the functionality, increasing the scalability, and extending the usability of OrthoFinder. By delivering these improvements this project will have impact on the accuracy and capability of thousands of studies that are underpinned by OrthoFinder. It will also improve the accuracy and utility of repositories of biological sequence data that rely on the method. Finally, it will improve access to high-level comparative genomics tools within the biological and biomedical sciences. |
| 24/01/2023 |
£3,948,802 |
IMPERIAL COLLEGE LONDON |
The first months of life represents a critical period for human immune system development1. Antibiotic exposure during this time perturbs microbial colonisation, derails the establishment of healthy immune-microbe relationships, and increases the risk of asthma and allergies2, autoimmune diseases like juvenile arthritis3, and even neurodevelopmental conditions like autism later in life1,3. Early in life the immune system must prevent pathogens from invading yet tolerate commensal microbes and avoid exuberant responses to harmless allergens. The detailed mechanisms involved in this balancing act are poorly understood but microbial metabolites are likely to be critical modulators4,5. Here we plan to search for microbial metabolites that modulate immune system development and investigate their mechanisms of action. We believe that better understanding of human immune development will help us develop new interventions that optimise this process and reduce risks of disease in all children in the future. Importantly, key microbial metabolites found in human newborns might also have potential as immunomodulatory agents beyond childhood, for example in adult patients with inflammatory diseases. Here I propose to combine the richness of a human birth cohort, with the potential of well-controlled in vitro systems to explore mechanisms by which microbial metabolites can modulate human immune systems. |
| 24/01/2023 |
£1,597,746 |
UNIVERSITY OF SHEFFIELD |
Covid-19 emphasises the need for urgent new analyses of the politics, processes and prioritisation of respiration and ventilation. The sudden emergence of global respiratory disease has reshaped our social, cultural, and political worlds and embodied experiences of health and illness. This project centres the lives of people who have had their lives saved and sustained by ventilatory medical technologies. Respiratory failure is common in many health conditions, and is a symptom of Coronavirus. Our explorations, led by disabled, chronically ill and ventilated people, do so in recognition that these growing communities of people and patients are often absent from contemporary social theorisations of respiration and ventilation, but also that their experiences have much to teach about living in cultures of compromised respiration. Centring arts-informed, archival, narrative and ethnographic approaches, this project develops Crip perspectives - forms of knowledge production that emerge from lived experiences of disability and chronic illness. Artists-in-Residence, experts-by-experience, disability and arts organisations and clinicians will work in collaboration to curate and coproduce new understandings of the experiences of ventilated people, across a host of identity positions, to interrogate the new cultural politics of respiration and ventilation in a continuing global pandemic, and as we imagine post-pandemic futures. |
| 24/01/2023 |
£2,561,158 |
UNIVERSITY OF WARWICK |
Errors in human chromosome segregation are infrequent yet devastating. Aneuploidy, in which entire chromosomes are gained or lost is a hallmark of cancer, ageing and reproductive failure. To minimise errors, dividing cells assemble a bipolar guidance scaffold, the spindle, and connect each chromosome to its own self-correcting molecular engine, the kinetochore. The remarkable feature of the kinetochore is that they monitor their own attachment state and use this information to eliminate mis-attachments, activate/deactivate checkpoints and direct chromosome movements. How kinetochore achieve this remains mysterious. Previously, kinetochore self-correction was thought to occur only during early mitosis, but we have recently shown that kinetochore self-correction persists deep into anaphase when the chromosomes are being segregated. I propose to understand both pre- and post-segregation self-correction mechanisms by harnessing cutting-edge live cell imaging, computational tools and genome engineering with a focus on the following challenges in the field:
1. Unravel how kinetochores sense and correct their own function.
2. Define how pre- and post-anaphase error correction control the risk of aneuploidy
3. Measure the forces human kinetochores generate in living cells and understand how kinetochores respond mechanically and functionally to force
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| 24/01/2023 |
£1,502,772 |
UNIVERSITY OF MANCHESTER |
This project on the history of humanitarian medicine as a set of emergency interventions, seeks to generate significant shifts in understanding its scientific and organisational specificity and role in developing clinical norms, debating ‘rights-based’ approach to health access and leading campaigns for access to drugs while deploying bespoke biotechnological tools.
This research project will investigate questions that have direct relevance to the future of medical humanitarianism:
How have humanitarian initiatives, non-governmental organisations (NGOs), international and national actors developed humanitarian medicine since the declaration of Alma Ata (1978) on primary healthcare?
How have they defined humanitarian medicine and its remit?
How have they established normative processes regulating their action and the reach of humanitarian medicine?
How have humanitarian medical providers engaged with pharmaceutical and biotech industries?
And finally, how have states sought to harness and control humanitarian medicine?
This history will inform humanitarian practice and contribute to ongoing debates on how humanitarian medical providers engage with pharmaceutical and biotech industries to disseminate, repurpose, and research drugs and diagnostic tools.
The project will develop four workpackages building up from patient-centred clinical norms and concerns on care to experimental initiatives in humanitarian setting and state-led norm-setting diplomacy through emergency medical teams (EMTs) initiatives.
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| 17/01/2023 |
£1,072,966 |
UNIVERSITY COLLEGE LONDON |
Peripheral hearing loss affects approximately 40% of people aged 55 and older. Although hearing aids provide some relief, comprehending speech in noisy places ("speech-in-noise") remains difficult and is one of the most pressing challenges for people with hearing loss. Auditory cognition has great potential to explain why people struggle to listen in noisy settings. Yet, how hearing loss interacts with auditory cognition is currently unclear. My overarching aim is to understand how hearing loss interacts with auditory cognitive effects on speech-in-noise perception. I propose a novel interdisciplinary approach, combining state-of-the-art techniques in cognitive neuroscience (ultra-high field MRI, simultaneous MEG-pupillometry, and behaviour), standardised tests from clinical audiology (audiometric thresholds), and biologically-relevant computational modelling (based on predictive coding): ultra-high field MRI will identify the cortical networks and hone in on laminar interactions; simultaneous MEG-pupillometry will test the time-courses of activity; clinical measures will reveal how hearing-loss severity interacts with cognitive factors; modelling will uncover the underlying causes of behaviour and brain responses and generate testable predictions. Together, the programme will create a quantitative, empirically-grounded model of how hearing loss interacts with cognitive effects on speech-in-noise perception, which will produce a step-change in understanding and potentially inspire novel interventions for hearing loss. |
| 17/01/2023 |
£2,057,308 |
UNIVERSITY OF OXFORD |
Maintenance of barrier tissue homeostasis and function depends on the integrated activity of epithelial, immune and neuroglial cellular systems with the local microbiota. In the lung, disruption of this balance, either spontaneous or in response to infection or inhaled antigens, has severe consequences for human health, manifested as respiratory inflammation and detrimental tissue remodelling of poorly understood aetiology. Recent reports in other barrier tissues uncovered roles for peripheral glia in homeostasis, immunity, and wound repair suggesting that these cells represent important regulatory nodes for maintaining and restoring the function of all barrier sites; pointing to a potential role of intrinsic neuroglial networks in shaping lung immunity, both at steady state and during disease. This proposal will employ state-of-the-art single cell RNA sequencing, imaging techniques and viral vector-mediated lung glia-specific in vivo targeting in conjunction with mouse models of lung inflammation and human tissue samples to understand how lung glia regulate immune homeostasis and inflammation and to determine underlying pathways that control their interaction with other lung tissues in health and disease. This research will provide fundamental knowledge that will likely advance the development of therapies for lung inflammatory conditions and inform our understanding of neuroglial-immune interactions in other barrier tissues. |
| 17/01/2023 |
£3,427,006 |
KING'S COLLEGE LONDON |
Salmonella is defined as a WHO-priority pathogen due to rising antimicrobial resistance. During antibiotic treatment, reservoirs of invasive non-typhoidal Salmonella capable of seeding infection relapse (called persisters) survive within macrophages. Eradication of persisters is challenging, necessitating sustained inflammation that can exacerbate Salmonella infection-associated pathology. Therapeutic technologies precisely modulating expression of individual genes in innate immune cells raise the possibility of controllably tuning macrophage phenotype for safe eradication of persisters. It remains unclear, however, how exactly this can be achieved. Here, we aim to identify host-directed perturbations enabling Salmonella persister eradication in the clinic. Focussing on host transcription factors and chromatin regulators, we will first identify and characterise candidate loss-of-function and gain-of-function perturbations redirecting persister-infected macrophage transcriptional networks to favour persister clearance. We will then use causal deep learning approaches and clinical data to determine which candidate perturbations are most likely to have therapeutic impact in patients undergoing antibiotic treatment for non-typhoidal Salmonella disease. In later years, we will extend our research to other bacterial infections where macrophage-resident persisters are similarly associated with infection relapse (Salmonella Typhi, Mycobacterium tuberculosis, Staphylococcus aureus). Collectively, we anticipate that our research will pave the way for development of next-generation antibacterial immunotherapies to eradicate recalcitrant infections. |
| 17/01/2023 |
£2,109,305 |
UNIVERSITY OF OXFORD |
Background Immune checkpoint blockade (ICB) re-invigorates T cells rendered exhausted by tumours and has revolutionised the treatment of cancers, including melanoma. However, clinical outcomes are heterogenous and ICB frequently triggers serious, multi-organ autoimmune complications. This clinical heterogeneity likely reflects inter-individual variation in sensitivity to ICB activity- the determinants of which are unresolved and contribution of germline genetics unexplored.I have previously shown T cell clonality and baseline expression influence survival. I hypothesise that genetic variation influences ICB responses in a cell-type specific manner, with consequences for patient outcomes. Research Proposed Using scRNA-seq with TCR-seq, I will systematically characterise peripheral immunocytes in terms of counts, gene expression and clonality, across samples from a longitudinal patient cohort (n > 280) I initiated. Results will be integrated with tumour mutational burden and clinical outcomes. Leveraging the large effect-sizes of regulatory variants, I will use genetics to explore interactions between gene-expression and ICB response. Using TCR-seq data I will delineate determinants and targets of long-lived T cell clones in patients with durable responses. Envisaged Outcomes A comprehensive cell-atlas with relevance to oncological responses, autoimmunity and immunodeficiency, describing inter-individual variation and the contribution of genetics to ICB responses and the identification of T cell markers of remission. |
| 17/01/2023 |
£3,236,784 |
UNIVERSITY OF OXFORD |
Depression is a highly prevalent and debilitating psychiatric disorder. Reduced motivation for pleasurable activities, or anhedonia, is a core depressive symptom. Motivational states are driven by environmental and internal reinforcers with their own reward values, which are perturbed in patients with anhedonic depression. Although preclinical research implicates the dopamine system in modulating motivation/anhedonia, translation of these findings to humans remains limited by traditional neuroimaging and behavioural measures. This project will extend my prior work in developing ultra-high-field MRI sequences and novel computational methods to not only measure but also directly modulate neural activity in dopaminergic circuits that underlies motivation/anhedonia in patients with anhedonic depression. In doing so, I will generate a comprehensive cognitive-computational framework of motivated action in anhedonia, and for the first time, probe the causal link between dopamine circuit function and motivation for distinct reinforcers, via three primary aims: 1) Optimise computational methods to measure cognitive processes underlying anhedonia. 2) Leverage ultra-high-field 7T-MRI to generate precise measurements of dopaminergic circuit function during motivated behaviour. 3) Develop tools to modulate neural activity in order to determine the causal impact of dopaminergic activation on motivation/anhedonia in individuals with and without depression, which promises to identify novel therapeutic targets for depression. |
| 17/01/2023 |
£3,116,833 |
UNIVERSITY OF CAMBRIDGE |
Wnt signalling pathways orchestrate a multitude of fundamental biological processes, including cell fate determination and differentiation during embryonic development. The overwhelming majority of Wnt research has focussed on the canonical Wnt/b-catenin pathway. By contrast, the non-canonical Wnt/ROR pathway, which constitutes a core developmental pathway that controls tissue morphogenesis during development, remains poorly characterised. Dysfunction of the Wnt/ROR pathway causes several rare genetic diseases and is implicated in neurological disorders and in driving the metastatic progression of many cancers. Therefore, defining the Wnt/ROR signalling pathway mechanistically is essential to develop better more targeted therapies and impact human health. My vision is to transform our understanding of the crucial Wnt/ROR pathway and elucidate how its misregulation drives developmental disease. My starting focus is on Wnt/ROR signalosomes, which are dynamic multiprotein complexes whose function and components require elucidation. I will use wildtype and disease-associated mutants in proximity labelling proteomic assays to systemically identify novel Wnt/ROR signalling partners. This will be combined with biochemical assays to define their direct interactions and innovative cell-based functional assays to determine those that are essential for signalling. I will determine: (1) Wnt/ROR signalosome components (2) ROR-receptor pseudokinase signalling mechanisms and (3) uncover how Wnt/ROR abnormalities cause developmental diseases. |
| 17/01/2023 |
£2,308,638 |
UNIVERSITY OF CAMBRIDGE |
Regeneration of appendages is relatively common among invertebrates. In mammals, however, multi-tissue regeneration is restricted to the distal portion of the digit tip. Removing more than 60% of the end of the digit culminates in wound healing and fibrotic scar formation. This raises the question of why this is so, since this restriction has major implications for therapeutic approaches to tissue repair. My working hypothesis is that cells within the mammalian limb are intrinsically capable of responding regeneratively however are diverted towards scarring by the injury microenvironment rather than due to the availability of regeneration-competent progenitors. To test this, we will use an interdisciplinary approach combining single cell genomic approaches, in vitro culture systems and in vivo assays to map regeneration-competent and -incompetent cellular injury microenvironments in the digit tip. This work will aim to i) identify signalling networks important for promoting/inhibiting tissue regeneration, ii) decipher how cell behaviour is influenced by tissue mechanics, and iii) provide a functional platform to validate regeneration-specific pathways in human tissue. By gaining an understanding of the regulatory mechanisms that promote mammalian digit tip regeneration, this will ultimately enable their targeted reactivation as a means to treat injuries and degenerative diseases in humans. |
| 17/01/2023 |
£2,246,457 |
UNIVERSITY OF CAPE TOWN |
Large-scale next-generation sequencing has rapidly advanced our understanding of the genetic architecture of Amyotrophic Lateral Sclerosis (ALS) spectrum disorders which is driving therapy development. Apart from our recent description of the first 100 cases, highly diverse and unique African genomes have not contributed to ALS gene discovery efforts. Critical insights into ALS biology remain to be gained from the application of long-read sequencing to study large structural variants and illuminate regions of the genome "hidden" to short-read technology. This project proposes to include Africans in this next frontier of disease gene discovery by expanding the generation of whole genome sequencing data on African patients with ALS and related disorders (~600 over 6 years). The merits of this project lie not in sample numbers, but rather in the deep phenotyping and genomic characterization of unique ALS phenotypes in diverse population groups which have the potential to make novel discoveries with global impact. Africa remains decades behind the genomic revolution due to lack of sequencing infrastructure, bioinformatics expertise and African genomic reference data. This project will strengthen the Neurogenomics Research Programme at UCT’s Neuroscience Institute, support African genomics capacity building and ultimately improve clinical care for ALS patients in Africa. |
| 17/01/2023 |
£2,351,143 |
UNIVERSITY OF CAMBRIDGE |
Gene regulation involves both transcriptional and translational regulation. At the translational level, codon usage has emerged as a ‘code inside the code’ that determines mRNA stability and influences protein folding. Synonymous mutations that were thought to be silent, instead have potential to directly regulate gene expression. Despite their importance, the mechanisms behind these processes remain obscure. I propose to systematically study codon usage through data-driven methods, enabling a more complete understanding of gene regulation. My proposed research will focus on development of open source tools and databases, in particular by systematically processing all published Ribo-seq data, that will subsequently be used to carry out large-scale analyses of translational dynamics (Aim 1). Moreover, I will improve sequence-to-function prediction by integration of codon usage into the deep learning models and use modelling to test specific hypotheses (Aim 2). Finally, I propose to establish an evolutionary Drosophila model to understand codon usage in the context of tRNA competition between mRNA and viruses or transposable elements (Aim 3). Altogether, this work will lead to a significant shift in our understanding of codon usage and provide a computational toolbox widely applicable also beyond these immediate questions. |
| 17/01/2023 |
£2,263,414 |
UNIVERSITY OF YORK |
Organisms must continually respond to changing environmental cues for survival. An extreme example are parasites transmitted between ecto- (insect vector) and endothermic (mammalian host) organisms, such as Leishmania, encountering dynamic changes including pH and temperature to which they must sense and adapt rapidly. Orthology from other organisms (G-protein coupled receptors and receptor tyrosine kinases) is absent in Leishmania and therefore little is known about how they sense and transmit these environmental cues, but protein kinases have an important role. These will be my focus in an aim to uncover how Leishmania detects pH and temperature change. I have used a kinome-wide deletion library to identify two Leishmania (haptomonad stage) differentiation kinases (HDK1 and HDK2), required in early response to decreased pH. I will resolve the HDK signalling pathway using proteomic methods and uncover kinases key to sensing increased pH and temperature change using two genetic library screens and phosphoproteomics. Additionally, I will test for a conserved role across other parasites by gene disruption in Trypanosoma cruzi. Finally, Leishmania causes a collection of debilitating and deadly diseases. As protein kinases are good drug targets, I will examine survival of mutants through the sand fly to test for transmission blocking potential. |
| 17/01/2023 |
£1,834,521 |
CARDIFF UNIVERSITY |
Neurodevelopmental disorders (NDDs), including intellectual disability, epilepsy, autism spectrum disorder and schizophrenia affect > 5% of the global population. However, the cause of most NDDs remains unknown, making it difficult to diagnose, mitigate or treat. Emerging evidence suggest that somatic mutations which occur during embryonic development represent one of the missing pieces in this puzzle but how and where these mutations occur remain unclear. Dysfunction in UPF1 and UPF3B are associated with inherited risk for developing NDDs. Recently, I have discovered that these two genes suppress mutations at DNA double-strand breaks (DSBs) by stimulating the formation of R-loops, enigmatic three-stranded structures containing DNA-RNA hybrids. This finding suggests that reduced R-loop-dependent DSB repair (DSBR) may exacerbate the accumulation of somatic mutations in developing embryo, disrupting genes required for neurodevelopment, and presents us with an innovative way to identify these mutations. I aim to investigate the mechanism of R-loop-dependent DSBR, and its role in suppressing mutations and neuronal dysfunction, by exploiting recent advances in single-molecule long-read sequencing, DSB mapping and stem cell technologies. This proposal will examine a novel mechanism for increased mental health risk to uncover new somatic mutations, risk factors or aetiology, contributing to improvement in diagnosis or mitigation of NDDs. |
| 17/01/2023 |
£3,182,835 |
UNIVERSITY OF CAMBRIDGE |
The human body plan is specified in the gastrulating embryo shortly after implantation. In mouse, this transformation is regulated by a dynamic signalling centre, the anterior visceral endoderm (AVE). However, the function of the primate AVE in gastrulation remains elusive. Implantation and body patterning are pivotal for healthy embryo development, but in human they have been notoriously hard to study for ethical and technical reasons. My lab recently delineated primate AVE formation by spatial transcriptome profiling of gastrulating marmoset embryos in vivo. Here, we will leverage our new extraembryonic stem cell lines to model the pre-to-postimplantation transition in human and marmoset. To interrogate the crosstalk between embryonic disc and AVE, we will engineer next-generation gastruloids by ‘printing’ AVE-like cells onto micropatterns and establish stem-cell-derived blastoid postimplantation cultures. Human and marmoset embryo models will be validated by transcriptomic comparisons to the embryo and assembled with knockout AVE-like cells to elucidate AVE-function. We will test the developmental potential of marmoset blastoids by transfer into receptive marmoset hosts and conduct lineage-tracing in vivo to determine the sequence of somatic cell-fate acquisition in primate gastrulation. Collectively, this research addresses major knowledge gaps in human development and establishes a proof-of-principle for stem-cell-derived pregnancies in primates. |
| 17/01/2023 |
£2,451,340 |
UNIVERSITY OF OXFORD |
Sister-DNAs produced during replication are entrapped within cohesin rings till anaphase, when the proteolytic cleavage of cohesin results in sister-DNA disjunction. This phenomenon called Sister Chromatid Cohesion (cohesion) is essential for orderly segregation of chromosomes. The mechanisms that control how cohesion is generated remain enigmatic. I have discovered that Topoisomerase II (TopoII) has an unexpectedly central role in cohesion establishment. This has important implications for the mechanism of cohesion establishment. I will build on this exciting new finding to systematically dissect the role of TopoII in generation of cohesion, focussing on how TopoII promotes DNA entrapment within cohesin rings and how cohesion is established by cohesin and TopoII. I will develop in vivo and in vitro single molecule assays to directly measure entrapment of sister-DNAs within cohesin rings and address the role of TopoII in promoting this. I will ask if cohesin and TopoII need to directly interact for cohesion. I will address the possibility that cohesion is built by complex topological structures arising from a collaboration between cohesin and TopoII. This work will deliver unprecedented insights into the mechanism of cohesion establishment and will bridge the gap in our understanding of a fundamental process that underpins orderly chromosome segregation. |
| 17/01/2023 |
£1,383,783 |
UNIVERSITY OF LEEDS |
Tick-borne encephalitis virus (TBEV) cases are increasing rapidly due to climate change and the introduction of tick vectors into new geographical areas. Despite this emergence, no effective anti-TBEV therapeutics are available. I previously investigated TBEV pathogenicity using chimeras of strains with a close genetic makeup, but highly variable pathogenic properties (Hypr and Vs strains). Vs causes asymptomatic infections whilst Hypr causes rapid cell death and severe disease. My preliminary data showed that Hypr-non-structural (NS) proteins induce apoptosis and cell death, whilst Vs-NS proteins activate anti-apoptotic proteins to promote the survival of infected cells. The precise viral-host determinants and the mechanisms that dictate the outcome of Hypr and Vs infections were not defined. This proposal will: (i) Identify the precise NS region(s) responsible for TBEV pathogenicity using current and newly developed Vs/Hypr chimeric viruses. (ii) Identify the host proteins/genes that are modulated during viral infection using transcriptomics and co-immunoprecipitation and mass spectrometry analysis. These targets will then be validated using CRISPR/Cas9 knock-outs and drugs. (iii) Understand the specific mechanisms of TBEV persistence in the brain using state-of-the-art nano-resolution imaging techniques, sophisticated in vitro human mini-brain organoids, and BBB-organ models. These experiments will reveal how viral/cellular factors shape the TBEV neuropathogenesis. |
| 17/01/2023 |
£1,517,293 |
UNIVERSITY OF CAMBRIDGE |
Where do symptoms come from? We usually assume a bodily symptom originates from tissue pathology, but our subjective experience of a symptom reflects both peripheral physiological signals and neurocognitive processes. This is exemplified in the case of "medically unexplained" somatic symptoms, which are common, disabling, and costly, accounting for 10% of NHS expenditure for the working-age population. My research investigates how expectations in the brain interact with the body’s internal environment to generate somatic symptoms. In the first stream (‘Somatosensory Expectations’), I develop an experimental model of conditioned somatosensory symptoms, using computational modelling to reveal how expectations alter bodily experience, and their role in clinical somatic symptoms. In the second stream (‘Appetitive Internal Expectations’), I use flavour-calorie conditioning to investigate metabolic reward learning and prediction error, testing whether disrupted expectations of internal appetitive reward might drive somatic symptoms in depression. In the third stream (‘Aversive Internal Expectations’), I investigate whether signals from the gut to the brain also drive expectations of an aversive internal state— learned disgust avoidance, a transdiagnostic behavioural phenotype. Together, my work will reveal how neurocognitive mechanisms generate symptom experience inside and outside the body, yielding novel insights into the common origins of mental and physical health.
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| 30/11/2022 |
£1,491,606 |
INSTITUTE FOR GLOBAL ENVIRONMENTAL STRATEGIES (IGES) |
Even as G7 countries pledge moderately stronger climate policies, lingering ambition and implementation gaps threaten the achievement of the Paris Agreement’s 1.5 Co goals. Integrating health co-benefits into climate planning can help close these gaps. While important nationally, robust evidence of co-benefits could potentially hold more sway locally. However, local governments often face a tension between the willingness to use and capacity to generate evidence of these benefits. This three-year transdisciplinary project will work with local governments in Japan to integrate health and related co-benefits into climate planning. The project will demonstrate a co-design approach—including 1) policy scoping, 2) co-benefits/interlinkages analysis, 3) initial policy recommendations, 4) feasibility assessments, and 5) final recommended policy and enabling reforms—in Kawasaki, Niigata, and Hachinohe, Japan. Parts of that approach will be then be adapted to Paris, France, and Austin, United States. Project activities will be strategically embedded in learning and dissemination activities (i.e. webinar series coinciding with Japan’s hosting of the G7 in 2023) to amplify impacts and drive transformative change. |
| 30/11/2022 |
£2,039,907 |
UNIVERSITY OF EDINBURGH |
A seminal moment in Scottish Food Policy, the new Good Food Nation (GFN) Act (became law on 26th July 2022, expected to formally commence Spring 2023) has been hailed as a ground breaking, progressive attempt at transformational food systems legislation, providing the statutory and policy conditions, and independent scrutiny mechanisms, required to drive forward health centred, net zero aligned food systems transformation in Scotland. Using an innovative "Food Systems Living Lab" model with 4 interconnecting units, this proposed transdisciplinary consortia of academic and policy partners (including the Scottish Government), cultivated during the GFN Bill process, will work to build connections between, and skills across, the Scottish food systems transformation community, provide essential analytical support to relevant authorities, advise on the effective delivery of the GFN Act, and showcase the value and importance of innovative metrics and partnerships in delivering health centred, net zero aligned food systems transformation. It will foster a skilled, agile, diverse community of practice, establish a basket of valid, easy to understand and far reaching indictors of progress and uncover the barriers to, and enablers of, positive health centred, net zero aligned food systems transformation. Key Words: Food, Systems, Transformation, Community of Practice, Health, Net Zero, Policy |
| 30/11/2022 |
£1,993,812 |
UNIVERSITY OF BIRMINGHAM |
Net-Zero policies have multiple and complex impacts across socio-environmental systems, with implications on health. A new policy approach which links Net-Zero considerations with socio-environmental impacts (e.g., air quality, physical activity), and expresses both in terms of optimal health outcomes – rather than legal compliance – can deliver the best outcomes. The overall aim of Heal-NZ is to transform regional Net-Zero policy solutions by adopting a health-centred systems approach. Heal-NZ is co-designed with West Midlands Combined Authority (WMCA), local authorities, Defra, and community stakeholders to address three "live" policies in the WM Decarbonising regional transport Net Zero Neighbourhoods Energy innovation Heal-NZ will first develop a new toolkit (Climate-LAT) integrating environmental exposure modelling, health / economic modelling and participatory systems mapping tools. We will apply this tool to the West Midlands as an exemplar to demonstrate the wider benefits of health-centred systems approach to Net-Zero policies. The Heal-NZ team, supported by two full-time researchers embedded in policy organisations, will integrate science evidence from observations, modelling, and public involvement into systems maps, and translate this evidence into policy domains. With the new toolkit and science evidence, the Heal-NZ team, particularly policymakers, will directly contribute to regional Net-Zero policy decisions, delivering transformative impacts. |
| 30/11/2022 |
£1,833,266 |
NEW YORK UNIVERSITY |
Increased exposure to outdoor air pollution is one of the primary mechanisms for adverse health impacts from climate change. It affects all regions of the world and is a strong motivation arguing for more aggressive climate mitigation efforts. However, despite its overall importance, air quality impacts are currently not included in the economic models and policy tools used to quantify the benefits of prospective climate policies. In response to the recommendations from a recent expert panel, the project team and stakeholders will carry out the necessary work to incorporate changes in air quality, and its associated health impacts, into estimates of the social cost of greenhouse used by federal policymakers in the US and Germany. The project consists of four inter-related components including: delineating which climate-related air quality impacts are suitable for inclusion into social cost of greenhouse gas estimates; quantification of the impacts of unit changes in temperature on ambient pollutant concentrations (primarily mediated through changes in wildland fire emissions and temperature impacts on ground-level ozone); determination of changes in health impacts attributable to climate-related changes in air quality; and incorporation of health impacts of air pollution into the GIVE model to estimate social cost of greenhouse gas values. |
| 30/11/2022 |
£938,611 |
UNIVERSITY OF ABERDEEN |
Reducing meat and dairy consumption is essential to mitigate climate change, but sustainable plant-based diets must be realistic, particularly given the cost-of-living crisis. This project will assess the potential of appealing, nutritionally balanced plant-based convenience foods to overcome barriers to sustainable diets. We will compare plant-based ready meals to home-cooked meals on dimensions of cost, convenience, appeal, nutrition, greenhouse gas (GHG) emissions. We will analyse real-life food decisions of young women in the transition to sustainable diets and co-create scenarios with them illustrating computationally modelled trade-offs between key dimensions. Creative illustrations and scenario narratives will provide accessible insights for policymakers to feed into successful, realistic policy. Using these outputs, we will work with our UK policy partners (heath and climate) to co-produce policy options and actionable climate change mitigation solutions with health co-benefits. Key goals Quantify cost, preparation time, GHG emissions and nutrition of plant-based ready meals and home-cooked meals; Compute GHG emission reductions of substituting meat-based meals with plant-based ready meals; Analyse real-life food decisions and potential impacts of plant-based convenience foods; Identify trade-offs of dimensions associated with plant-based convenience foods; Create visuals and narratives depicting scenarios for realistic sustainable diets; Co-produce with policymakers context-relevant options for policy development. |
| 30/11/2022 |
£1,623,481 |
BOSTON UNIVERSITY |
Some states in the United States are pursuing policies that would require that household appliances have low to zero NOx emissions. Effectively, this would amount to regulations requiring that buildings have electric appliances rather than combustion appliances. These policies are being explored as ways to meet greenhouse gas reduction commitments and as ways to reduce air pollution. Here, we propose to use a novel atmospheric modeling and health impact platform to model potential health benefits of these policies, and then use this platform to support regulations in select states in the United States where these policies are being considered. Specifically, we will identify priority states with live policy opportunities and necessary data, develop potential policy proposals that could be implemented in these states, and model the air quality and health benefits of these policies at high-resolution, using a regulatory grade air pollution and health benefit modeling platform that is commonly used and trusted by state and federal policymakers in the U.S. We will then share results with key stakeholders in the priority states, including air agencies, policy public comment dockets, and other policy stakeholders, along with the public and media. |
| 30/11/2022 |
£2,039,784 |
UNIVERSITY COLLEGE LONDON |
PAICE will inform and evaluate UK Net Zero policies using transdisciplinary approaches to generate and implement evidence. Climate change mitigation policy must consider population health and health equity alongside reductions in greenhouse gas emissions, and would benefit from an integrated, intersectoral approach. We will develop shared priorities with stakeholders, understand current and planned policies, build models to assess their cross-sectoral impact, consolidate a monitoring framework, and evaluate and help accelerate delivery. PAICE brings together experts from four Wellcome-funded projects (CUSSH, SHEFS, Pathfinder Initiative and HEROIC) that have generated evidence on the connections between climate and health in the energy, housing, food and transport sectors. We will: (1) co-develop a programme theory and linked monitoring and evaluation plan, (2) work with the UK Climate Change Committee (CCC) using system dynamics to analyse policy opportunities, (3) build a model of the effects of these policies on population health, health equity and greenhouse gas emissions, (4) apply the findings to the CCC monitoring framework, and (5) use the programme theory to evaluate achievement of processes and objectives. PAICE responds to the opportunity to directly influence national policy development and implementation through the pivotal CCC and by sharing findings with G7 partners. |
| 29/11/2022 |
£2,598,177 |
UNIVERSITY COLLEGE LONDON |
First-line antidepressants target serotonin, dopamine and noradrenaline. A large body of detailed experimental and theoretical work in reinforcement learning (RL) has led to detailed understanding of the roles these neuromodulators play in higher cognitive function, affect and learning, and related them to depression. However, it is unknown if these RL processes are the mechanisms through which antidepressants relieve depression. The translational gap exists because studies in this area have rarely involved patients and have mostly been small cross-sectional rather than substantial longitudinal treatment studies. We propose to definitely test whether specific RL processes are the mechanisms of action by which different antidepressants work. To achieve this, we propose to run two large trials (n=516x2) in which primary care patients with depression are randomized to escitalopram (serotonergic), bupropion (dopaminergic/noradrenergic) or placebo. RL processes will be assessed using online tasks, and through electroencephalography. The first trial will broadly assess RL domains (spanning instrumental and Pavlovian learning, effort and control). The second trial will build on the results and test specific RL mechanisms. We also aim to use our experience to kick-start a new open science approach to facilitate rapid translation of neuroscience findings into treatment improvements in the longer term. |
| 29/11/2022 |
£3,673,010 |
UNIVERSITY OF EDINBURGH |
Lithium has been in use for 70 years and is the most effective treatment for bipolar disorder. It has many actions but the precise mechanism of action in bipolar disorder is uncertain. Recent evidence suggests that lithium may work by stabilizing aberrant circadian rhythms of mood, cognition and rest/activity, possibly via an action at the level of the retina. Specifically, individuals with bipolar disorder who are hypersensitive to the destabilizing effects of excess light in the evening may respond to lithium because it acts on the retina to make light-induced circadian disruption less likely. This is a plausible and exciting hypothesis that, if true, could herald a new era of chronotherapeutic approaches. We will test whether people with bipolar disorder are hypersensitive to evening light stimuli and whether lithium works by increasing retinal resilience to light-induced circadian disruption. In parallel, we will test the effect of light stimuli and lithium treatment on retinal organoid cells derived from individuals with bipolar disorder. People with bipolar disorder are involved in every aspect of this project, from design to dissemination, and we will also co-produce a range of knowledge exchange activities on the theme of ‘Bipolar Disorder, Lithium and Light’. |
| 29/11/2022 |
£828,433 |
KING'S COLLEGE LONDON |
This proposal aims to advance understanding about the effectiveness and mechanisms of problem solving (PS) and behavioural activation (BA) as early interventions for youth depression. Both PS and BA have the potential to be used as brief and effective standalone interventions, yet they have rarely been evaluated outside of multi-component packages. We will investigate these active ingredients in India, which is home to 20% of the world’s youth population, focusing on university students in Delhi who screen positive for subthreshold or case-level depression. A 3-arm, individually randomised controlled trial, with a mediation analysis and embedded process evaluation, will test PS, BA and an attention control condition delivered by Peer Counsellors for N=714 participants. The primary outcome will be self-reported depression at 12 months post-randomisation; self-reported anxiety and social functioning will be secondary outcomes. Intermediate outcomes will be measured at 6 weeks and 6 months. Young people with relevant lived experience will co-adapt existing evidence-based PS and BA protocols prior to the trial. We will also validate measures of putative ingredient-specific and generalised mediators in a pre-trial psychometric study. The project will generate vital evidence on optimally efficient and scalable early interventions for youth depression in low-resource settings. |
| 29/11/2022 |
£1,622,555 |
SANGATH SOCIETY |
This proposal aims to advance understanding about the effectiveness and mechanisms of problem solving (PS) and behavioural activation (BA) as early interventions for youth depression. Both PS and BA have the potential to be used as brief and effective standalone interventions, yet they have rarely been evaluated outside of multi-component packages. We will investigate these active ingredients in India, which is home to 20% of the world’s youth population, focusing on university students in Delhi who screen positive for subthreshold or case-level depression. A 3-arm, individually randomised controlled trial, with a mediation analysis and embedded process evaluation, will test PS, BA and an attention control condition delivered by Peer Counsellors for N=714 participants. The primary outcome will be self-reported depression at 12 months post-randomisation; self-reported anxiety and social functioning will be secondary outcomes. Intermediate outcomes will be measured at 6 weeks and 6 months. Young people with relevant lived experience will co-adapt existing evidence-based PS and BA protocols prior to the trial. We will also validate measures of putative ingredient-specific and generalised mediators in a pre-trial psychometric study. The project will generate vital evidence on optimally efficient and scalable early interventions for youth depression in low-resource settings. |
| 29/11/2022 |
£3,135,991 |
UNIVERSITY COLLEGE LONDON |
Social anxiety and depression are common in young people and often co-occur, leading to substantial impairment. However, young people can also experience great improvements in both their anxiety and depressive symptoms when they are treated with Cognitive Therapy for social anxiety disorder. Our programme will deliver a novel mechanistic understanding of anxiety and depression improvement and enhance our ability to maximise these benefits by answering the following questions: What mechanisms underlie young people’s improvement in anxiety and mood symptoms and how we can maximise these benefits for each individual. Whether the mechanisms of the intervention and their use for treatment seem meaningful and ethically acceptable to young people. We hypothesise that successful Cognitive Therapy for social anxiety relies on positive surprises in social interactions, such that young people experience better outcomes than they expected. We also hypothesise that such surprises only happen if young people modify specific aspects of self-processing, such as self-focused attention and negative self-imagery. We will directly manipulate the putative processes and delineate their neural and interoceptive underpinnings across five work packages. We will examine the ethics and acceptability of our mechanistic research in co-design and co-production with young people in a separate cross-cutting work package. |
| 29/11/2022 |
£2,991,998 |
UNIVERSITY OF OXFORD |
Genetic, epidemiological, and experimental evidence suggests that sleep and circadian rhythm disruption is implicated in the causation of psychiatric disorders. We hypothesise that such disruption influences neurobiological mechanisms that underpin emotion regulation, driving the development and maintenance of anxiety and depression. This research will examine how sleep restriction therapy (SRT), the most effective single component treatment strategy for insomnia, improves mental health. We will perform two randomised controlled trials to test the effects of SRT on sleep physiology, circadian timing, arousal, and neural mechanisms sub-serving emotion regulation. In a third study, we will develop and test an adaptation of SRT - combining it with light therapy - aimed at augmenting depression outcomes. We will recruit young adults because this is the recognised risk period during which symptoms typically incubate, and the time at which early intervention may be most helpful. Our programme of work is informed by lived experience experts, who will be involved in every aspect of the research, and supported by Vocal, an organisation dedicated to inclusive public involvement in health research. Our work will deliver new insights on the link between sleep disruption and mental health, and lead to refinement of sleep intervention for patient benefit. |
| 29/11/2022 |
£5,037,110 |
UNIVERSITY OF EXETER |
Repetitive negative thought (RNT, worry, rumination) influences the onset and maintenance of anxiety and depression. Reducing RNT is an established active therapeutic ingredient. Although cognitive-behavioural therapy (CBT) targeting RNT is effective, the mechanisms underpinning treatment effects are unknown. Our key goals are to delineate the active therapeutic components and associated mechanisms-of-action of CBT targeting RNT, via experimental manipulation of treatment components within internet-delivered RNT-focused CBT and assessment of mediators in a large-scale factorial trial for individuals with elevated RNT. Combining components in a factorial experiment is more efficient for sample size and resource than conducting separate experiments and better tests the main effects and interactions of each factor than dismantling designs. Hypothesized mechanisms include (i) shifting from overgeneral abstract to specific thinking; (ii) breaking out of RNT-as-a-habit; (iii) replacing self-criticism with self-compassion; (iv) improved present-moment focus; (v) increased patient understanding of difficulties. People with Lived Experience will shape research questions and design: they will guide prioritising which mechanisms-to-study and they will co-design adaptations to existing interventions to better manipulate these mechanisms. This novel project will test these hypotheses experimentally, leading to more potent, economical, and accessible treatments for RNT available via an online platform to transform early intervention. |
| 29/11/2022 |
£5,364,467 |
THE FRANCIS CRICK INSTITUTE |
The first-line treatment for early psychosis is antipsychotic drugs. Antipsychotic drugs efficaciously reduce psychotic symptoms but have severe side effects. To advance interventions for early psychosis, it is crucial to understand the specific mechanisms mediating the therapeutic effects of antipsychotics so that they may be segregated from the mechanisms mediating adverse effects. Emerging evidence suggests that psychosis can be caused by immune responses targeting the brain, and that antipsychotic drugs favourably modulate this immune dysregulation. Here, we aim to elucidate whether and how immune processes contribute to antipsychotic treatment response. Drawing on our combined expertise in neuroscience, immunology, and psychiatry, we shall integrate investigations of blood and cerebrospinal fluid from individuals affected by psychosis with mechanistic investigations in mouse models. We shall use unbiased, high-throughput, high-resolution immunophenotyping alongside targeted immunological assays to delineate the immune processes most affected by antipsychotic treatment. Exploiting our mouse model for psychosis-like behaviour, we shall use causal interventions to validate these immune mechanisms underlying observed antipsychotic effects. Appropriate data-sharing pipelines will ensure that our findings provide a resource for future research. By systematically interrogating the immune system during antipsychotic treatment, we expect to gain mechanistic insights to guide future targeted immune-based interventions for early psychosis. |
| 29/11/2022 |
£4,404,593 |
UNIVERSITY COLLEGE LONDON |
The sense you have of the internal state of your body—interoception—is key to detecting, interpreting, and regulating emotion. Interoception is a common mechanism underlying emotion-based active ingredients targeted in the treatment of anxiety and depression: affective awareness, emotional granularity, emotional controllability, and emotion regulation. We propose a three-stage approach to assess, augment, and clinically track interoceptive mechanisms of emotion in mental health treatments. In WP1, we will establish a comprehensive battery of interoceptive assessments and determine their links with emotion-based active ingredients, depression and anxiety, allowing us to characterise dimensions and disruptions of interoceptive signaling on an individual basis. In WP2 we will demonstrate causality, showing how targeted modulation of interoception across different hierarchical levels improves emotion-based active ingredients. In WP3, we will use reverse-translation to link efficacy of an established treatment, mindfulness training, to enhancements in emotion-based active ingredients and their interoceptive mechanisms. Experiments will take place across the UK and Argentina, fully integrating lived experience expertise from conceptualization to dissemination. Uncovering the interoceptive mechanisms of emotion-based active ingredients could transform treatment options, helping identify who might benefit from interoceptive targeting, and leading to the development of interoceptive ‘boosters’ to improve treatment outcome for depression and anxiety |
| 29/11/2022 |
£3,699,108 |
UNIVERSITY COLLEGE LONDON |
Depression is very common, and has a devastating impact on people’s lives. Physical activity is an effective treatment, but the mechanisms driving symptom improvement, particularly psychological and brain processes, remain unclear. Such information could help inform new treatment strategies. We hypothesise that physical activity boosts reward processing, specifically effort-based decision-making, through reducing inflammation, increasing dopamine transmission and modulating reward-processing brain circuitry. We will test this hypothesis with a mechanistic randomised controlled trial in 250 depressed participants, undergoing eight weeks of either aerobic exercise (active intervention) or relaxation/stretching (control). To measure reward processing we will use computerised cognitive tests combined with computational modelling. We will assess changes in reward/effort-processing brain circuity using functional neuroimaging, dopamine using positron emission tomography, and acquire blood samples to assess immune-metabolic markers. We predict that exercise will initially preferentially improve depressive symptoms related to motivation and cognition, which we will test using dynamic structural equation modelling of daily smartphone measurements. This design allows us to answer three central questions addressing causality: whether exercise changes these proposed mechanisms (modulation); the degree to which such changes are related to improvements in symptoms (mediation); and whether symptomatic improvement following the exercise intervention can be predicted from baseline measures (moderation). |
| 29/11/2022 |
£4,459,478 |
UNIVERSITY OF CAMBRIDGE |
In an uncertain situation, people rely on clues from the environment – things known to be predictable from past experience – to determine what will happen next. If someone cannot predict what will happen next, anything could seem like a threat. Intolerance of uncertainty is increasingly recognised as a key risk factor in a range of mental health difficulties, most notably anxiety disorders. Research suggests that two neurotransmitters targeted by anti-anxiety medication, serotonin and noradrenaline, are crucially involved in how the brain represents uncertainty. Furthermore, psychological therapies incorporate various techniques (e.g., reinterpretation) targeting the belief that uncertainty is threatening. We propose that these two effective interventions act via a common core causal mechanism: altered uncertainty processing. To address this, we will use computational models that can capture an individual's ‘uncertainty fingerprint’ – a measure of how people process different kinds of uncertainty in different cognitive contexts. By working across scales and species, we will reveal how anxiety medications and psychological therapy improve symptoms via changes in how the brain encodes uncertainty, moving from cells and circuits to clinical treatment. This primes the field for the development of precision medicine approaches in anxiety, tailoring treatments according to each person's 'uncertainty fingerprint'. |
| 29/11/2022 |
£2,701,827 |
UNIVERSITY OF OXFORD |
The efficacy of the selective serotonin reuptake inhibitor (SSRI) fluoxetine has been well characterized in young people with depression. However, our understanding of how SSRIs work in this age group is still in its infancy. Developmental differences affect symptoms, diagnosis, and treatment response in depression, highlighting the need for age-specific development of experimental medicine models to understand treatment action. The current proposal will therefore take a developmental and interdisciplinary approach to analyse how fluoxetine affects neurocognitive function relevant to adolescents with depression. WP1 defines the measures used in this work together with our young advisors with lived experience and utilizing pilot data from our lab focused on anger/irritability, a core debilitating presentation of youth depression. We will perform detailed mechanistic studies in healthy volunteers to isolate markers of fluoxetine treatment (WP2) and apply these to adolescent depression to characterise mechanisms of clinical response (WP4) as well as withdrawal from treatment (WP5). We will also use complementary affective models in adolescent rodent models to refine our mechanistic model development (WP3). A better understanding of the mechanisms underpinning the effects of SSRIs in young people with depression will help formulate human experimental medicine models to optimize treatments of the future. |
| 29/11/2022 |
£4,715,101 |
KING'S COLLEGE LONDON |
This proposal will use genomic approaches to advance our mechanistic understanding of antidepressant action and response. We will leverage recent advances in causal inference, electronic health data and genomic datasets to deliver real-world antidepressant exposure and response data at an unprecedented scale to better understand the active ingredients of how antidepressants work and why individuals vary in their response. We will openly share new methods and datasets generated from this project. This proposal will deliver mechanistic insights, paving the way for clinical predictors of antidepressant action, framed by lived experience throughout. Our key goals are to Develop measures of antidepressant exposure and response from NHS electronic health records, linked to research studies and genomic datasets Provide large, publicly available genome-wide association study datasets of antidepressant exposure and response Provide association study datasets of antidepressant exposure and genomic markers (DNA methylation, protein expression, metabolites) Use these genomic association datasets to improve our mechanistic understanding of antidepressant actions and response. Test the results from our genetic studies in experimental cell-based in vitro models Conduct our research in collaboration with individuals with lived experience to increase trust, facilitate research that is relevant and important to patients, and improve dissemination and impact |
| 29/11/2022 |
£1,361,279 |
INSTITUTO NACIONAL DE SALUD PUBLICA |
Rural community members in Low and Middle Income Countries (LMIC) are particularly vulnerable to heat-related illness (HRI) due to their reduced access to healthcare, significant numbers of outdoor workers namely in agriculture, aging demographics, and higher rates of poverty and marginalization. At the same time, Action plans that include an early warning system, capacity building for healthcare workers to identify, prevent, or treat heat-related illness, and information dissemination have been shown to consistently positive results that aide the public in understanding and evaluating their own risks and take the appropriate steps for prevention and preparedness. The goal of this project, therefore, is to reduce HRI and mortality rates in our rural partner communities in southern Mexico through the development of a community-based heat action plan. Working in six rural communities of similar size and socio-economic profiles, our team will co-develop, test, and evaluate a locally relevant, culturally appropriate, user-driven heat-health action plan consisting of an 1) early warning and surveillance system, 2) capacity building and network for healthcare workers to identify and respond to HRI, and 3) prevention education and communication tools to address local heat-health risk management challenges including an inter-community information sharing network and communication platform. |
| 29/11/2022 |
£1,923,263 |
WITS HEALTH CONSORTIUM (PTY) LTD |
Temperatures in Southern Africa are rising at twice the global rate, with major health implications for maternal and newborn health. The HAPI study aims to advance heat-adaptation policies and practices in low- and middle-income countries. We will develop and test a multi-level (from individual- to international policy-level) and multi-component intervention, encompassing behavioural, built environment, nature-based, health services, and policy components. Following multi-layered ethnographic observations, and thermal, emissions and cost-consequences modelling, we will co-produce an intervention package based on progressively-optimised programme theory. The intervention will be refined over two action-research cycles, each lasting six months. We will apply a quasi-experimental design involving 1600 women pre- and post-intervention to assess process, feasibility, cost and biomedical outcomes. Activities will take place in six maternity facilities, and surrounding communities and households in urban Tshwane, South Africa, and rural Mount Darwin District, Zimbabwe. These areas have contrasting climatic conditions, economies, and socio-cultural practices, allowing for greater transferability of findings. The study builds on a Horizons Europe project and related field experience. Capacity-building at individual-, institutional- and societal-level will be integrated into all research activities, and take place within inclusive and diverse research environments. Key words: Climate change, maternal and newborn health, heat-related adaptation, southern Africa |
| 29/11/2022 |
£2,059,071 |
UNIVERSITY OF CAPE TOWN |
Robust evaluation of the environmental, health and socio-economic outcomes of heat adaptations are limited for Africa, especially in real-world settings, despite high vulnerability to heat-related health risk. HABVIA aims to address these evidence gaps by gathering high-quality cohort data on physiological and mental health, alongside climate, environmental and socio-economic information, in four heat-vulnerable study sites in Ghana and South Africa where heat adaptations are underway or can easily be implemented because of pre-existing community-health research partnerships. The project will focus on physical and behavioural adaptation for two vulnerable groups, manual labourers and informal/low-income house dwellers, as well as the development and testing of adaptation-relevant heat warning systems. Capacity building of African health-climate researchers will be leveraged via two African research assistants who will enroll for PhDs, one UK PhD student, ideally from a developing country, three African post-doctoral researchers, development and delivery of heat-adaptation summer/winter training schools, and pro-active engagement in the growing Africa and global health-climate communities of practice. HABVIA’s interdisciplinary team comprises leading researchers from climate risk and adaptation science, climate-health research, public health, international development and behavioural science, with collaborators from national meteorological agencies and humanitarian/development non-governmental organisations. |
| 29/11/2022 |
£1,995,263 |
THE AGA KHAN UNIVERSITY, PAKISTAN |
Climate change has resulted in increased average global temperatures and increased number, duration and intensity of extreme heat events with South Asia emerging as one of the worst affected regions. The objectives of this study are to 1)synthesize global evidence-base of community interventions for heat adaptation/reduction strategies; 2)conduct an assessment of feasibility and acceptance of possible interventions through community participation and pilot testing; 3)evaluate a heat adaptation and reduction bundle (HAB) comprising of education, behavioural change and incentivized structural interventions through a cluster randomized controlled trial(cRCT). The intervention will be implemented in a representative urban and rural setting of Pakistan and target children, women including pregnant women, and other vulnerable adult labourers and elderly. The cRCT will primarily evaluate the impact of HAB on heat-related illnesses and a range of secondary outcomes including standardized heat measurements at household level, physiological strain, dehydration, thermal comfort/sensation, sleep hygiene, pregnancy outcomes (gestational weight gain, low birthweight, preterm births, stillbirths), mental health and overall cost effectiveness 4)assess the feasibility, and generalisability of scaling up the trial findings. This project will emphasize capacity building and gender equity and findings will be disseminated to relevant policy makers and researchers globally for potential uptake in other LMICs. |
| 29/11/2022 |
£2,081,241 |
KENYA MEDICAL RESEARCH INSTITUTE (KEMRI) |
Heat stress and strain result in heat-related illnesses that affect an individual´s ability to work and reduce economic productivity at the community level. While the body maintains a heat balance through the thermoregulatory system, an increase in heat load overwhelms the body leading to illness. Global warming is expected to exacerbate heat-related illnesses, especially in Africa. To mitigate these consequences, it is important to maintain indoor temperatures within recommended thermal comfort zones. This is achieved through openings on dwellings such as doors, windows, and eaves. These openings are often not oriented to achieve cooling indoors, and double up as entry points for malaria mosquitoes further risking the health of occupants. We propose to implement simple house modifications with screened windows, doors, and eaves to provide cooling while preventing indoor entry of mosquitoes ultimately attaining thermal comfort and lowering the incidence of malaria. |
| 29/11/2022 |
£1,765,253 |
LEAD FOUNDATION |
The UN has declared 2021-2030 as the decade of ecosystem restoration, and identified trees in agricultural landscapes as a viable means of meeting sustainable development goals. This is due to the pivotal role of trees in climate change adaptation and mitigation. The human health benefits of such restoration in mitigating against heat-stress is poorly evidenced. Outdoor agricultural workers are among the worst affected by extreme heat exposure. In Tanzania, this workforce forms 70% of the working population, making heat exposure both a health and economic concern. The proposed study will be most comprehensive work to date, evaluating the role of trees in mitigating the health effects of extreme heat exposure on agricultural workers. We will work with local and international experts in medicine, epidemiology, forestry, climatology, agriculture, and anthropology, and build on our land restoration work in Tanzania which has championed local farmers to regenerate 9 million native trees. The research will start by understanding heat risk and local adaptation practices, and thereafter, evaluate how trees on croplands alter microclimates to potentially protect workers against chronic kidney disease, dehydration, and cardiovascular strain. The findings will be disseminated through bespoke education and training packages co-developed and co-delivered with local stakeholders. |
| 29/11/2022 |
£1,916,402 |
UNIVERSITY OF AUCKLAND |
Adaptation is essential for mitigating adverse human health effects from increasing heat exposure. However, we currently lack evidence – generated through empirical studies – guiding the uptake of interventions to reduce heat stress in low- and middle-income countries (LMICs). Preliminary findings from our ongoing trial in Nouna, Burkina Faso, show that affordable sunlight reflecting cool-roof coatings reduces indoor temperature up to 2.7 °C leading to possible health benefits. We leverage our expertise in executing housing-health intervention trials to conduct a global multi-centre study of cool-roof effectiveness on health (environmental and economic) outcomes in four urban LMICs – Ouagadougou, Burkina Faso (sub-Saharan Africa), Ahmedabad, India (Asia), Niue (Oceania), and Sonora, Mexico (Latin America). Selected sites represent hotspots where people experience a triple burden from heat exposure, chronic health issues and vulnerable housing conditions (slums, informal settlements and low socioeconomic housing). The four sites exhibit diversity in climate profiles, level of socioeconomic development, population density and rates of urbanisation. Our trial will test the reproducibility of results globally and quantify whether cool roofs are an effective passive home cooling intervention with beneficial health effects for vulnerable populations. Findings will inform global policy responses on adaptation to increasing heat exposure from climate change. |
| 29/11/2022 |
£1,954,922 |
INSTITUTE OF ECONOMIC GROWTH |
Heat Stress is a growing concern in India, although the magnitude and pattern of health risks and impacts is insufficiently understood. Effective interventions are needed in a context of rising heat waves to protect those most at risk. This research, to be conducted through field studies in Bhubaneswar and Jodhpur, will: 1) evaluate the effectiveness of interventions specified within Heat Action Plans for reducing heat related health risks for children, elderly and outdoor workers; and 2) identify, pilot, and evaluate additional (household) heat adaptation measures at selected field sites in these two cities in India. The key outcomes of the research include: mapping of heat-stress exposure pathways; quantified heat-related health outcomes and healthcare seeking behaviour; assessment of ongoing programmes and policies; identification and testing of additional interventions from pilots and simulations on the built environment; costs of heat-health risks and cost-effectiveness of interventions that reduce health risks; capacity building, and policy engagement. The outcomes will be synthesized to document and quantify the effectiveness of interventions on the key domains of health risk reduction, economic feasibility, social acceptability, and regulatory and policy viability for heat-health adaptation interventions, highlighting lessons for policy and practice in low and middle-income country contexts. |
| 29/11/2022 |
£153,636 |
UNIVERSITY COLLEGE LONDON |
Heat Stress is a growing concern in India, although the magnitude and pattern of health risks and impacts is insufficiently understood. Effective interventions are needed in a context of rising heat waves to protect those most at risk. This research, to be conducted through field studies in Bhubaneswar and Jodhpur, will: 1) evaluate the effectiveness of interventions specified within Heat Action Plans for reducing heat related health risks for children, elderly and outdoor workers; and 2) identify, pilot, and evaluate additional (household) heat adaptation measures at selected field sites in these two cities in India. The key outcomes of the research include: mapping of heat-stress exposure pathways; quantified heat-related health outcomes and healthcare seeking behaviour; assessment of ongoing programmes and policies; identification and testing of additional interventions from pilots and simulations on the built environment; costs of heat-health risks and cost-effectiveness of interventions that reduce health risks; capacity building, and policy engagement. The outcomes will be synthesized to document and quantify the effectiveness of interventions on the key domains of health risk reduction, economic feasibility, social acceptability, and regulatory and policy viability for heat-health adaptation interventions, highlighting lessons for policy and practice in low and middle-income country contexts. |
| 29/11/2022 |
£1,967,644 |
MONASH UNIVERSITY MALAYSIA |
Increasing heat exposure will profoundly influence human health in the following decades, particularly in climate-vulnerable countries in Southeast Asia. In Malaysia, heat-related mortality is projected to increase by 295 percent by 2030. More heatwaves will increase, as will severe rainstorms and tropical cyclones. To strengthen heat adaptation in Southeast Asia, we will evaluate simple behavioral and structural interventions that have the potential to protect vulnerable communities from the health effects of extreme heat. Addressing climate change and health requires fundamental behavioral changes in individuals and communities to prevent them from the adverse health effects of heat. We will introduce interventions that will strengthen heat health literacy and fluency for individuals and communities (behavioral intervention). Climate change adaptation is critical for vulnerable groups to cope with rising average temperatures and severe heat waves. As a structural intervention, we will test a passive cooling (cool roof) technology to decrease indoor exposure to extreme heat. The South East Asia Community Observatory (SEACO) health and demographic surveillance system (HDSS) serves as a solid foundation to conduct these interventions, equipping it with individual, home-based, and community-based sensors to enable cutting-edge climate change and health research, focusing on heat effects on health. |
| 24/11/2022 |
£807,024 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
The hypnozoite stage of Plasmodium vivax malaria causes relapsing infections, responsible for a high proportion of clinical and > 70% of recurrent infections. Relapses may also be critical for the onward malaria transmission to mosquitoes and undermine malaria elimination efforts. However, the precise contribution of relapses has yet to be quantified. I hypothesize that the rapid production of P. vivax gametocytes renders many relapsing infections transmissible, but that acquisition of specific immunity will reduce transmission efficiency. My proposal aims to examine the infectivity of relapsing infections compared to incident infections and identify the key host and parasite factors that influence transmission. I will compare the kinetics of parasite and gametocyte densities in the incident and recurrent infections and integrate these data with a detailed assessment of transmissibility to mosquitoes in relation to the transmission-modulating effect of antibody responses to gametocyte antigens. I will deploy advanced genotyping tools to determine the genetic associations between the incident and recurrent infections in humans and subsequent mosquito infections. My proposal will provide the most comprehensive assessment to date of parasite kinetics and transmissibility in natural P. vivax infections, quantifying the importance of relapse infections to the infectious reservoir and informing malaria control and elimination strategies. |
| 24/11/2022 |
£718,730 |
CARDIFF UNIVERSITY |
In this fellowship, I will transform our understanding of the pathophysiological events behind the development of Alzheimer’s disease (AD). The prevailing theory of AD progression is neuron-centric and provides no explanation for the silent incubation period of AD. The very latest non-invasive neuroimaging techniques can now robustly quantify new biomechanical and compartment-specific microstructural features in vivo. An extensive, multi-domain characterization of AD pathology can potentially discover perturbations initially amenable to treatment before pathology develops into irreversible, progressive neurodegeneration. Knowledge on changes to the cellular microstructure and glial reactivity related to chronic neuroinflammatory processes is limited, particularly before the emergence of the typical hallmarks of AD (amyloid plaques, neurofibrillary tau, and neurodegeneration). To address these important knowledge gaps, I will longitudinally examine brain health in midlife with and without inherited AD predisposition (APOEepsilon4 carriership) by combining state-of-the-art magnetic resonance elastography (MRE) and diffusion-weighted magnetic resonance spectroscopy (dMRS), with novel causal inference statistics. My original published work using advanced MRE to understand the biomechanics of aging and neurodegeneration is recognized internationally. Basing my Fellowship at CUBRIC, a world-leading site for microstructural neuroimaging, puts me in an unrivaled position to answer these questions.
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| 24/11/2022 |
£448,393 |
UNIVERSITY OF MANCHESTER |
Climate change will impact the epidemiology of infectious diseases globally, with fungal infections posing a particularly serious challenge, imposing an economic burden on healthcare ( > $10 billion globally) and causing 1.5 million deaths annually. The spread of fungal species towards the poles due to climate change has already been observed, as has an increase in abundance of thermophilic and pathogenic fungi coupled with rising levels of antifungal resistance. Together these factors have driven increasing prevalence of fungal infections in humans, animals and crops and have reduced available treatment options. Aspergillosis in the UK and continental Europe is generally caused by Aspergillus fumigatus, but interestingly in other parts of the world, such as Pakistan, India and the Middle East A. flavus dominates. It is assumed A. flavus is better adapted to hot climates. The impact and risks of climate change on fungal diseases is currently very poorly understood. My aim, therefore, is to understand adaptation of Aspergilli to thermal and antifungal stresses, and how these fungal traits combine to determine the establishment and severity of infections.
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| 24/11/2022 |
£647,303 |
AFRICA HEALTH RESEARCH INSTITUTE |
Defining the mechanisms that determine the size of the viable HIV-1 reservoir will be crucial for the success of HIV-1 eradication strategies. HIV-1 reservoirs are maintained through cellular longevity or clonal expansion. Since energy metabolism is closely linked to cellular function, quiescent or activated cells have different bioenergetic needs and variable metabolic profiles. Moreover, in HIV-1 infection, the bioenergetic profile of immune cells is a major determinant of their susceptibility to infection and fate. The modulation of immunometabolism as a promising new approach for HIV-1 cure is hampered by paucity of information on determinants of cellular metabolism and how metabolism influences HIV-1 reservoir characteristics and its reactivation potential. I hypothesize that the immunometabolic profile during acute HIV infection is influenced by transmitted/founder viruses’ characteristics and these associate with the immune modulatory activity of replication-competent viral reservoirs following suppressive antiretroviral therapy. I will study cellular and plasma metabolic profiles prior to and during treated acute HIV-1 infection, alongside transmitted/founder virus replication capacity and HIV-1 reservoir profiles. These studies will elucidate biological determinants of altered cellular metabolism following HIV-1 infection and how these link to virus and reservoir characteristics. This information may open new strategies for HIV-1 cure or long-term remission.
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| 24/11/2022 |
£582,893 |
UNIVERSITY OF CAMBRIDGE |
The sequelae of children and young people's (hereafter: CYP) mental disorders are broad and long-lasting.1,2 Despite pledges to increase mental health funding in the UK,3 CYP experience difficulties accessing services and long wait times.4 Since the start of the COVID-19 pandemic, population studies suggest that CYP’s mental health deteriorated,5–8 with a 53% increase in contacts made to CYP’s mental health services (MHS) in England compared to before the pandemic.9 Given rising demands, it is crucial that MHS for CYP are optimised. There is a paucity of information regarding effectiveness of treatment-as-usual MHS in CYP, with uncertainties regarding which individuals improve, and whether similar outcomes would be seen without treatment.10 This proposal aims to:
assess the effectiveness of community MHS on CYP’s mental health and functioning compared with those who do not to access treatment;
better understand which MHS contacts are helpful for whom (moderation) and why (mediation);
determine whether prior contact with MHS protect CYP against pandemic-related impairments and under what circumstances.
Findings will inform clinicians and policy makers of how to optimise the effectiveness of MHS, and to improve commissioning and delivery to better meet the needs of CYP.
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| 24/11/2022 |
£1,244,028 |
UNIVERSITY OF CAMBRIDGE |
Almost all effective vaccines rely on antibody-mediated immunity. Despite increasing evidence that antibodies play a role in immunity to tuberculosis (TB), the current pipeline of TB vaccine candidates has focused on eliciting cellular immunity. One critical bottleneck that prevent maximising the utility of antibody-mediated immunity for novel TB vaccines is lack of understanding how antibodies protect against infection by M. tuberculosis (Mtb). To address the mechanisms of antibody-mediated immunity, our preliminary data supports a role for antibodies in stimulating inflammasome-mediated interleukin-1beta release from Mtb-infected macrophages. Using genetic and chemical tools, we will determine the mechanisms by which inflammasome stimulation mediates protection, both in vitro and in animal infection. Moreover, we have shown that protective antibodies alter the relative abundance and activation status of both innate and adaptive effector cells in the Mtb-infected murine lung. Using single-cell RNA sequencing, we will identify the cellular phenotypes and spatial organisation associated with antibody-mediated protection. Finally, I will investigate the role of activatory and inhibitory Fc receptor signalling in mediating antibody-mediated protection. Taken together, the proposed studies will help rationally improve future TB vaccines taking into consideration antibody-mediated immunity.
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| 24/11/2022 |
£486,626 |
KING'S COLLEGE LONDON |
The cGAS-STING pathway has emerged as an essential innate immune sensing system, which recognizes DNA and triggers potent innate immune responses. In addition to DNA from various pathogens, cGAS can also recognise endogenous DNA in micronuclei, chromatin fragments, mitochondrial DNA and DNA derived from retrotransposons, resulting in the formation of membraneless cGAS-DNA phase-separated organelles. Regulation of DNA sensing by cGAS is critical in preventing autoinflammatory diseases such as Aicardi-Goutières syndrome. Although cGAS mediated induction of IFN by cytoplasmic DNA derived from aforementioned sources is extensively studied, the spatiotemporal, biochemical and functional fate of the DNA detected by cGAS has not been investigated. Furthermore, it remains unknown how the pathway is regulated in the phase-separated organelles to allow efficient immune responses without resulting in pathological aggregates. My preliminary data indicates that cGAS silences foreign DNA in a STING/IFN independent manner. In this project, I will carry out mass-spectrometry guided CRISPR-Cas9 and siRNA screens to identify cGAS co-factors that regulate cGAS-DNA phase-separation and couple DNA sensing with DNA silencing. In addition to providing a better understanding of fundamental aspects of cGAS functions within the cell, improved insights into these aspects will inform the development of potential therapeutic strategies in many auto-inflammatory diseases.
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| 24/11/2022 |
£1,054,112 |
UNIVERSITY OF CAMBRIDGE |
Hypoxia-inducible factors (HIF-1/HIF-2) are oxygen-regulated transcription factors with widespread roles in adaptive physiology. HIFs also have roles in development that are less well understood but could provide a mechanism for observations that developmental hypoxia programmes adult cardiovascular dysfunction. HIF-2 is of particular interest, given that HIF-2-activating mutations (pseudohypoxia) drive chromaffin cell tumours (pheochromocytoma/paraganglioma: PPGL).
HIF-2 expression in PPGLs is associated with downregulation of PNMT, which catalyses adrenaline biosynthesis and labels differentiated chromaffin cells. My work on pseudohypoxic mice links loss of PNMT+ chromaffin cells to expansion of cells overexpressing HIF-2, which are disorganised in peri-adrenal locations, suggesting impaired migration and differentiation of sympathoadrenal precursors. Here, I will exploit sympathoadrenal development as a paradigm for understanding how hypoxia controls development, the embryonic stages most susceptible, and the HIF-2-dependent component.
I will use chicken embryos and sympathoadrenal differentiation of human iPS cells as complementary models of development that allow hypoxic, pharmacological and genetic interventions activating HIF-2, without confounding effects of materno-placental physiology, and provide the potential to follow effects on adult chickens. These tractable approaches will allow me to determine how and when hypoxia affects proliferation, migration and differentiation of chromaffin precursors, and how hypoxia/HIF-2 impacts adult physiology to programme cardiovascular disease.
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| 24/11/2022 |
£734,944 |
UNIVERSITY COLLEGE LONDON |
Sexualised drug use (SDU) refers to using drugs before/during sex. ‘Hi-fun’ in Thailand (‘chemsex’ in Western settings) is the intentional use of specific substances (e.g. methamphetamine, GHB/GBL) to prolong sex with multiple partners. Men-who-have-sex-with-men’s (MSM) SDU is a global public health concern because of negative impacts on wellbeing, mental and sexual health.
MSM SDU is increasingly visible in Thailand, where unique sociocultural/political environments shape sexual cultures and harms. Research investigating the diversity of SDU practices, who experiences which harms and which groups might benefit from support is urgently required.
Focus groups will explore boundaries between hi-fun and other SDU. Systematic mapping will identify potential interventions. Online surveys of SDU-engaged MSM (n=1000+) will examine behavioural patterns, harms and intervention acceptability. In-depth interviews and diaries will explore SDU accounts; data will be interwoven with survey latent class analysis, producing innovative, mixed-methods grounded theory, informed by transnational queer sociology, exploring how economic growth, globalisation, criminalisation and pleasure shape SDU cultures. Finally, workshops will synthesise findings with the COM-B model of behaviour change, co-developing a care framework supporting service provision.
This interdisciplinary multi-method research will transform understandings of how social/economic forces shape SDU cultures and co-develop innovative support strategies for SDU-engaged MSM in Thailand.
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| 24/11/2022 |
£670,368 |
NEWCASTLE UNIVERSITY |
Treatment of bacteria with several classes of antibiotics leads to generation of reactive oxygen species that damages DNA. Single and double-strand DNA breaks result in genetic instability and cell death if not repaired, however at present we lack a full understanding of damage repair pathways. To address this, I developed a novel CrispR-Cas approach to introduce one single or double-strand break at a defined position on the bacterial chromosome. As proof of concept, I used this to identify novel proteins essential for DNA repair in the model organism Bacillus subtilis. I have now adapted this to study DNA repair in the related bacterium Staphylococcus aureus, a critical drug-resistant pathogen. Importantly, my preliminary data showed that homologs of Bacillus proteins are also indispensable for DNA repair in S. aureus. I will build on these findings to define the repertoire of proteins essential for S. aureus DNA repair and how they interact with one another during repair processes. I will investigate the requirement of repair pathways for virulence and their potential to be targeted by small molecule inhibitors. Collectively this work will define essential pathways for genome maintenance in an important human pathogen that may serve as targets for antibacterial drug development.
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| 24/11/2022 |
£496,120 |
UNIVERSITY OF OXFORD |
Animals can form predictive associations of environmental cues with the availability of rewards such as food or sex, which aids future resource procurement. Across phyla dopaminergic neurons are central to coding of predictive associations. However, it is poorly understood how dopaminergic neurons encode cue and the reward information and how they distinguish between different types of reward and deprivation states. For instance, animals that are hungry are more likely to seek food associated cues while ignoring sex associated cues, but it is unclear how neural mechanisms permit these adjudications. It is therefore essential to determine how satiation states influence the robustness of reward signals. Anatomy and transcriptomics have established that dopaminergic neurons are heterogeneous which raises the possibility that distinct dopaminergic neuron subtypes provide reward-specific roles in these motivational processes. This proposal aims to understand neuronal mechanisms that allow satiation state to gate behavioural approach of a reward associated cue, at the level of single dopaminergic neurons using behavioural neurogenetics and in-vivo electrophysiology. The results will have relevance across phyla for understanding how the brain encodes reward. These findings will also inform how dysregulated reward seeking can give rise to disease states such as addiction and depression.
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| 24/11/2022 |
£252,177 |
UNIVERSITY OF EXETER |
This is an anthropological investigation of the moral terrains navigated by those engaged in Green Social Prescribing in the UK. Green Social Prescribing is a new government initiative intended to tackle health inequalities and improve mental wellbeing while simultaneously alleviating the need-supply shortfall in NHS mental health provision. Green Social Prescribing involves referring people into voluntary sector organisations that engage with nature, including city farms and gardening groups. My research uses 13 months of ethnographic fieldwork and two rounds of semi-structured interviews to investigate the moral experience of being prescribed access to nature and the moral challenges involved in delivering this form of care. This research attends to staff and service users' perspectives and explores Green Social Prescribing as a site of multiple and sometimes conflicting moral values. It investigates how the ideals of connecting well with nature, and connecting well with others, interact with biomedical sensibilities. It considers how responsibilities and obligations are distributed, negotiated and experienced. Finally, it investigates the impact of particular environments on the moral relationships formed within them. This research is ground-breaking, in that it initiates a new trajectory for medical anthropology, investigating the role morality plays in mediating relationships between nature and health.
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| 24/11/2022 |
£387,542 |
UNIVERSITY OF OXFORD |
This project will explore the role and impact of health provision on people inside immigration detention centres in Greece and after release. The focus will be on Greece as a key entry point for migrants and asylum seekers and a testing ground for European policies. The extant, albeit limited, scholarship has focused almost exclusively on the detrimental effects of immigration detention on the physical and mental health of those behind bars. This project seeks to make a unique and timely contribution to the literature by examining how the immigration and public health systems coalesce in detention to shape and legitimate these contested institutions. Drawing on a range of sources of evidence, it will also explore the continuity of experiences of medical care across and beyond these spaces and through time. Taking an historical approach, it will trace connections between zones of quarantine and confinement for those deemed undesirable in the country. Empirically grounded, this project will consist of fieldwork in four immigration detention facilities and in the community with a wide range of actors. Ethnographically oriented, it seeks to make visible the people confined within these hidden spaces.
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| 24/11/2022 |
£471,250 |
KING'S COLLEGE LONDON |
International cancer classifications are fundamental to oncology. They structure diagnostic routines, research programmes, treatment pathways, and grounds for correspondence and comparison across settings. They are vital to cancer epidemiology, which influences national and global health investment and policy. Importantly, the process of classification is not simply a matter of discerning biological difference; it also demands ethical and political choices, which have major social consequences around the world. They are made largely by classification experts in elite settings in the Global North and overseen by the WHO's International Agency for Research on Cancer. Decision-making is therefore rooted in particular moral frameworks and assumptions about technical capabilities for diagnosis, which might not be appropriate to the situations of practitioners (and patients) in low- and middle-income countries, who often face the challenges of severely limited resources and healthcare infrastructure. I will address these urgent concerns in my fellowship through a 5-year multi-sited ethnographic research project with a regional focus on Sub-Saharan Africa—a region with generally extremely limited cancer diagnostics and treatments, and what as been described as an emerging cancer epidemic—and a disease focus on brain cancer—an aggressive and highly complex disease, understandings of which are currently undergoing major change.
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| 24/11/2022 |
£707,047 |
UNIVERSITY OF CAMBRIDGE |
Molecular profiling and lineage tracing studies have revealed that a sub-set of cell types with highly convergent cellular states are commonly generated multiple times during embryonic development by non-identical differentiation pathways. For example, blood forming endothelial cells, called haemogenic endothelium (HE), arise in sequential waves during embryogenesis from various precursor embryonic tissues. How alternative differentiation pathways affect the molecular and functional properties of highly convergent cell types is poorly understood. To explore the role of developmental history in the face of molecular convergence, I will dissect the intrinsic and extrinsic regulatory networks that coordinate HE differentiation. This project will exploit comprehensive unpublished transcriptomic datasets that capture various waves of HE formation during mouse embryonic development. I have developed a robust embryonic stem cell differentiation model of HE formation that I will use as a platform throughout this project to: (i) identify extrinsic conditions that drive HE formation via alternative pathways, and (ii) investigate intrinsic molecular programmes that coordinate HE specification and drive development of its chromatin landscape(s). This research will improve our understanding of the mechanisms that regulate acquisition of cellular identities during embryogenesis and aid the development of new technologies for regenerative medicine.
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| 19/10/2022 |
£9,557,976 |
UNIVERSITY OF MANCHESTER |
Extracellular matrix is essential for multicellular life. As a third of body mass, it surrounds cells, defines tissue architecture, and provides instructive signals for diverse cellular processes. Altered matrix is a hallmark of almost all genetic and acquired disorders leading to debilitating tissue degeneration and fibrosis. Major gaps in understanding the normal assembly, maintenance and turnover of matrix have limited disease studies and prevented the development of effective matrix-targeted therapies. Our goal is to identify strategies to reprogramme matrix and thereby prolong tissue health. However, there are key conceptual and technical barriers to understanding how altered matrix leads to tissue decline. By innovating and improving technologies we aim to overcome three important barriers: 1) Resolve matrix in high definition including post-translational modification and physical properties; 2) Create tools to track and manipulate the living matrix to understand turnover and spatial dynamics; and 3) Integrate and model matrix data to predict, test and define the transition from tissue health to decline. We will build capacity and improve access to matrix research in broader scientific and clinical communities. Success will enable early diagnostics to detect loss of matrix regulation and the development of precision strategies for matrix reprogramming across multiple disease aetiologies. |
| 19/10/2022 |
£5,731,167 |
UNIVERSITY OF OXFORD |
The ANTITHESES Platform for Transformative Inclusivity in Ethics and Humanities addresses an urgent need for research able to engage meaningfully with the radical value disagreements, polarisation, and informational uncertainty characteristic of contemporary medical science, practice, and policy. Available approaches to ethics and humanities research lack the concepts, methods, and tools to do this work. They have insufficient diversity of voices, are overly safe and conservative, and overwhelmingly Western. They have tended to exclude some problems and values as not ‘worthy’ of investigation or ‘too difficult’. New approaches are needed. The Platform’s activities, which will develop and test tools and methods for achieving this, are organised under six complementary and connected thematic programmes. Bringing together expertise from history, philosophy, the fine arts, design bioethics, sociology, and global bioethics, each programme addresses a different need for new concepts, methods, digital tools, and collaborative partnerships capable of engaging with radical value disagreements in medical science, practice, and policy. To ensure that they work effectively together, and benefit from expertise in other disciplines, our ‘connectors’ programme will engage with problems arising out of the convergence of these challenges to foster collaboration. |
| 19/10/2022 |
£9,546,079 |
UNIVERSITY OF CAMBRIDGE |
Metabolism is the process by which organisms handle energy and the materials needed to grow, reproduce, and remain healthy. These processes require sophisticated coordination, largely provided by hormones, circulating at low concentrations and interacting with receptors with high affinity and specificity. As well as controlling the disposition of macronutrients, hormones act on the brain to control appetite and food intake. Dysfunction of these processes underpins highly prevalent disorders such as obesity, Type 2 diabetes, fatty liver disease, thyroid disorders, and cachexia, which are quintessentially disorders of systems, not simply cells. A major challenge to the field, both basic and translational, has been the requirement to work across many levels in cells, humans and model organisms and to meaningfully integrate data. Building on our exceptional track record, we propose to create a Discovery Research Platform (DRP) that will integrate information from cellular studies, model organisms, human genetic, physiological and population studies to break down barriers between classical disciplines and provide a rich resource for the research community. We will engineer the DRP to be a beacon for advances in research culture that value and support participants in their efforts to understand human integrative biology and exploit that knowledge for human benefit. |
| 19/10/2022 |
£9,558,000 |
UNIVERSITY OF DURHAM |
The Wellcome Platform for Medical Humanities (WPMH) will tackle intellectual and practical barriers – of diversity, connection, risk, evidence and scale – faced in medical humanities research. Through its Sites, Labs, Networks and Training, the WPMH will equip and empower researchers to develop novel approaches to intractable questions of health and so extend its evidence base. The WPMH reaches beyond Durham University to anchor community, clinical and creative partnerships in three physical Sites: a GP practice in an area of high blanket deprivation, a radical community mental health centre, and an international cultural festival. Site activity will generate new connections, research questions and opportunities for co-production. These will inspire and influence the work of six intersecting Labs focused on methodological innovation: Narrative Practices, Visual and Material, Moving Bodies, Literature and Cognition, Measurement, and Affective Experience. Comprehensive programmes of training and career development will enable academics, health and voluntary sector professionals, and experts by experience to become skilled interdisciplinary collaborators and produce ambitious new programmes of research. These are urgently needed to address enduring health challenges and ultimately take forward our understanding of human experience. |
| 19/10/2022 |
£9,557,001 |
UNIVERSITY OF CAMBRIDGE |
Importance of Barrier and Potential to Overcome it: Biomedical research is performed at multiple scales, ranging from the molecular up to populations. To capitalize on discoveries made at one particular scale, we must work smoothly across scales, for example to translate a molecular discovery into a new treatment. Particularly for research focused on human biology and disease, the tissue or organ scale is a major bottleneck. Stem cells build, maintain, and repair our tissues. The Cambridge Stem Cell Institute represents the leading centre for stem cell research in Europe, and is therefore in prime position to tackle the Tissue Scale bottleneck. We have identified organs in a dish, lineage analysis, tissue scale imaging/molecular profiling and computational modelling as specific barriers which we will break down to empower a new era of Tissue Scale Biology research. Breadth of Impact: Underpinned by a new network of technologists from local and international centres of excellence, our innovations will enable a new wave of discovery and translational science relevant for most areas of biomedical research. Research Environment: Personal development and positive culture are integral to this application, bolstered by over £2M Institutional Support, including new degree apprenticeships with Anglia Ruskin University to widen participation. |
| 19/10/2022 |
£9,558,000 |
UNIVERSITY COLLEGE LONDON |
There is arguably no more important goal than understanding how the human brain supports daily life. However, the neuronal instantiation of lived experiences has eluded detailed scrutiny. Our proposed Platform seeks to change this and establish a new world of opportunity for neuroscience. We will create, at scale, an internationally unique facility dedicated to studying the embodied human brain as it engages with the real world. To do this we will overcome very significant and long-standing barriers to deliver: (1) transformative imaging technology capable of measuring neuronal activity from the entire brain and spinal cord that adults and children can wear comfortably while they behave naturally; (2) the capacity to deploy novel experimental designs that probe lived experiences in real-world settings; and (3) innovative analytics that will transform our mechanistic models of the brain, increasing their explanatory power and their capacity to inform new strategies for maintaining and improving brain function. Studying the real-world cognition that supports everyday life could revolutionise our understanding of lived experiences associated with neurological and mental health conditions, accelerating impactful discoveries that directly benefit the whole community. We will nurture a research culture of inclusivity, and can-do, bold, creative thinking to achieve these ambitious goals. |
| 19/10/2022 |
£9,558,000 |
UNIVERSITY OF EDINBURGH |
Biological research is in an era of prolific data generation. This provides unprecedented opportunities for deep insights into cells, from infectious single-celled bacteria to the multitude of human cell types. However, technical limitations and investigative bias have left numerous "blind spots". Functions of numerous proteins remain unknown, cellular sub-structures are unseen at nano-scale and rare cellular events go unnoticed. These knowledge gaps – the Hidden Cell – arise from the absence of appropriate technology and/or because well-studied topics attract further research, and are major barriers to progress, The proposed Hidden Cell Discovery Research Platform (HCDRP) will overcome these barriers. Scientists and Technologists from diverse disciplines will work together to develop innovative approaches that render currently intractable and/or neglected areas accessible. Three integrated HCDRP pipelines will: Discover key components hidden amongst uncharacterised proteomes Bridge biological structure between atomic and cellular scales Capture pivotal biological events that are rare, short-lived or stochastic HCDRP is designed to address current challenges of biomedicine and revolutionise approaches to solving biological questions in the scientific community. It will deliver insights that stimulate mechanistic research in overlooked and unexpected areas, including uncharacterised genetic diseases, the emergence of microbial drug resistance and new generation tool development. |
| 30/09/2022 |
£500,000 |
COUNCIL FOR AT-RISK ACADEMICS |
Cara was founded by academics and scientists in the UK to rescue their colleagues from Nazi Germany and other countries under fascism. Almost ninety years later, many academics and scientists around the world are still at grave risk because of what they say and write, because of violence and conflict, or for other reasons. We have a network of 129 UK university partners, and others abroad, who provide places and some funding for those who need to get away, with their families. But it is often our ability to contribute funds of our own too, for example to cover travel and up-front costs (visas, NHS surcharge) and the additional costs of family members (we try to limit the latter costs to £7,500 pa per case), that makes it possible to finalise the placement.
Recent events, in Afghanistan and Ukraine in particular, have led many more people to seek our help - some 750 from Afghanistan, and a growing number from Ukraine (though martial law currently prevents men aged 18-60 from leaving), on top of the continuing flow from other parts of the world, the Middle East in particular.
This funding would significantly increase our ability to help those in danger.
|
| 30/09/2022 |
£17,731 |
BABRAHAM INSTITUTE |
Not available |
| 30/09/2022 |
£42,889 |
MQ TRANSFORMING MENTAL HEALTH |
To have the greatest impact and be its most inclusive, the discipline of mental health science needs opportunity to convene, develop a common language and enable connection. Through discussions with Wellcome's Mental Health Team, we present this proposal to together convene the sector to achieve five outcomes:
To (a) catalyse new collaborations between diverse and often fragmented disciplines in mental health (b) with a particular highlight on combining or providing access to datasets and/or personalised and effective treatments
Engage 100 low-middle income country (LMICs) attendees and increase their representation amongst speakers whilst building their research capacity
To advance and promote the use of common metrics for mental health
Engage policy makers to ensure the relevance and importance of research is recognised, acted upon and invested in
To provide a meaningful and impactful opportunity for public and patient involvement and engagement to (a) influence the trajectory of mental health research and (b) be a showcase for government and NGOs
This desired progress can be accelerated through partnership within the mental health science family. We are delighted to be exploring how a partnership with Wellcome through an investment of expertise and £42,484, would allow us to convene the sector, increase impact.
|
| 30/09/2022 |
£1,009,420 |
UNIVERSITY OF OXFORD |
Taking the lessons learned from the international success of ISARIC’s COVID-19 data platform, we will expand the platform to answer new questions on COVID-19 and build data systems to respond to future outbreaks of infectious diseases. This collaboration brings together scientists who have developed world-leading data integration, processing and analytic technologies with health care workers and public health specialists who will use and tailor the technologies to deliver evidence that's relevant to patient care and public health policy decisions. Together we will expand the data platform to 1) integrate epidemiological and clinical data so that we can analyse research questions at an individual level and a population level; 2) integrate genomic data so that we can understand how different virus variants affect patient outcomes; and 3) provide the infrastructure to scale data processing and grow our international network to generate more evidence on emerging infectious diseases. We will analyse these integrated data sets to generate evidence on the impact of vaccination and new variants in COVID-19 infection and post-acute COVID-19 syndrome. We will also develop methods to accelerate science on the characterisation of future disease outbreaks.
|
| 30/09/2022 |
£107,641 |
GLOBAL HEALTHCARE INNOVATION ALLIANCE ACCELERATOR |
The GHIAA MAPGuide enables users to explore a range of approaches used to address key issues in global health agreements. As of 1 November 2021, the MAPGuide contained analysis of 387 provisions from 59 agreements, and our team is constantly working to expand on this. An important next step in widening the impact of the MAPGuide is to create educational resources that present key information and best practice recommendations in a format that can be easily understood by all stakeholders.
The objective of this application is to develop materials that provide guidance to global health funders, PDPs and government ministries as they work to develop equitable access policies and ensure that they are translated into actionable agreements. The materials will draw on the agreements and provisions in the MAPGuide to examine the key pillars of equitable access and how they can be achieved through meaningful and enforceable contract terms. This information will be presented on the MAPGuide website in an easy to use format using a combination of infographics and a series of ‘plain English’ articles that explore key topics in more detail.
|
| 30/09/2022 |
£18,096,927 |
COALITION FOR EPIDEMIC PREPAREDNESS INNOVATIONS (CEPI) |
Funding will go toward critical R & D to meet the challenges of this rapidly evolving pandemic & facilitate equitable access to safe effective vaccines. Objectives are:
Enable equitable access to vaccines to reduce circulation of virus—thereby limiting opportunities for viral mutation—and reducing the disease burden on health systems.
Create conditions where vaccines can be rapidly adapted (within 100 days) to the new strains, and increase manufacturing capacity to make enough for global need
Optimise and deploy the existing suite of vaccines, including through the testing of ‘mix and match’ regimens and booster doses.
Support development of new strain-specific vaccines and second-generation vaccines that are more robust to viral evolution
Accelerating development of breakthrough vaccine candidates
Funding would support:
Next generation vaccine candidates with potentially significant health impacts, e.g. candidates that elicit mucosal immunity or single dose candidates. Scale-up development of promising candidates.
Expanding CEPI’s "Agility Programme" to understand the impact of variants on vaccine efficacy & support decision making on the need to adapt existing vaccines.
Building protection against variants to prepare for the emergence of potential new variants.
Developing a broadly protective coronavirus vaccine that could eliminate the risk of existing coronaviruses & new, unknown coronaviruses.
|
| 30/09/2022 |
£40,000 |
HARRIS ACCESS CONSULTING LTD |
In 2021, Harris Access Consulting and Charles River Associates were commissioned to provide an analysis of the vaccines regulatory ecosystem in low- and middle-income countries, especially on the African continent. The study was developed and delivered with a view to informing future investment decisions through a cost-benefit analysis on a range of selected, high-impact interventions by Wellcome and others that could accelerate systemic change. The next phase of the project will involve socialisation and dissemination of the results of the work, building on several opportunities and approaches to engage stakeholders and co-create solutions.
This will allow Wellcome to achieve the following objectives:
Engage with the stakeholder community and build trust
Validate findings, and listen to feedback and preferences
Demonstrate desire and capacity to engage in dialogue with funders and the wider set of partners in this space.
This work will involve professional and technical support for a five day digital event to deliver the fifth Scientific Conference on Medical Products Regulation in Africa and the African Medicines Regulators Conference (AMRC) in November 2021, using a professional company called Maximise Your Time (MYT) and their affiliate ManMade Productions to support AUDA-NEPAD and WHO, the agencies accountable for delivery of these events.
|
| 30/09/2022 |
£1,381,673 |
UNIVERSITY OF MINNESOTA |
Improved influenza vaccines are urgently needed to reduce the global burden of seasonal influenza and enable an effective public health response to the ongoing pandemic threat from emerging influenza viruses. The Influenza Vaccines R & D Roadmap (IVR), completed in September 2021 following an extensive global stakeholder engagement process, provides a framework for guiding R & D activities aimed at accelerating the development of improved seasonal influenza vaccines and broadly protective or universal influenza vaccines. To ensure successful implementation of the roadmap’s strategies, follow-up activities are needed to promote awareness, encourage stakeholder buy-in, and track outcomes. CIDRAP proposes to conduct a 3-year project to: (1) monitor and evaluate progress in achieving the IVR goals and milestones, including changes in the status of knowledge gaps and barriers to influenza vaccine R & D; (2) revise and update the roadmap to reflect R & D progress, changes in timelines, new knowledge gaps and barriers to influenza vaccine R & D, and learnings from the ongoing development of COVID-19 vaccines; and (3) maintain and update the IVR website as a communications hub for the influenza vaccine R & D community to strengthen engagement and share information and new developments.
|
| 30/09/2022 |
£35,547 |
ONWARD |
The ambition to become a science superpower present an opportunity to reconsider exactly what kind of science and technology system we are trying to build.
Should we be doubling down on basic science or investing more around translation and commercialisation?
Should government take more or less of a role in directing science investment, through strategic funds, pull-through procurement and new research institutions?
What role do we want privately funded R & D to play and how does it interact with publicly funded research and institutions? How do we define success, and how will we know if we have achieved it?
This paper will use both primary and secondary research to answer these questions and articulate a vision for what "becoming a science superpower" means in practice for a country like the UK. We will analyse how we spend existing science and technology funding – across the public, private and HE sectors – and the measurable outcomes that flow from that investment. We will compare this to the models and outcomes of other major developed economies. We will also explore the relationship between different kinds of research on total factor productivity and innovation, and what kinds of institutions generally return what results.
|
| 30/09/2022 |
£10,000 |
IMPERIAL COLLEGE LONDON |
Dr Philip Green agreed with Dame Bridget Ogilvie on 4 February 2020 to support the Sir Stanley Peart Memorial Symposium event with a grant of £10,000. The event was postponed due to the COVID-19 pandemic and been re-arranged for Friday 29 October 2021 at the Royal Society. We appreciate your support.
|
| 30/09/2022 |
£63,195 |
THE FRANCIS CRICK INSTITUTE |
Not available |
| 30/09/2022 |
£72,871 |
UNIVERSITY OF LIVERPOOL |
Not available |
| 30/09/2022 |
£46,394 |
UNIVERSITY COLLEGE LONDON |
Not available |
| 30/09/2022 |
£27,506 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
Not available |
| 30/09/2022 |
£107,587 |
UNIVERSITY OF OXFORD |
Not available |
| 30/09/2022 |
£110,960 |
UNIVERSITY OF OXFORD |
Not available |
| 30/09/2022 |
£152,585 |
UNIVERSITY OF OXFORD |
Not available |
| 30/09/2022 |
£61,511 |
INSTITUTE OF CANCER RESEARCH |
Not available |
| 30/09/2022 |
£351,809 |
KING'S COLLEGE LONDON |
Not available |
| 30/09/2022 |
£200,577 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
Not available |
| 30/09/2022 |
£13,151 |
THE PIRBRIGHT INSTITUTE |
Not available |
| 30/09/2022 |
£5,981 |
UNIVERSITY OF DURHAM |
Not available |
| 30/09/2022 |
£194,999 |
UNIVERSITY OF DUNDEE |
Not available |
| 30/09/2022 |
£806,724 |
UNIVERSITY COLLEGE LONDON |
Not available |
| 30/09/2022 |
£33,489 |
UNIVERSITY OF YORK |
Not available |
| 30/09/2022 |
£43,890 |
UNIVERSITY OF WARWICK |
Not available |
| 30/09/2022 |
£55,624 |
UNIVERSITY OF SUSSEX |
Not available |
| 30/09/2022 |
£10,565 |
UNIVERSITY OF STRATHCLYDE |
Not available |
| 30/09/2022 |
£8,442 |
UNIVERSITY OF ST ANDREWS |
Not available |
| 30/09/2022 |
£29,272 |
UNIVERSITY OF SOUTHAMPTON |
Not available |
| 30/09/2022 |
£87,606 |
UNIVERSITY OF SHEFFIELD |
Not available |
| 30/09/2022 |
£26,404 |
QUEEN'S UNIVERSITY BELFAST |
Not available |
| 30/09/2022 |
£57,332 |
QUEEN MARY UNIVERSITY OF LONDON |
Not available |
| 30/09/2022 |
£963,442 |
UNIVERSITY OF OXFORD |
Not available |
| 30/09/2022 |
£74,503 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
Not available |
| 30/09/2022 |
£37,488 |
UNIVERSITY OF NOTTINGHAM |
Not available |
| 30/09/2022 |
£108,308 |
NEWCASTLE UNIVERSITY |
Not available |
| 30/09/2022 |
£180,418 |
UNIVERSITY OF MANCHESTER |
Not available |
| 30/09/2022 |
£22,233 |
UNIVERSITY OF LEICESTER |
Not available |
| 30/09/2022 |
£54,831 |
UNIVERSITY OF LEEDS |
Not available |
| 30/09/2022 |
£13,780 |
KEELE UNIVERSITY |
Not available |
| 30/09/2022 |
£339,663 |
IMPERIAL COLLEGE LONDON |
Not available |
| 30/09/2022 |
£141,242 |
UNIVERSITY OF GLASGOW |
Not available |
| 30/09/2022 |
£50,159 |
UNIVERSITY OF EXETER |
Not available |
| 30/09/2022 |
£391,412 |
UNIVERSITY OF EDINBURGH |
Not available |
| 30/09/2022 |
£14,755 |
UNIVERSITY OF EAST ANGLIA |
Not available |
| 30/09/2022 |
£68,275 |
CARDIFF UNIVERSITY |
Not available |
| 30/09/2022 |
£800,457 |
UNIVERSITY OF CAMBRIDGE |
Not available |
| 30/09/2022 |
£179,295 |
UNIVERSITY OF BRISTOL |
Not available |
| 30/09/2022 |
£88,741 |
UNIVERSITY OF BIRMINGHAM |
Not available |
| 30/09/2022 |
£27,104 |
BIRKBECK UNIVERSITY OF LONDON |
Not available |
| 30/09/2022 |
£17,347 |
UNIVERSITY OF ABERDEEN |
Not available |
| 30/09/2022 |
£522,860 |
PROTAS |
The Good Clinical Trials Collaborative (GCTC), currently hosted by Wellcome, is completing the first phase of the project during which it has developed new global guidance for the delivery of Randomised Controlled Trials. Phase 2 will focus on the uptake and application of the guidance by all groups of key stakeholders in the clinical trials sector, including major regulators, clinical researchers, funders of trials including industry and those supporting clinical research in LMICs such as Wellcome and BMGF.
Success for the GCTC project is wide adoption and utilisation of the guidance principles, both through established channels (e.g. updates to ICH or major Regulatory Authority guidance and practice that closely reflect the GCTC principles) and (where appropriate) through direct adoption and utilisation of GCTC guidance for relevant settings/jurisdictions. Successful delivery of this project will lead to better evidence of health interventions across all settings including challenging areas such as vaccines, mental health, common communicable diseases and particularly in LMICs.
Protas, a new, independent, not-for-profit company, created to design and deliver appropriately large randomized trials that address key patient care and public health needs, has offered to host the GCTC moving forward as Wellcome embarks upon its new organisational strategy.
|
| 30/09/2022 |
£1,189,735 |
UNIVERSITY OF WARWICK |
Not available |
| 30/09/2022 |
£292,811 |
WORLD HEALTH ORGANIZATION, SWITZERLAND |
As announced by the United Kingdom (UK) in its G7 Presidency, the World Health Organization (WHO) will lead an Implementation Consultation Group (ICG), supported by the Wellcome Trust and working with other governments’ centres of disease control, NGOs and research organizations, to launch the International Pathogen Surveillance Network – the ‘Global Pandemic Radar.’ The Secretariat for this global pathogen surveillance network will support the ICG in its work and will be provided by WHO, Wellcome, and the UK government and other interested parties. Resources for the Secretariat are requested from Wellcome.
|
| 30/09/2022 |
£1,549,553 |
KING ABDULLAH UNIVERSITY OF SCIENCE AND TECHNOLOGY |
We propose to form a consortium of researchers representing the MENA region (‘COVID-19 Genomics MENA’) with access to COVID-19 samples for setting up sequencing and analytical pipelines for large-scale sequencing-based genomic surveillance of the circulating lineages of the SARS-CoV-2 virus. The consortium will consist of investigators from four countries in the Middle East (Saudi Arabia, Qatar, Oman, and Kuwait) and three countries (Algeria, Morocco, and Egypt) in North Africa. The aim of this proposal is to sequence a large number of SARS-CoV-2 genomes for molecular tracking of the circulating lineages of the virus during the active vaccination period for the next 12 months. We pledge to sequence 12,000+ SARS-CoV-2 genomes and collect relevant clinical meta-datasets during the next 12 months in these seven countries in the MENA region. We shall be using a combination of next-generation sequencing technology platforms (Illumina, Oxford Nanopore, and Ion Torrent) and standard genome assembly, genomic-epidemiology analytical pipelines already available within the laboratories in the consortium. The resulting datasets will be made publicly available through the GISAID data portal for wider accessibility of the datasets. We also aim to integrate a ‘training component’ for local capacity building at the participating institutions in the MENA region.
|
| 30/09/2022 |
£745,891 |
BRITISH RED CROSS SOCIETY |
The Global Taskforce on Cholera Control (GTFCC) is a multi sectoral partnership of more than 50 institutions who support countries in the implementation of ENDING CHOLERA: A GLOBAL ROADMAP TO 2030. In October 2020, in response to countries' expressed needs, the GTFCC launched a Country Support Platform (CSP) that will support efforts - primarily at national level - to control and eliminate cholera. The International Federation of Red Cross and Red Crescent Societies (IFRC) has been selected to host the CSP on behalf of the GTFCC. This proposal outlines the establishment of a Senior Research Officer, Cholera Research to work with the GTFCC on research uptake at both global and country levels. The research focal point will support the GTFCC to strengthen and advocate for evidence-informed decision making whilst being embedded at the British Red Cross (BRC) on behalf of the IFRC as host of the CSP. The focus of the research focal point will be to act as Senior Research Officer (SRO), under the coordination of the GTFCC Secretariat to support and enable collaborative research uptake: the identification, generation, access and use of research evidence to inform policy and practice in cholera control.
|
| 30/09/2022 |
£500,001 |
HUMAN CELL ATLAS, INCORPORATED |
Funding is requested to support the 2022-23 operations of the Human Cell Atlas (HCA) Executive Office. HCA is an international scientific project whose mission is to create comprehensive reference maps of all human cells — the fundamental units of life — as a basis for both understanding human health and diagnosing, monitoring, and treating disease. The requested funds would support Phase 1 of the HCA initiative, which includes developing standardized experimental and computational methods to allow HCA scientists to compare diverse cell and tissue types and samples across human communities in consistent ways, ensuring that the resulting resource is comprehensive and global. The scientific and geographic scope and complexity of this project necessitate professional staff support to coordinate the activities of multiple governance and working groups and to create, collect, organize, and distribute a wide range of resources to the HCA community, as well as to support the scientific and legal processes that are required to build the Atlas. Support for these and other secretariat functions will be critical to ensure the continued smooth operation of the HCA consortium and the coherent assembly of the first draft of the Human Cell Atlas.
|
| 30/09/2022 |
£434,726 |
DATAKIND, INC |
In 2018, DataKind launched a new program to tackle common problems within the frontline health systems ecosystem through the creation of scalable data science tools. One high potential area of opportunity is to strengthen trust in frontline healthworker-generated data by identifying problematic data in leading mHealth platforms upstream.
Workstream 1 (WS1) is a continuation of this data integrity tooling. Due to the commonality of the problem the output of WS 1 – production-level data integrity assuring software – is both attainable and a realization of creating sector-impacting tools. In doing so, DataKind will also have developed a roadmap for integration of this tool with commercial, NGO, and individual health systems.
Workstream 2 is an extension of DataKind’s exploratory work, wherein we co-create a prototype tool with a local organization to provide meaningful learnings for a sector. Furthermore, as the Wellcome Trust embarks on scoping projects with the African Population Cohorts Consortium (APCC) we expect there to be pieces of digital infrastructure and software tools that are necessary to realize the underlying ambition of the APCC. Our expert data science teams would be glad to help shape a data science roadmap and complement the suggestions made by the APCC scoping team.
|
| 30/09/2022 |
£246,375 |
DUKE UNIVERSITY |
Successfully combating drug-resistant infections and antimicrobial resistance (AMR) requires innovative antibiotics to treat resistant infections and innovative bacterial diagnostics to enable improved prescribing and antibiotic stewardship. But despite the implementation of pre-market regulatory changes and progress toward post-market pull-incentives, antibiotic and bacterial diagnostic manufacturers continue to face uncertain markets and limited revenue. As a result, antibiotic and bacterial diagnostic development has slowed and many developers have abandoned the market or even gone bankrupt.
Duke-Margolis will conduct 18 months of focused policy research that informs efforts among policymakers and expert stakeholders as they design and implement pull-incentives to restore and sustain the market for critical novel antibiotics and bacterial diagnostics. As policymakers consider implementing substantial pull-incentives for novel antibiotics and bacterial diagnostics, focused policy research can inform feasible, effective designs and encourage stakeholder consensus.
The project will advance existing policy research and encourage stakeholder consensus on (a) next steps toward administrative and legislative pull-incentives for novel antibiotics, and (b) feasible reforms to advance bacterial diagnostic development, coverage, reimbursement, and utilization.
Duke-Margolis will advance policy research, disseminate strategic communications, and encourage stakeholder consensus through stakeholder convening, written deliverables including include white papers, issue briefs, or journal articles, and through conference presentations.
|
| 30/09/2022 |
£1,288,680 |
GRIFFITH UNIVERSITY |
Our world is heating up. WHO estimates that the number of persons exposed to extreme heat increased by around 125 million from 2000 to 2016. Climate change will increase the frequency, intensity, and duration of these extreme heat events globally. It is important to find ways to protect the most vulnerable from increasing heat-health risks. Older people are particularly vulnerable - exacerbated by reduced thermoregulatory function and high comorbidity. While existing heat warning systems target whole populations, response systems that consider individualised risk profiles for older citizens are largely missing. There is an urgent, unmet need for innovative solutions to enable older people, especially those who are isolated or socially disadvantaged, to effectively monitor and mitigate extreme heat effects.
This project will develop an individualised, early warning system to protect vulnerable older populations from increased heat risks. Our co-design approach combines best evidence in climate-heat-health impact research and advances in digital technologies. Key outputs will include a toolkit of research findings & code libraries, a community of practice, and a localised software application. Together, these outputs will enable older people to maintain healthy and safe home environments and provide a robust platform for expansion towards other sub-populations or countries.
|
| 30/09/2022 |
£799,862 |
BARCELONA SUPERCOMPUTING CENTER |
Extreme climatic events, environmental degradation and socio-economic inequalities exacerbate the risk of infectious disease epidemics. We lack the evidence-base to understand and predict the impacts of extreme events and landscape changes on disease risk, leaving communities in climate change hotspots vulnerable to increasing health threats. This is in part due to a lack of ‘ground truth’ data describing environmental change in remote and under-resourced areas, as well as a lack of trained research software engineers and data scientists. HARMONIZE will convene a transdisciplinary community of stakeholders, software engineers and data scientists to develop cost-effective and reproducible digital infrastructure for stakeholders in climate change hotspots, including cities, small islands, highlands and the Amazon rainforest. We will strategically undertake one-off longitudinal ground truth data collection using drone technology and low-cost weather sensors, to improve classification algorithms and downscaling of coarser-resolution environmental datasets (e.g., satellite images, climate reanalysis and forecasts). We will then harmonize this post-processed data with socio-economic and health data in an automated workflow packaged for users in bespoke hotspot-specific toolkits. These sustainable tools will facilitate generation of actionable knowledge to inform local risk mapping and build robust early warning and response systems to build resilience in low-resource settings.
|
| 30/09/2022 |
£390,082 |
UNIVERSIDAD PERUANA CAYETANO HEREDIA |
Extreme climatic events, environmental degradation and socio-economic inequalities exacerbate the risk of infectious disease epidemics. We lack the evidence-base to understand and predict the impacts of extreme events and landscape changes on disease risk, leaving communities in climate change hotspots vulnerable to increasing health threats. This is in part due to a lack of ‘ground truth’ data describing environmental change in remote and under-resourced areas, as well as a lack of trained research software engineers and data scientists. HARMONIZE will convene a transdisciplinary community of stakeholders, software engineers and data scientists to develop cost-effective and reproducible digital infrastructure for stakeholders in climate change hotspots, including cities, small islands, highlands and the Amazon rainforest. We will strategically undertake one-off longitudinal ground truth data collection using drone technology and low-cost weather sensors, to improve classification algorithms and downscaling of coarser-resolution environmental datasets (e.g., satellite images, climate reanalysis and forecasts). We will then harmonize this post-processed data with socio-economic and health data in an automated workflow packaged for users in bespoke hotspot-specific toolkits. These sustainable tools will facilitate generation of actionable knowledge to inform local risk mapping and build robust early warning and response systems to build resilience in low-resource settings.
|
| 30/09/2022 |
£577,375 |
UNIVERSIDAD DE LOS ANDES - BOGOTA |
Extreme climatic events, environmental degradation and socio-economic inequalities exacerbate the risk of infectious disease epidemics. We lack the evidence-base to understand and predict the impacts of extreme events and landscape changes on disease risk, leaving communities in climate change hotspots vulnerable to increasing health threats. This is in part due to a lack of ‘ground truth’ data describing environmental change in remote and under-resourced areas, as well as a lack of trained research software engineers and data scientists. HARMONIZE will convene a transdisciplinary community of stakeholders, software engineers and data scientists to develop cost-effective and reproducible digital infrastructure for stakeholders in climate change hotspots, including cities, small islands, highlands and the Amazon rainforest. We will strategically undertake one-off longitudinal ground truth data collection using drone technology and low-cost weather sensors, to improve classification algorithms and downscaling of coarser-resolution environmental datasets (e.g., satellite images, climate reanalysis and forecasts). We will then harmonize this post-processed data with socio-economic and health data in an automated workflow packaged for users in bespoke hotspot-specific toolkits. These sustainable tools will facilitate generation of actionable knowledge to inform local risk mapping and build robust early warning and response systems to build resilience in low-resource settings.
|
| 30/09/2022 |
£710,042 |
THE FOUNDATION FOR SCIENTIFIC AND TECHNOLOGICAL DEVELOPMENT IN HEALTH |
Extreme climatic events, environmental degradation and socio-economic inequalities exacerbate the risk of infectious disease epidemics. We lack the evidence-base to understand and predict the impacts of extreme events and landscape changes on disease risk, leaving communities in climate change hotspots vulnerable to increasing health threats. This is in part due to a lack of ‘ground truth’ data describing environmental change in remote and under-resourced areas, as well as a lack of trained research software engineers and data scientists. HARMONIZE will convene a transdisciplinary community of stakeholders, software engineers and data scientists to develop cost-effective and reproducible digital infrastructure for stakeholders in climate change hotspots, including cities, small islands, highlands and the Amazon rainforest. We will strategically undertake one-off longitudinal ground truth data collection using drone technology and low-cost weather sensors, to improve classification algorithms and downscaling of coarser-resolution environmental datasets (e.g., satellite images, climate reanalysis and forecasts). We will then harmonize this post-processed data with socio-economic and health data in an automated workflow packaged for users in bespoke hotspot-specific toolkits. These sustainable tools will facilitate generation of actionable knowledge to inform local risk mapping and build robust early warning and response systems to build resilience in low-resource settings.
|
| 30/09/2022 |
£366,656 |
TASK FORCE FOR GLOBAL HEALTH |
Following a 2019 meeting of global health leaders with expertise in influenza, vaccinology and pandemic preparedness in London hosted at the Wellcome Trust, Ready2Respond was formed as a global collaboration of partners committed to enhancing low- and middle-income countries’ readiness to respond against influenza and respiratory pandemics. With a Secretariat hosted at The Task Force for Global Health, Ready2Respond identified challenges and actionable solutions to promote pandemic preparedness. Though initially based on influenza, the organization's plan now includes COVID-19. Under the oversight of a Management Secretariat, Expert Working Groups design and execute cross-collaborative projects organized in 3 strategic pillars:
Burden of Disease
Risk Communication and Community Engagement
Vaccine Access
Ready2Respond seeks a grant from the Wellcome Trust of US$ 492,970. This grant will enable Ready2Respond to focus on two initial and critical projects identified in the Burden of Disease pillar. This grant will also allow for retention of paid Director, responsible for ensuring that identified projects represent discrete operational improvement activities for LMICs, and cover part-time staff. Finally, this grant will help secure communication activities aimed at raising awareness and funding from potential partners. This Phase 2 of funding will span September 2021 - February 2022.
|
| 30/09/2022 |
£4,955,809 |
OFFICE FOR NATIONAL STATISTICS |
This proposal is for a collaboration between the Office for National Statistics (with the UK Health Security Agency and the Cochrane Climate-Health Working Group) and two national statistical institutes in the African region, to develop a transparent and globally generalisable framework and technical platform for official statistics on climate change, environment and health, and a set of statistical methods to better estimate climate-related health risk using real world data sources, including modelling local-level impacts. By addressing the current lack of harmonised approaches, developing new methods in close partnership with LMICs and building capability, the project will advance global research on climate and health, help to address gaps in the knowledge base and support national monitoring and evidence-based policy. Users of the outputs will include government and NGO decision-makers who will be able to access information to guide interventions in clearer, more comprehensive and more actionable forms; producers of official statistics, especially in LMICs, whose ability to monitor effects of climate change will be increased by provision of practical, coherent standards and open source tools; and producers and consumers of climate change research who will benefit from faster study development based on shared approaches and more consistent ‘language’ for systematic communication.
|
| 30/09/2022 |
£976,251 |
CGD EUROPE |
Antimicrobial resistance (AMR) is a huge problem worldwide. Already thought to kill more than 700,000 people a year, some estimates suggest AMR could lead to 10 million deaths a year by 2050 if left unchecked. It is critical that we bolster funding for antibiotic research and development (R & D) and find ways to reduce unnecessary use. The Center for Global Development’s (CGD) goal under this proposal is to develop actionable global R & D policies that improve the landscape for antibiotics in LMICs, focusing on overcoming constraints on policy implementation at a national level within LMICs. We will explore how to improve incentives for pharmaceutical companies to sell their products in LMICs, specifically by improving access and supporting R & D. Policy recommendations will aim to improve both access to antibiotics, as well as reduce unnecessary use. We plan to develop these policy recommendations through a CGD working group made up of economists, epidemiologists, health practitioners, policy makers and representatives from the pharmaceutical industry. Recommendations will be informed by three extensive country case studies and CGD-commissioned research projects in participating LMIC countries and will be widely socialised through events and private meetings with key stakeholders.
|
| 30/09/2022 |
£1,226,240 |
HEPTARES THERAPEUTICS LTD |
Our company core values are to make a significant contribution to improving the quality of life and health of people around the world. We felt compelled to leverage our expertise in SBDD to discover an effective treatment for COVID-19. Our focused Not-for-Profit program, supported by our parent company Sosei, has employed SBDD to rapidly identify a potential clinical candidate to be used as an anti-viral treatment. This fulfilled our initial objectives, completing this stage of the program.
Having successfully identified compounds potentially suitable to be used as oral agents to treat COVID-19, we are well placed to progress compounds into preclinical development, after which we anticipate the program to be progressed by interested parties with expertise in antiviral clinical development. The UK Antiviral Task Force have confirmed a qualified candidate is required for further funding to be potentially be made available. Given the urgent clinical need for antiviral agents, we are seeking funding to progress our molecules up to the potential nomination of a pre-clinical candidate. We have designed a concise program of in vitro and in vivo profiling activities encompassing tolerability, safety, selectivity and efficacy to proceed rapidly, considering the likely desired dose regimen and route of administration. |
| 30/09/2022 |
£136,622,056 |
THE FRANCIS CRICK INSTITUTE |
Not available |
| 30/09/2022 |
£2,762,200 |
WORLD HEALTH ORGANIZATION, SWITZERLAND |
In 2020 The Pan American Health Organization (PAHO) established and now coordinates the COVID-19 Genomic Surveillance Regional Network. It includes 21 collaborating countries of which 10 do not have any appropriate in-country sequencing capacity and instead send their samples externally for sequencing to the network reference laboratories in Brazil and Chile. Here we propose to build direct sequencing and analytical capacity in all participating laboratories to generate relevant genomic data that can be used for public health decision making. Where batch sequencing capacity already exists we propose to use MinIon platforms to extend the within-country capacity to investigate changing patterns of disease. Combined, this will dramatically increase our understanding of the known and new SARS-CoV-2 variants circulating in this region. We will develop a hub-and-spoke organization with PAHO at the center forming the hub for coordination, training and data flow and the Network laboratories forming the spokes. Laboratories with existing genomics expertise will help build genomics surveillance capacity in those that don’t. Combining local and international expertise we aim to develop a regional network able to produce actionable SARS-CoV-2 data now with the potential to become a sustainable network able to track other diseases of regional importance in the future.
|
| 30/09/2022 |
£45,594 |
UNIVERSITY OF CAMBRIDGE |
The introduction of SARS-CoV-2 sequencing to new settings during the COVID-19 pandemic can be hampered by a lack of understanding of the value of genomic surveillance and concerns which may be amplified by alarmist media messaging. Clear public engagement to accompany SARS-CoV-2 sequencing training is beneficial to ensure maximum public health benefit.
We will use the combined sequencing and communications expertise of COG-Train (University of Cambridge) with the public engagement, radio and co-production experience of the Malawi Liverpool Wellcome Trust Clinical Research Programme (MLW) to improve public and community engagement in Malawi.
We will deliver in-person and online training courses in the communication of SARS-CoV-2 variant information to scientists and public health officials in Malawi. The courses will be devised by communications specialists at the Malawi University of Business Studies using COG-Train material and include collaborative consultations via established radio listening clubs. A series of eight radio programmes will be aired and feedback collected from audiences. The training material and broadcasts will be repackaged to create online resources suitable for sharing with the Wellcome Africa and Asia Partnership (AAP) countries.
We hope that the proposal will contribute to an open environment where trustworthy genomics research can benefit all of society.
|
| 30/09/2022 |
£170,092 |
UNIVERSITY OF OXFORD |
During the COVID-19 pandemic, genomic sequencing has provided valuable information on the spread of SARS-CoV-2 to ensure timely and targeted public health responses. Genomic surveillance programmes have been set up within Wellcome’s Africa/Asia Programmes (AAPs) and CIDRI in South Africa. However, there is suboptimal national-level resource allocation, insufficient strategy for sampling of specimens to optimize epidemiological and clinical inference, and gaps in meta-data needed to fully and quickly interpret genomic sequencing information. Policy makers presented with genomic data to support decision making must decide if a response is needed, how large the response should be, for whom, and when. To do this, a systematic approach to assessing genomic evidence is needed. It is also unclear what the public knows about SARS-COV-2 genomic sequencing, even though some media reports and anecdotal data from current policy and public engagement work being undertaken in the AAPs may suggest limited understanding of SARS-CoV-2 variants among this audience.
Through a suite of engagement activities at the AAPs, we will target both the public and policy makers to 1) increase the public's understanding of SARS-COV-2 genomic sequencing, and 2) support national level strategies by developing tools that guides the assessment of genomic evidence.
|
| 30/09/2022 |
£31,860 |
BIRAT NEPAL MEDICAL TRUST |
The Wellcome Trust funded Epidemic Intelligence project has implemented large scale genome sequencing for SARS CoV-2 at the only functioning sequencing laboratory in country, and stimulated discussion on the future role of pathogen sequencing and approaches to build capacity in Nepal.
COVID Kurakani (Covid Conversations) will engage stakeholders to stimulate increased understanding of the role of pathogen sequencing, allow researchers to listen to, be informed by and respond to community perceptions and concerns around sequencing, build trust between participating communities and the researchers and facilitate capacity building for genome sequencing in the country.
Our key goals are:
Build capacity among the epidemic intelligence team to develop and deliver high quality public engagement activities surrounding pathogen sequencing for epidemic response.
Conduct an EDGE analysis of public engagement status at BNMT.
Conduct an internal workshop to design the public engagement strategy, including the senior management team.
Utilise media expertise among the research team to develop and deliver a series of panel discussion programmes for national broadcast with three participatory target audiences.
Understand community and stakeholder perceptions of COVID-19 sequencing.
Address knowledge gaps and concerns among stakeholders to build trust and inform the dialogue surrounding pathogen sequencing.
|
| 30/09/2022 |
£250,000,000 |
WELLCOME LEAP INC. |
Wellcome Leap Inc. has been established by Wellcome as a US, wholly owned not for profit entity with the aim of delivering breakthroughs in human health and demonstrate seemingly impossible results on seemingly impossible timescales. This will be achieved through the creation of a small portfolio of goal focused Programmes selected based upon their potential to improve health globally rather than by their potential financial or commercial return.
Wellcome provides initial funding of $306.9M to Leap to cover their first 10 years of operation (although further funding may be provided over this 10 years). This funding will support Leap’s operational costs and ‘Programmatic costs’ which will include (but not be limited to) the employment of Programme Directors to build and orchestrate large research programmes, subject matter advice and support to formulate a programme and the funding of sub-awardees to carry out research in pursuit of a programme goal.
Wellcome Leap’s strategic plan was approved by the BoG in August 2020. Since this time, Wellcome Leap have met or exceeded all Y0/Y1 goals, including launching 5 programmes with an average funding of $50M. Looking ahead, the Wellcome Leap BOD are recommending to the Wellcome BoG the commitment of an additional £250M to Wellcome Leap in FY 22/23 in order to launch ~5 programmes at the same pace as seen in Wellcome Leap’s first year of operation. Following approval of this request by BoG, the awarded amount was converted from GBP (£250,000,000) to USD ($337,087,500). |
| 30/09/2022 |
£71,618 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
Across the world viral genomic surveillance has been key to understanding SARS-CoV-2 and how it spreads through populations. The AFRICO19 project aims to understand SARS-CoV-2 infection in three regions of Africa: Uganda, The Gambia and Kenya. This involves building capacity for rapid diagnosis and sequencing of SARS-CoV-2 to enhance genomic surveillance, inform contract tracing, variant detection and public health measures. However, through conversations with local colleagues and members of the public in Entebbe, Uganda and from an initial survey it has become apparent there is some misinformation and mistrust of the value of genomic surveillance within local communities. This has had potential knock-on effects for understanding the purpose of surveillance, vaccine uptake and acceptance of taking approved therapeutics.
Therefore during this project we aim to support researchers to engage with members of the public by building capacity and confidence through training opportunities, develop resources exploring viruses and their variants, the immune system and the importance of genomic surveillance, and build a platform to open dialogue between researchers and public groups. By doing this we aim to address misconceptions and mistrust associated with viral genomic sequencing therefore building public trust and awareness of the importance of this work.
|
| 30/09/2022 |
£100,000 |
QUEEN'S UNIVERSITY BELFAST |
Background One of the hallmarks of cancer is evasion of cell death, which promotes tumourgrowth, metastasis and therapy resistance. FLIP regulates cell death by modulating theactivity of caspase-8 and is frequently overexpressed in cancer, including non-small cell lung cancer (NSCLC). NSCLC is a therapy-resistant disease with a dismal prognosis. When it occurs, therapyinduced cell death can lead to dramatic response rates in NSCLC, leading to disease control as evidenced by the effectiveness of targeted therapies against NSCLCs with mutated EGFR or EML4-ALK rearrangements. Our pre-clinical work suggests that activating core |
| 30/09/2022 |
£100,000 |
CARDIFF UNIVERSITY |
Around 1% of the population will suffer from schizophrenia at some point in their life. Symptoms such as paranoia and/or hearing voices can be reasonably well treated by existing medications. However, these drugs have little effect on the other symptoms (lack of motivation and impaired social function) and impaired cognition, including difficulties with attention, memory and problem-solving that result in a "brain fog". These largely untreated symptoms remain a huge barrier to the resumption of a fully functional, "normal" life for these individuals and are associated with an annual estimated cost in the UK alone of around £12 billion. Professor Simon Ward from the University of Sussex has received a Seeding Drug Discovery Award to identify and develop drug which is a selective modulator of the AMPA receptor which has the potential to provide an innovative new treatment for patients with schizophrenia. If successful the team expect to have a compound ready for clinical evaluation in just over three years time. Nerve cells (neurons) communicate with each other by releasing chemicals known as neurotransmitters that interact with proteins called receptors on adjacent neurons. Levels of the neurotransmitter glutamate, which is crucial for normal cognitive function, are altered in schizophrenia. A specific subtype of glutamate receptor, the AMPA receptor, is thought to be associated with cognition and therefore increasing AMPA receptor function should improve cognitive performance in schizophrenia and thereby addressing an unmet need and revolutionizing the functional outcome of this patient population. |
| 30/09/2022 |
£253,183 |
UNIVERSITY OF OXFORD |
1. Total number of current applications in progress for LMICSSs by Administering Organisation (for all Programmes they administer) - 3
2. Total number of current applications in progress for LMICSSs to be held at the AAP/Centre to which the application relates - 3
|
| 30/09/2022 |
£100,000 |
UNIVERSITY OF MANCHESTER |
Basal-like breast cancer (BLBC) accounts for 10%-20% of breast cancer cases, with higher incidence in young, premenopausal women. Most BLBC cases are negative for progesterone receptor (PR), oestrogen receptor (ER) and human epidermal growth factor receptor 2 (Her2), thus there is a significant overlap between BLBC and triple-negative breast cancer (TNBC). There are currently no approved targeted therapies for patients diagnosed with BLBC and/or TNBC, and these patients have a poor prognosis with high rates of disease recurrence and mortality following treatment with conventional cytotoxic agents.
Data from patient samples and our unpublished cell biology experiments demonstrates that dysregulation of CaMK1D signaling has an important role in a high proportion of TNBC/BLBC tumours. We have developed highly selective inhibitors of CaMK1D with drug-like properties that show promising activity in cellular models. The proposed project will advance these leads further, particularly through optimisation of in vivo pharmacokinetic properties, allowing us to demonstrate that inhibition of CaMK1D following oral drug administration results in the inhibition of tumour growth in validated in vivo models. This is a key stage towards development of compounds that will permit the clinical evaluation of CaMK1D inhibitors in breast cancer. |
| 30/09/2022 |
£67,365 |
UNIVERSITY OF OXFORD |
1. Total number of current applications in progress for LMICSSs by Administering Organisation (for all Programmes they administer) - 3
2. Total number of current applications in progress for LMICSSs to be held at the AAP/Centre to which the application relates - 3
|
| 30/09/2022 |
£810,600 |
PFIZER INC |
Chagas disease (CD) is among the most neglected global diseases. Despite millions of affected people, treatments are limited with significant safety, efficacy, ease-of-use and cost deficiencies. Research and development has evolved in recent years; however, there is still a critical need for new therapeutic options.
The goal of this project is to deliver a Phase 2-ready compound for the treatment of Chagas disease that addresses the significant deficiencies of current standard of care medications. We will use Target Product Profiles (TPPs) to ensure we deliver a compound that will meet patient needs (see Appendix 3 for TPP). The targeted clinical candidate will combine anti-protozoal efficacy with an acceptable safety profile and pharmacokinetics/physicochemical properties commensurate with oral delivery for testing against Chagas disease. properties commensurate with oral delivery for testing against Chagas disease.
|
| 30/09/2022 |
£959,763 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
Evidence-based health policy needs FAIR data from multiple sources, with high quality data management and analysis by African data scientists. The Big Data ecosystem provides the strength to integrate data from multiple sources and utilise advanced artificial intelligence for the analysis. The INSPIRE network has used an OMOP database to share open-access longitudinal population-based health data, and the environment to use these data effectively in low-and-middle income countries (LMIC).
This proposal outlines the areas to achieve the aim of establishing the infrastructure to systematically integrate and share public health data. Firstly the proposal develops the Secretariat to link to stakeholder, including national data offices, data providers and international data scientists. Secondly the proposal will develop several technical components, to develop standardized vocabularies, and the mechanism (ETL) for bringing data into the OMOP database, and making data available for analysts to use. Thirdly is developing the human resources needed by training new data scientists, building a community of practice.
This proposal builds on initial work by INDEPTH and ALPHA network. It learns from the SAPRIN experience in South Africa, and will feed into the NIH Data Science Initiatives in Africa, and the proposed Wellcome Trust African Population Cohorts Consortium.
|
| 30/09/2022 |
£1,870,596 |
IMPERIAL COLLEGE LONDON |
This project aims to use samples collected during the world’s first SARS-CoV-2 human challenge studies to investigate in depth how pre-existing immunity and virus-host interactions affect the outcome of infection. Two SARS-CoV-2 human challenge studies are currently underway that together are enrolling naïve, previously infected and vaccinated young adults for controlled infection with a well-characterised viral inoculum. This proposal will investigate the genomic and cell-specific variations in host response that may be responsible for differential clinical outcome and within-host viral variation. Since in-host mutation is the mechanism by which viruses escape vaccine-mediated protection, further understanding of its drivers is an urgent priority to help anticipate the emergence of vaccine-resistant variants. Single-cell RNAseq will be used to analyse the transcriptional patterns of blood and nasal cells over the course of infection. These will be correlated with the transcriptional responses of the virus in concurrent nasal samples and whole genome sequencing to identify stable mutants that arise. Incorporating each participant’s genomic sequence, integrative analysis of virus and host factors that correlate with susceptibility and protection from infection and disease will be achieved. Thus, we will maximise the value of the human challenge programme and identify specific targets for vaccine improvement.
|
| 30/09/2022 |
£110,536 |
UNIVERSITY OF CAMBRIDGE |
This proposal aims to engage key audiences in Ghana such as SARS-CoV-2 Genomic Surveillance researchers, university students, high school students, media professionals, and animators to guide the development and use of animation toolkits for aiding public engagement with SARS-CoV-2 Genomic Surveillance, create three animations on SARS-CoV-2 genomic surveillance, and train researchers and media professionals to use the toolkits to engage key audiences including university and high school students, and other members of the public.
The animations will focus on issues including how viruses mutate, use of sequencing to detect variants, and how variants affect COVID-19 evolution.
We will assess toolkits’ impacts using surveys and focus group discussions with priority audiences, including researchers and media professionals who will use the toolkits. We will use the findings to develop best practice for implementing and evaluating public engagement with genomic surveillance.
To build capacity in public engagement with genomic surveillance, we will use a) train-the-trainer approach, and b) focus group discussions, key informant interviews and a deliberative workshop with genomic researchers and media professionals to create two research strategies: one focusing on how researchers could engage with members of the public, and a second focusing on researchers-media professionals’ engagement with genomic surveillance.
|
| 30/09/2022 |
£6,371,429 |
UK BIOBANK LTD |
Not available |
| 30/09/2022 |
£2,441,190 |
DIAMOND LIGHT SOURCE LTD |
Not available |
| 30/09/2022 |
£9,647,571 |
DIAMOND LIGHT SOURCE LTD |
Not available |
| 30/09/2022 |
£999,990 |
FUNDAçãO FACULDADE DE MEDICINA |
Purpose: To conduct research for optimising antimicrobial use in humans through three interlinked themes identified through a research roadmap and landscape review (medicines management; technology and innovation for optimised prescribing; culture, context, and behaviours). Structure: Researchers will be connected via a global network built on existing collaborations between National Hubs (UK, Uganda, South Africa, India, Brazil) with complementary research theme expertise. Opportunities for geographic (South-South and North-South) bilateral learning in research projects will maximise implementation and translational activities, facilitated by a comprehensive programme for knowledge mobilisation, capacity strengthening, and co-production for local context-specific, sustainable interventions. National Hubs will link with existing structures and supported by quality-assured technology and research and development laboratories (Malawi, Ghana, Thailand) to support activities. Development of an Antimicrobial Resistance Data Warehouse will provide underpinning network infrastructure for the global good. Network growth: Shadow national sites (Pakistan, Bangladesh, Timor Leste) will participate in network activities to actively build research collaborations and capacity with the National Hubs. In years 1-2, they will identify national research priorities and conduct a pilot project in year 3. The goal for a future iteration of CAMO-Net is that shadow national sites would become National Hubs, and new shadow sites would be identified. |
| 30/09/2022 |
£2,700,000 |
INFECTIOUS DISEASES INSTITUTE MAKERERE UNIVERSITY |
CAMO-NET aims to address the global impact of antimicrobial resistance (AMR) on human health via optimised antimicrobial use by establishing a sustainable global research ecosystem developed across HICs and LMICs. The CAMO-NET Uganda application is led by the Infectious Diseases Institute Makerere University (IDI) and comprises three research projects: Investigating the patterns and trends in antibiotic prescribing among people living with HIV (PLHIV) enrolled in routine cohorts at IDI Clinics. This project will include qualitative studies and cohort analyses to improve understanding of antibiotic prescribing in an LMIC HIV clinic. Innovative approaches to optimize antibiotic therapy for patients with multimorbidity in an outpatient HIV clinic in Uganda. This project will develop a multidisciplinary clinical platform for optimizing antibiotic use in the context of multimorbidity among PLHIV, develop, validate a population pharmacokinetic-pharmacodynamic models for selected antibiotics and evaluate innovative point of care therapeutic drug monitoring and its adoption for selected antimicrobials in PLHIV. Understanding trends in antibiotic consumption and use among patients attending six regional referral hospitals in Uganda to inform and evaluate pharmacy staff-led interventions. Additionally, IDI will serve as capacity-building lead providing a platform for collaborative and capacity-strengthening activities for CAMO-NET consortium partners. |
| 30/09/2022 |
£17,188,037 |
GLOBAL HEALTH INNOVATIVE TECHNOLOGY FUND |
Since 2013, GHIT has invested $276M in 114 projects, using its signature private-public partnership model to advance global health R & D. In GHIT 3.0, the next phase of its work, GHIT will (1) continue to pursue its core mandate of funding R & D programs to combat tuberculosis, malaria, and neglected tropical diseases by maximizing the efficiency of its portfolio and accelerating the progression of its most promising products through the critical milestones of regulatory approval and launch; and (2) invest in a carefully curated bank of "repurposable" technologies. These are technologies that can be applied to both the endemic diseases that disproportionately affect LMICs and the as-yet-unknown pathogens that will cause future pandemics. In less than a decade, the collaboration between GHIT and the Wellcome Trust has attracted talent, resources, and expertise to neglected communicable diseases in Japan and globally, with one novel product already CE-marked, one on the verge of approval, and many more in the pipeline. If GHIT 3.0 is able to benefit from the combined knowledge, resources, and vision of GHIT and the Wellcome Trust, it has the potential to significantly impact the global health R & D ecosystem in the next 5 years, with dramatic implications for health in LMICs. |
| 30/09/2022 |
£1,004,367 |
ST GEORGE'S, UNIVERSITY OF LONDON |
This observational, mixed methods pilot study will measure the causes and prevalence of resistance in patients with acute urinary tract infections (UTIs) presenting at community drug retail outlets (CDROs) and outpatient clinics (OPDs), together with patient and pharmacists behaviours around the use and dispensing of antibiotics in two socioeconomically differing neighborhoods in Kampala, Uganda over 24 months. We will investigate the causes, treatment, and outcome of acute UTIs in patients and compare these with the resistance profiles reported to WHO-GLASS. Our secondary aims are to 1) determine the prescribing and dispensing patterns in CDROs/OPDs for acute UTIs; 2) explore the demographic, illness history, and housing status of patients seeking treatment; 3) determine the prevalence of multi-drug resistance in carriage organisms from patients. exploring links between socioeconomic factors, antibiotic resistance, and antibiotic use in these neighbourhoods. Simple frameworks and surveys on dispensing practices, socioeconomic and cultural factors encouraging appropriate antibiotic use will be devised and freely available. This data will provide evidence on the patterns of antibiotic use and AMR outside the healthcare settings while helping formulate solutions through improving awareness about inappropriate/misuse of antibiotics locally, results fedback to community and hospitals, local decision-makers, and policymakers, and international efforts on AMR. |
| 30/09/2022 |
£3,497,450 |
THE FOUNDATION FOR SCIENTIFIC AND TECHNOLOGICAL DEVELOPMENT IN HEALTH |
As a large middle-income country with extraordinary geographic diversity and stark social inequalities, Brazil offers a unique living laboratory for identifying specific factors that may modify and mediate the impacts of climate change on health. To generate new knowledge on the links between climate and health that is currently not available from existing dissipated and unlinked resources and to inform mitigation and adaptation responses, this proposal seeks to develop a new CIDACS Climate and Environmental Platform. Our primary aim is to integrate geo-referenced climatic data (e.g., hydrometeorological and remote sensing satellite-derived indicators) from Brazil in an accessible platform that will be interoperable with the existing nationwide health and socioeconomic data linked in the 100 Million Brazilian Cohort (N=131,697,800 low-income individuals, 2001-2018) and the CIDACS Birth Cohort (N=28,631,390 maternal-child dyads, 2001-2018). To achieve this aim, we are requesting resources to: (i) strengthen CIDACS’ computational infrastructure including high-performance computing clusters, (ii) bolster CIDACS’ technical capacity related to data linkage and interoperability, machine learning, and bias assessment, (iii) develop the CIDACS Climate and Environmental Platform data resource, (iv) conduct hypothesis-driven proof-of-concept studies to demonstrate the platform’s utility and validity, and (v) expand CIDACS’ public interface and governance mechanisms to facilitate ethical data access. |
| 30/09/2022 |
£419,213 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
As a large middle-income country with extraordinary geographic diversity and stark social inequalities, Brazil offers a unique living laboratory for identifying specific factors that may modify and mediate the impacts of climate change on health. To generate new knowledge on the links between climate and health that is currently not available from existing dissipated and unlinked resources and to inform mitigation and adaptation responses, this proposal seeks to develop a new CIDACS Climate and Environmental Platform. Our primary aim is to integrate geo-referenced climatic data (e.g., hydrometeorological and remote sensing satellite-derived indicators) from Brazil in an accessible platform that will be interoperable with the existing nationwide health and socioeconomic data linked in the 100 Million Brazilian Cohort (N=131,697,800 low-income individuals, 2001-2018) and the CIDACS Birth Cohort (N=28,631,390 maternal-child dyads, 2001-2018). To achieve this aim, we are requesting resources to: (i) strengthen CIDACS’ computational infrastructure including high-performance computing clusters, (ii) bolster CIDACS’ technical capacity related to data linkage and interoperability, machine learning, and bias assessment, (iii) develop the CIDACS Climate and Environmental Platform data resource, (iv) conduct hypothesis-driven proof-of-concept studies to demonstrate the platform’s utility and validity, and (v) expand CIDACS’ public interface and governance mechanisms to facilitate ethical data access. |
| 30/09/2022 |
£865,801 |
UNIVERSITY MEDICAL CENTRE GRONINGEN |
Outcome of psychosis is heterogeneous, with chronic relapsing-remitting course in the majority. Relapse in the early years is the best predictor of a chronic course. Maintenance treatment with antipsychotics effectively reduces relapse risk but has many side-effects. In our changing society, the attitude towards long-time use of antipsychotics has become negative and for many patients and clinicians, maintenance treatment is no longer acceptable. Without maintenance treatment, relapse can still be prevented, if it is predicted accurately, as timely warnings provide a window of opportunity for patients, informal caregivers, and clinicians to take effective actions to prevent relapse. We hypothesize that computational analysis of speech can provide such accurate, timely warnings. Psychosis affects both form and content of thoughts, which are detectable in speech. Natural language processing (NLP) can accurately differentiate people with psychosis from healthy individuals and predict which high-risk individuals will develop psychosis. In this project we will test if NLP can also predict emerging psychotic relapse, to provide a window of opportunity for relapse prevention. We aim to improve outcome of individuals with psychosis by gaining scientific knowledge on speech as a biomarker of relapse and, in a next step, by creating an e-health tool to predict relapse. |
| 30/09/2022 |
£109,429,145 |
COALITION FOR EPIDEMIC PREPAREDNESS INNOVATIONS (CEPI) |
CEPI’s 2022-2027 strategic priorities are founded on the three pillars of Prepare, Transform and Connect. CEPI will prepare for known epidemics and pandemic threats by developing vaccines and promising biologics against the most prominent known threats, building on COVID-19 achievements and CEPI 1.0. CEPI will transform the response to the next novel threat by harnessing innovations in technology and systems to significantly reduce the global vulnerability to threats from novel pathogen outbreaks. CEPI will enhance and expand global collaboration by connecting emerging infectious disease stakeholders to enable rapid countermeasure development, effective response and equitable access for those in need. If the products developed with CEPI’s funding are to realise their potential, they should flow through a system with pre-agreed governance, financing, allocation, and distribution mechanisms to govern their ultimate use. CEPI is already contributing to and helping shape a post-pandemic consensus, creating a well-prepared ecosystem able to react quickly without leaving anyone behind. |
| 30/09/2022 |
£2,328,408 |
UNIVERSITY OF CAMBRIDGE |
Osteoarthritis (OA) is a common degenerative condition that frequently affects the knee joint and results in chronic pain. Knee pain is sensed when sensory neurones innervating the joint relay this information into the spinal cord, from where it is propagated to the brain leading to perception. Our understanding of the neuronal substrate driving chronic knee pain is limited, with a distinct lack of knowledge of the spinal circuitry underlying normal or chronic joint pain. Our preliminary data in the destabilisation of the medial meniscus (DMM) model of knee pathology shows that knee-innervating sensory neurones become hyperexcitable as pain behaviour develops, with single-cell RNA-sequencing analysis of these neurones identifying three distinct populations involved in this process. Furthermore, we find that chemogenetic inhibition of knee-innervating sensory neurones normalises joint pain. In this project, we will establish the DMM model in transgenic mouse strains and use viral constructs to both determine the roles of distinct primary afferent populations in OA pain and define the spinal circuitry involved in this condition. Human tissue samples will then be used to replicate our studies in mice, providing a means for understanding how OA pain is generated in patients and opening the door to novel therapeutic treatments. |
| 30/09/2022 |
£997,033 |
SERVAREGMP |
ServareGMP is currently funded under award 224693/Z/21/Z to develop an optimized bioprocess for a very low cost, highly effective monoclonal antibody against Vibrio cholera. This effort will be validated through small scale manufacturing and performance analytics. The project has already achieved a number of its program milestones as detailed below. A key aspect of the program is its adaptability to other mAbs targeting diseases for unmet needs in vulnerable populations. This current proposal adds five additional work project areas intended to increase the likelihood of success of the initial awarded project. The five work project areas are: 1) Development/Testing of second antibody variant; 2) Bioprocessing expansion including lyophilization development; 3) Regulator pathway development; 4) Technology transfer development; 5) Feasibility of oral formulation These work packages were developed to increase the likelihood of success toward meeting the project and program objectives and deliverables. All five Work Packages are designed to either improve the development of ZAC3 as a successful monoclonal antibody against cholera or improve the overall program designed to ensure successful deployment of ZAC3. Additionally, the work packages will assist in creating LMIC-based biologics manufacturing capacity, where ZAC3 could be the model initial candidate for that capacity. |
| 30/09/2022 |
£700,000 |
UKRI-MRC |
Not available |
| 30/09/2022 |
£1,000,000 |
UK BIOBANK LTD |
Not available |
| 30/09/2022 |
£1,905,912 |
UKRI-MRC |
Not available |
| 30/09/2022 |
£10,000,000 |
INTERNATIONAL BANK FOR RECONSTRUCTION AND DEVELOPMENT |
Pandemic prevention and preparedness is under-funded on an international scale, despite the recent experience of the overwhelming social, health and economic costs of being unprepared for pandemics. A new Financial Intermediary Fund (FIF) that pools international funding has been established at the World Bank to address gaps in pandemic prevention, preparedness and response (PPR). Wellcome has made a £10 million commitment to World Bank as a founding donor to this fund. This fund has the potential to be one of the most meaningful reforms for global preparedness and response to infectious disease outbreaks. |
| 30/09/2022 |
£1,861,068 |
UNIVERSITY OF OXFORD |
Understanding the nature, effectiveness and durability of the human immune response to SARS CoV2 is crucial for vaccine development and effective public health management. We are beginning to understand the pattern and kinetics of the humoral response to natural infection but are less certain about other aspects of the response. We are unable to establish with certainty whether an individual with a particular titre of antibody, or a particular T cell response, is likely to be protected from reinfection and, if so, for how long. These are central questions for the development of an effective vaccine. A controlled human infection model will provide a more detailed understanding of the protective immune response. It will provide the opportunity to interrogate the full extent of the immune response at the time of exposure and will also allow the evaluation of the durability of immune responses of all kinds and how they correlate with protection.
Key goals:
To establish an MHRA-approved SARS CoV2 viral stock for use in a controlled human infection model
To determine a challenge dose which is safe and allows virus to be recoverable from infected subjects
|
| 30/09/2022 |
£794,916 |
UNIVERSITY OF OXFORD |
Current applications in progress - 3
Total number of current applications in progress for LMICSSs to be held at the AAP/Centre to which the application relates - 3
|
| 30/09/2022 |
£1,981,331 |
WORLD ECONOMIC FORUM |
Not available |
| 30/09/2022 |
£302,844 |
AMREF HEALTH AFRICA |
Increasing temperatures and sea levels, changing precipitation patterns and more extreme weather is threatening human health and safety, food and water
security and socio-economic development in Africa. As a result, climate change is becoming a major cause of mortality, leading to an estimated 150,000 deaths annually. Despite the glaring effects of climate change on Africa’s population, the voice of the most vulnerable has not found space in decision-making tables. In addition, regional and national cross-sectoral collaboration is weak, and local climate change and adaptation measures are dismal. Nearly all African countries have committed to enhancing climate action by reducing their greenhouse gas emissions and building resilience. However, many of these commitments are conditional upon receiving adequate financial, technical and capacity-building support. Accountability to these commitments has been weak, and the weak voice of civil societies has led to absolute complacency by some governments. Through multilateral pan-African partnerships, systematic advocacy and government engagement Amref Health Africa has an ambition to bring health to the forefront of global climate change action. It will do this through advocacy to increase regional understanding of the effects of climate change and generate evidence for framing advocacy interventions and policies that protect and improve human health.
|
| 30/09/2022 |
£215,796 |
PANORAMA GLOBAL |
Lead CSO consultation and engagement in the design, start-up and governance of the Pandemic Fund
Enable diverse, meaningful, and timely CSO engagement in strategy and decision-making during the design and start-up phases of the Fund to build support and improve its governance, and impact.
Activities/Outputs
Series of multi-stakeholder consultations to inform Fund design and decision-making, in partnership with two or more Southern-led CSOs or networks, producing written outputs which summarize the consultations.
Online portal to provide timely information on the evolving design and activities of the Fund, to serve as a go-to resource for CSOs and other stakeholders seeking to engage in Fund-related advocacy.
Rapid selection process, in partnership with two or more Southern-led CSOs or networks, to identify two interim CSO representatives and two alternates to serve on the Fund’s governing board.
Briefings and technical assistance for the interim CSO representatives to prepare for and support their engagement in meetings and decisions of the Fund’s governing board, including ongoing consultations to solicit input from CSOs across the global North and South.
Proposal for a permanent CSO engagement hub and CSO representative selection process for the Fund, based on best practices and learnings from other global financing mechanisms
|
| 30/09/2022 |
£60,102 |
UK HEALTH SECURITY AGENCY |
As part of the WHO research and product development (R & D) Blueprint initiative for epidemic prone diseases, in 2018 the UK Health Security Agency (UKHSA) partnered with WHO to develop an R & D roadmap for Crimean-Congo Haemorrhagic fever (CCHF). An advanced draft roadmap was produced that prioritised the development of those countermeasures – diagnostics, therapeutics and vaccines for human or animal use - that are most needed by CCHF-affected countries, and set the direction and timelines for future CCHF product R & D activities. Progress was then interrupted by the COVID-19 pandemic.
This proposal focuses on updating and launching the WHO R & D Roadmap for CCHF and supporting activities for its dissemination and early adoption. The knowledge landscape since 2018 will be reviewed, the priorities and timelines set in the draft CCHF roadmap revisited and updated and a finalised roadmap delivered to WHO for formal publication on their website. A companion publication will be submitted to an open-access scientific journal. After launch, a stakeholder event will raise awareness of the CCHF roadmap and identify R & D activities planned by stakeholders that align with the roadmap priorities, thus facilitating its early adoption. An additional objective is to update a comprehensive landscape analysis and make this openly available.
|
| 30/09/2022 |
£3,120,676 |
IMPERIAL COLLEGE LONDON |
The Vaccine Impact Modelling Consortium (VIMC) was founded in 2016 to deliver a more sustainable, efficient, and transparent approach to generating disease burden and vaccine impact estimates. This grant will enable VIMC to better assess the implications of climate change for vaccination strategy, with a focus on low- and middle-income countries (LMICs). Two interlinked research strands will: (a) assess the long-term impacts of climate change on disease range, burden and strategic implications for vaccine strategy and stockpiling; (b) examine how climate drives seasonal variation in disease transmission and burden, the impacts of increasingly frequent extreme climate events for disease burden, and model optimal prophylactic or reactive vaccination campaigns for mitigation. Programmatic research priorities will be informed by consultation with the VIMC stakeholder network. We will prioritise five climate-sensitive infections – malaria, dengue, yellow fever, cholera, and meningitis. The research will be collaborative with academic partners in LMICs most affected by these infections. It will also be cross-fertilizing between disease areas, developing generic inferential and projection platforms, software, and data resources. In addition, the grant will support capacity-strengthening via the recruitment of two foundational VIMC modelling groups from sub-Saharan Africa with expertise in health economic, operational, climate and/or geospatial modelling.
|
| 30/09/2022 |
£5,117,461 |
INTERNATIONAL VACCINE INSTITUTE |
DuoChol is a thermostable oral cholera vaccine (OCV) consisting of a lyophilized mixture of formalin-killed isogenic V. cholerae O1 Ogawa and Inaba bacteria and cholera toxin B-subunit in an enteric capsule, which has been preclinically developed by scientists at University of Gothenburg (UGOT) with financial support from the Wellcome Trust. The present application is now asking for support for the next stage, clinical development of DuoChol comprising GMP manufacturing, toxicity testing and Phase 1 clinical testing, which are all planned to be undertaken in Sweden. The phase 1 study will be a randomized, investigator blinded, parallel groups, active-controlled safety and immunogenicity study, where DuoChol will be compared with a WHO prequalified comparator OCV, Dukoral™, in 90 healthy Swedish adults (18-65 years). Each of DuoChol and Dukoral™ will be given twice orally as capsules and liquid suspension, respectively 2 weeks apart. Participants will be followed up for 2 weeks after each dose for immunogenicity (blood samples at Day 0, Day 14 prior to the first and second vaccinations, respectively, and Day 28, and for safety surveillance for 1 month after the last dose). The project will be coordinated by the International Vaccine Institute (IVI) with UGOT as a collaborator.
|
| 30/09/2022 |
£3,120,479 |
UNIVERSITY OF YORK |
Vector-borne diseases, mostly mosquito-borne, account for > 17% of all infectious diseases of humans. Disease caused by ARthropod-BOrne viruses (arboviruses, e.g. dengue, chikungunya and Zika viruses) continue to escalate, the burden falling overwhelmingly on Low-and-Middle-Income Countries (LMICs) and likely exacerbated by climate change affecting mosquito distribution. These ‘neglected tropical diseases’ impact development, e.g. Millennium Development Goals, as well as their direct human burden. Arboviruses are also among the key emerging infectious diseases/priority diseases of epidemic potential.
New cost-effective, sustainable, environmentally-friendly methods for controlling arboviruses are sorely needed. Here we propose to develop broad-spectrum anti-viral traits in engineered mosquitoes. By "broad-spectrum" we mean active against multiple arboviruses, in contrast to the current state of the art for synthetic anti-viral ("reduced vector competence") traits, RNAi-based systems which provide resistance only against specific viruses or virus strains. This is important for vectors such as Aedes aegypti, which can transmit a range of important viral pathogens.
Such tools could be delivered to wild vector populations via mating between released modified mosquitoes and wild mosquitoes. These methods are egalitarian – everyone within the protected area is equally protected, irrespective of wealth, ethnicity, gender, education etc.
|
| 30/09/2022 |
£2,977,154 |
UNIVERSITY OF SHEFFIELD |
Disability Matters will transform health research and research environments through a paradigm shift to disability as the driving subject of inquiry. We will develop anti-ableist and anti-disablist approaches that promote inclusive research cultures, broaden health research priorities, innovate research methodologies, generate positive disability representations and cultivate a new generation of equitable health researchers across five countries. Health research still tends to adopt disability as a passive object of intellectual curiosity, empirically investigate disability as a chronic illness or understand disability in terms of impairment or pathology. Disability exists as an ‘absent presence’ - a present problem to be solved by research but absent as a research colleague or scholarly authority - and disabled health researchers are conspicuously absent. Health research often ignores the specificities of disabled people’s lives and the health inequalities that they endure as a consequence of disabling systemic factors. Poor, working class, female, LBGTQ+ and black disabled people are particularly at risk of being forgotten. Our programme of work will address these omissions and generate transformative equity, diversity and inclusion knowledge; thus supporting Wellcome’s strategy to lead the Science and Health sector in challenging ableism and disablism in the practices and cultures of health research.
|
| 30/09/2022 |
£1,526,638 |
IFAKARA HEALTH INSTITUTE |
Transmission of mosquito-borne diseases can be affected by climate and land-use patterns in different ways. Increased temperatures can shorten the latency of malaria parasites thereby enabling transmission in previously-temperate zones. Yet extended droughts could crash populations of vectors such as Anopheles gambiae, which breed in small, open and drought-sensitive habitats. In contrast, flooding can increase populations of container-breeding dengue vectors, Aedes aegypti.
Most investigations of climate and vector-borne diseases are too expansive to be computationally-practical; and often overlook local data on entomological, anthropological or land-use characteristics. Fortunately, advanced cloud-based data processing, sensor design and on-board computing now enable highly-sensitive multi-modal systems with real-time data acquisition and integration. Microsoft Premonition offers a surveillance platform that autonomously lures, identifies and selectively captures arthropods for downstream studies, including metagenomics. With Gates-Foundation support, we are deploying this system in Tanzania to enhance malaria vector surveillance.
Here, we propose extending the Premonition platform to investigate local associations between climate, land-use and mosquito-borne diseases. By combining capabilities in vector-biology, spatial analytics, machine learning and mathematical modeling, we will: i) integrate environmental and entomological data-streams to predict transmission risk, ii) investigate climate-dependent survival strategies of medically-important mosquitoes and iii) evaluate entomological data for monitoring climate and land-use.
|
| 30/09/2022 |
£40,000 |
UNIVERSITY OF YORK |
Not available |
| 30/09/2022 |
£40,000 |
NATIONAL CENTRE FOR SOCIAL RESEARCH |
The project aims to unravel the dynamics between social connection and the development of depression and anxiety in young people. The team will investigate whether different types of social ties (e.g. family, friends, community) at key timepoints in childhood protect against depression and anxiety in early life (up to 30 years old). First, the team will use the Avon Longitudinal Study of Parents and Children (ALSPAC) to map the trajectory of mental health across youth and early adulthood. They will then explore whether these trajectories differ between people who had experienced strong and weak social connections, across different domains, in childhood. The project aims to identify key transition points – where changes in social connection are strongly associated with changes in mental health. The team will visualise the results to improve understanding of how differences in social connection are associated with changes in mental health symptoms over time. The team will then co-produce a tool wherein, researchers, policy makers and those with lived experience can explore the dynamics of social networks and their effects on the development of mental health problems over time.
|
| 30/09/2022 |
£40,000 |
BLACK THRIVE GLOBAL |
Not available |
| 30/09/2022 |
£40,000 |
CARDIFF UNIVERSITY |
Not available |
| 30/09/2022 |
£40,000 |
UNIVERSITY OF BIRMINGHAM |
Not available |
| 30/09/2022 |
£40,000 |
ULSTER UNIVERSITY |
Not available |
| 30/09/2022 |
£40,000 |
SOUTH AFRICAN MEDICAL RESEARCH COUNCIL |
Not available |
| 30/09/2022 |
£40,000 |
UNIVERSITY OF SURREY |
Not available |
| 30/09/2022 |
£40,000 |
UNIVERSITY OF YORK |
Not available |
| 30/09/2022 |
£4,949,992 |
UNIVERSITY OF LIVERPOOL |
Purpose: To conduct research for optimising antimicrobial use in humans through three interlinked themes identified through a research roadmap and landscape review (medicines management; technology and innovation for optimised prescribing; culture, context, and behaviours).
Structure: Researchers will be connected via a global network built on existing collaborations between National Hubs (UK, Uganda, South Africa, India, Brazil) with complementary research theme expertise. Opportunities for geographic (South-South and North-South) bilateral learning in research projects will maximise implementation and translational activities, facilitated by a comprehensive programme for knowledge mobilisation, capacity strengthening, and co-production for local context-specific, sustainable interventions. National Hubs will link with existing structures and supported by quality-assured technology and research and development laboratories (Malawi, Ghana, Thailand) to support activities. Development of an Antimicrobial Resistance Data Warehouse will provide underpinning network infrastructure for the global good.
Network growth: Shadow national sites (Pakistan, Bangladesh, Timor Leste) will participate in network activities to actively build research collaborations and capacity with the National Hubs. In years 1-2, they will identify national research priorities and conduct a pilot project in year 3. The goal for a future iteration of CAMO-Net is that shadow national sites would become National Hubs, and new shadow sites would be identified.
|
| 30/09/2022 |
£1,296,981 |
UNIVERSITY OF CAPE TOWN |
Purpose: To conduct research for optimising antimicrobial use in humans through three interlinked themes identified through a research roadmap and landscape review (medicines management; technology and innovation for optimised prescribing; culture, context, and behaviours). Structure: Researchers will be connected via a global network built on existing collaborations between National Hubs (UK, Uganda, South Africa, India, Brazil) with complementary research theme expertise. Opportunities for geographic (South-South and North-South) bilateral learning in research projects will maximise implementation and translational activities, facilitated by a comprehensive programme for knowledge mobilisation, capacity strengthening, and co-production for local context-specific, sustainable interventions. National Hubs will link with existing structures and supported by quality-assured technology and research and development laboratories (Malawi, Ghana, Thailand) to support activities. Development of an Antimicrobial Resistance Data Warehouse will provide underpinning network infrastructure for the global good. Network growth: Shadow national sites (Pakistan, Bangladesh, Timor Leste) will participate in network activities to actively build research collaborations and capacity with the National Hubs. In years 1-2, they will identify national research priorities and conduct a pilot project in year 3. The goal for a future iteration of CAMO-Net is that shadow national sites would become National Hubs, and new shadow sites would be identified.
|
| 30/09/2022 |
£3,140,701 |
THE BIOVAC INSTITUTE |
Covid-19 has highlighted the urgent need to establish vaccine development and manufacturing capacity at scale in Africa
By focusing on the development and commercialisation of an oral cholera vaccine (OCV) in partnership with IVI this project will deliver much needed capability for the manufacture of clinical trial material (CTM) in Africa. OCV will be Biovac’s first fully manufactured and WHO PQ’d product.
The overall aim is to receive a technology transfer package for a simplified OCV from IVI at small scale, follow a stepwise scale up of the process, manufacture CTM, perform clinical studies, achieve licensure in South Africa with SAHPRA and then progress to achieve WHO PQ in order to be a supplier of OCV to Gavi/Unicef. Thereafter, the process will be transferred to a new large-scale facility (yet to be built).
This proposal covers the first 3 stages of a multi-stage project and includes:
Stage 1: Lab demonstration of the IVI technology
Stage 2: Readiness of API facility for process scale-up
Stage3: Process scale Up
The remaining stages to follow include:
Stage 4: GMP manufacture of Clinical Trial material
Stage 5: Clinical Trials, licensure and WHO PQ
Stage 6: Transfer the process to a new manufacturing facility
|
| 30/09/2022 |
£40,000 |
UNIVERSITY OF EDINBURGH |
Not available |
| 30/09/2022 |
£40,000 |
UNIVERSITY OF EDINBURGH |
Not available |
| 30/09/2022 |
£999,998 |
UNIVERSITY OF BIRMINGHAM |
BactiVac was established in 2017 with a mission to advance vaccine development against global bacterial infections to reduce disease, death, and antimicrobial resistance, and enhance economic development. We have brought together academia, industry, policy-makers and funders from high-income countries and LMICs, in a network of over 1,300 members from 78 countries, 48% from LMICs. We have supported member collaborations in vaccine development through Catalyst Project Awards which have leveraged 560% of follow-on funding. We have delivered key training and supported training exchanges. Annual Network Meetings brought the Network together. We have advocated for bacterial vaccines at available opportunities.
The goal of BactiVac Phase 2 is enhanced Network impact over the next four years. This will be achieved through building on successes with further Catalyst Projects, Annual Network Meetings, Catalyst Training, and skills courses. Training will focus on addressing bottlenecks and capacity-building among LMIC early-career researchers. As an established network, we will expand advocacy initiatives and improve communications through development and delivery of media content. Network growth will focus on increasing industry interactions, and strengthening links to organisations with aligned missions. This will enable us to become a network within a highly-functioning network of networks, promoting bacterial vaccines.
|
| 30/09/2022 |
£6,448,347 |
UNIVERSITY OF LIVERPOOL |
The global burden of mental health conditions is a profound public health challenge, worsened by the COVID-19 pandemic, and yet we know little about their early-life origins. Compelling evidence points towards microbial gut colonisation, strongly influenced by breastmilk, as an important determinant of neurodevelopment trajectories and mental well-being via the microbiota-gut-brain axis, but there is little definitive research on the mechanisms. To help close this knowledge gap, we propose ‘4M: Microbes, Milk, Mental Health and Me’ – enhancing the Children Growing up in Liverpool (C-GULL) programme by enabling collection of additional bio-samples, state-of-the-art gut microbiota and breastmilk profiling, and rigorous mechanistic exploration of the causal pathways underlying adverse mental health outcomes in this richly-phenotyped birth cohort. We will generate, integrate, and interrogate large-scale genomic and epidemiological datasets to perform experimental testing, biological discovery, causally robust epidemiology, and translational science. We will also create an internationally unique archive of paired bio-samples from mothers and babies and identify keystone bacteria and milk constituents that influence neurodevelopment and mental health. This will generate robust evidence for preventative and therapeutic interventions (e.g., diet, Live Bacterial Therapeutics) to restore and select for age-appropriate beneficial species to optimise a child’s resistance to adverse mental health conditions.
|
| 30/09/2022 |
£706,033 |
WELLCOME SANGER INSTITUTE |
The global burden of mental health conditions is a profound public health challenge, worsened by the COVID-19 pandemic, and yet we know little about their early-life origins. Compelling evidence points towards microbial gut colonisation, strongly influenced by breastmilk, as an important determinant of neurodevelopment trajectories and mental well-being via the microbiota-gut-brain axis, but there is little definitive research on the mechanisms. To help close this knowledge gap, we propose ‘4M: Microbes, Milk, Mental Health and Me’ – enhancing the Children Growing up in Liverpool (C-GULL) programme by enabling collection of additional bio-samples, state-of-the-art gut microbiota and breastmilk profiling, and rigorous mechanistic exploration of the causal pathways underlying adverse mental health outcomes in this richly-phenotyped birth cohort. We will generate, integrate, and interrogate large-scale genomic and epidemiological datasets to perform experimental testing, biological discovery, causally robust epidemiology, and translational science. We will also create an internationally unique archive of paired bio-samples from mothers and babies and identify keystone bacteria and milk constituents that influence neurodevelopment and mental health. This will generate robust evidence for preventative and therapeutic interventions (e.g., diet, Live Bacterial Therapeutics) to restore and select for age-appropriate beneficial species to optimise a child’s resistance to adverse mental health conditions.
|
| 30/09/2022 |
£4,973,992 |
OFFICE FOR NATIONAL STATISTICS |
This proposal is to build on ONS’s pandemic response experience and its world class expertise to develop a toolkit comprising of practical guidance, statistical methods, knowledge products, case studies and training materials. The goal is to help NSIs, especially in low- and middle-income countries (LMICs), maximise existing resource in the monitoring of the scale and impacts of infectious disease (in partnership with public health infrastructure) and developing in-country capability to inform and guide policymakers in making evidence-based decisions.
The project is planned over five years, with the initial year focussed on building strong partner relationships with international organisations, as well as identifying and establishing agreements with LMIC partner countries.
ONS will initially work with three NSI partners to co-create the toolkit/initiate pathfinder projects, illustrating how these NSIs can leverage the toolkit in their specific contexts. Through a multi-disciplinary approach to knowledge transfer and capacity building, we will co-design the toolkit to maximise national fit and sustainability, seeking synergies with other initiatives, increasing data capability and use of data at the heart of decision making.
To ensure long-term sustainable impact, we will work towards mobilising global and local resources to support the longer-term sustainability of the toolkit and pathfinders.
|
| 30/09/2022 |
£9,369,000 |
WELLCOME TRUST GGMBH |
Wellcome approved the establishment of a Germany Office in 2017/18 in order to test the benefits of an international presence, to strengthen Wellcome’s policy influence and brand outside of the UK, particularly in Europe, and to inform its Brexit strategy from the Germany Office experience.
The Germany office has shown successes in policy impact and has expanded its network and reach.
We have not only advanced our ability to influence and shape policy of a large and highly committed donor to global health, but we have also developed strong alignment with wider Wellcome objectives. Germany’s political interest is gravitating towards Wellcome’s health challenges, and we have been able to help create new leads to help priority areas to maximize their impact.
On the basis of this development, ELT recommended to the BoG to approve the establishment of a German legal entity, in form of a gGmbH, in November 2021, which was approved. Following, it was decided that the new legal entity, called Wellcome Trust gGmbH, will be funded through a grant process between Wellcome U.K. and the new entity.
This proposal outlines the planned activities and related funding asks for the next 5 years of Wellcome Trust gGmbH in Berlin.
|
| 30/09/2022 |
£883,506 |
UNIVERSITY OF OXFORD |
The ongoing COVID-19 health emergency exposed significant problems with funding and research structures at a global level in a pandemic, resulting in an uncoordinated, fragmented and ultimately inefficient research funding response. The Pandemic Analytical Capacity and Funding Tracking Programme (Pandemic PACT) proposes to build on our work during the COVID-19 pandemic, to develop a broad prospective research funding tracking and analysis capability linked to major funding decision makers. The programme will collate global funding data for a wide range of epidemic prone diseases and broader epidemic and pandemic research preparedness activities on an ongoing basis. It will map these against research domains, research agendas and living Rapid Research Needs Appraisals*. The outputs will include an interactive database of the relevant research funding landscape mapped to domains and priority roadmaps (the tool); regular analyses of funding trends and research gaps; and a standing capability to rapidly identify research needs in the event of a novel outbreak or disease. These outputs will support evidence informed decision making and coordination by the world’s major research funders and key policy stakeholders through directly feeding in to GloPID-R’s response plan and regional hubs with the goal of improved efficiency and effectiveness of research responses.
|
| 30/09/2022 |
£2,138,660 |
UNIVERSITY OF TEXAS AT AUSTIN |
Global mental health research requires sharing biological and behavioural measures across international cohorts to accelerate equitable development of treatments for all peoples. While brain and mental health research strives to become international, the lack of transparency and navigability of existing legal, ethical, and sociocultural guidance imposes barriers to data sharing.
Building on the momentum of the International Brain Initiative, we propose a bottom-up approach to address these challenges by developing foundations for an International Data Governance Framework (IDGF). The long-term goal of this program is to form a sustainable global consortium to develop, operate and disseminate a robust brain and mental health IDGF similar to what has been accomplished in genetic research via GA4GH. A series of white papers and annual workshops will jump-start the process. International data exchange workflows will be implemented and tested on study-case, validation datasets. A diverse group of stakeholders consisting of scientific, institutional and governmental representatives, legal experts, funders, industry representatives as well as Persons With Lived Experience (PWLE; through gmhpn.org) will be engaged.
Completion of these activities will produce invaluable tools and infrastructure for researchers, PWLE, and policy-makers for navigating international data sharing and lay a solid foundation for a continuing global consortium.
|
| 30/09/2022 |
£1,025,960 |
WORLD HEALTH ORGANIZATION, SWITZERLAND |
The activities described in this proposal will strengthen the World Health Organization’s (WHO) ability to advance its scientific activities on mental health, placing the agency in a more advantageous position to deliver on WHO’s 13th General Programme of Work (GPW13) and the Comprehensive Mental Health Action Plan (2013-2030). This proposal describes mental health scientific activities for one year, which focus on: (a) evidence-based guidelines for depression, anxiety and psychosis applicable in primary health care (PHC) and other non-specialized care settings under WHO’s mhGAP programme; (b) measurement of coverage through the development of a WHO STEPS mental health surveillance module; and (c) partnership activities to strengthen advocacy, open access and use of common measures.
|
| 30/09/2022 |
£451,572 |
ENVIRONMENTAL DEFENSE FUND |
EDF proposes holding a series of dialogues on the intersection of methane emissions and public health, which is not well understood currently. Our goal is to advance a policy and research agenda that better characterizes the health benefits of cutting methane pollution and drives more targeted interventions that will deliver significant health and climate benefits at a local, national and global scale. With countries poised to take meaningful action under the Global Methane Pledge, now is the time to ensure that health is central in the identification, assessment and prioritization of methane mitigation policies and interventions. These dialogues will take place over the next 18 months, with a kick off at COP 27 in November followed by more in-depth discussions on regional and sectoral issues on the road to COP 28, and culminating in a draft statement to be presented at the COP in 2023. The COP provides an ideal platform for advancing progress on the methane problem amongst key stakeholders— including researchers, policy makers and funders. Through these dialogues, we will dive into regional and sectoral activities associated with methane emissions and consider their multidimensional health impacts, with a focus on identifying near-term priorities to accelerate durable solutions.
|
| 30/09/2022 |
£99,996 |
RESTLESS DEVELOPMENT |
The 2021 ‘Young People as Changemakers on Issues of Climate and Health’ study undertaken in Zimbabwe was a relatively small research pilot with significant results. Participants identified crucial barriers relating to young people’s leadership in climate change mitigation and adaptation - particularly around access to resources and decision-making spaces. The findings sparked a number of new lines of enquiry relating to climate change, and in light of this, Restless Development proposes a Research and Development (R & D) phase to help design a second phase of the project. During this R & D phase, Restless Development will engage stakeholders including climate and health scientists and young people to define the objectives, target groups and activities for Phase 2. The R & D phase will answer; Who should be the priority, bearing in mind the intersectionality of issues related to climate change and health? Which partners should Restless Development work with? What geographical focus will give greatest results, and which climate change adaptation strategies will be key?
Consultations will include, advocacy landscape mapping, engagement meetings with researchers and campaigners, and stakeholder meetings with those identified in phase 1 of the project including climate and health scientists, policy makers and health practitioners.
|
| 30/09/2022 |
£4,842,966 |
UNIVERSITY OF QUEENSLAND |
The Mekong Delta Region (MDR) of Vietnam is vulnerable to climate change which results in more frequent and intense mosquito-borne dengue outbreaks. Current dengue control measures are mostly reactive due to the absence of an early warning system (EWS) tailored to the needs of the local health systems. Local health practitioners and the community are, therefore, not adequately empowered to deploy preventive actions to reduce the impact of a dengue outbreak. We propose to develop and evaluate a digital dengue early warning system (E-DENGUE), based on a prediction model, to assist the local health systems and the local communities affected by dengue to proactively mitigate the impact of outbreaks in the MDR. The specific aims are: i) to build a predictive dengue model that accurately predicts dengue risk, at the district level, two months in advance; ii) to develop E-DENGUE––an open-source software system with a user-friendly web-based and mobile-app interface––aimed at local health practitioners to predict dengue incidence and outbreaks at the district level; iii) to evaluate the effectiveness of E-DENGUE in reducing dengue incidence using a cluster-randomised control trial based in the MDR; iv) To evaluate the cost-effectiveness of E-DENGUE for outbreak prevention in the MDR.
|
| 30/09/2022 |
£262,737 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
The magnitude of antimicrobial resistance in Africa and its impact on clinical and economic outcomes are not well understood. The Surveillance Partnership to Improve Data for Action on Antimicrobial Resistance (SPIDAAR) consortium has commenced a multi-centre study of the burden of healthcare associated infections (HCAI) among hospitalised patients in sub-Saharan Africa. A key measure of success of this programme will be a series of peer reviewed publications led by the in-country SPIDAAR RWE leads, and support has been requested in both the analysis of the data and with manuscript writing for these manuscripts by the country leads.
Aim
For the RWE sites to be able to interpret and analyse their data, and turn it into actionable information for use at facility and ministry of health level to change practice and reduce HAI.
Objectives
To hold a data analysis and writing workshop bringing together up to 5 participants from each of the four sites to support capacity strengthening in technical writing and data analysis;
To deliver a clinical study report to Pfizer in compliance with relevant Pfizer SOPs;
To author a series of manuscripts. One primary study-level manuscript and a further secondary manuscript per site.
|
| 30/09/2022 |
£3,240,789 |
WORLD HEALTH ORGANIZATION, SWITZERLAND |
Within the overall Wellcome Trust-WHO strategic partnership on climate change and health, this project aims to significantly strengthen multidisciplinary capacity and partnerships to address the health risks of extreme heat in vulnerable populations, particularly in low- and middle-income countries (LMIC). In close cooperation with the World Meteorological Organization and the co-sponsored initiative, the Global Heat Health Information Network, this project proposes to expand regional-level partnerships and capacity; to build community across world regions and new stakeholder groups (e.g. engineering, design and architecture); to develop new technical and evidence based tools, case studies, and guidance on heat and health; and to scale up awareness and accessibility to technical information by enhancing existing web-resource platforms (e.g. GHHIN.org and ClimaHealth.info). These activities will help deliver the following expected outcomes:
Strengthened interdisciplinary partnerships, capacity, and access to expertise through dialogues and peer-learning;
Enhanced regional interdisciplinary and institutional capacity to address extreme heat risks to health;
Accelerated translation of evidence to action on health risks of extreme heat and effective solutions to protect vulnerable populations in LMICs;
Increased awareness of climate change and extreme heat risks to health as a result of effective advocacy, community building, and access to technical resources.
|
| 30/09/2022 |
£1,973,174 |
MEDICINES AND HEALTHCARE PRODUCTS REGULATORY AGENCY (MHRA) |
There is a growing mental health illness burden for individuals and society. The National Health Service Long Term Plan and Life Science Vision has committed to improving mental health care. At the same time there has been a significant increase in the number of digital mental health products available and used, giving hope of a way to help those in need, but these products present many regulatory challenges.
As the UK safety regulator for healthcare products, we (the MHRA) recently outlined a programme to deliver bold improvements to the regulatory framework for software as a medical device. Further work is needed to translate these broad requirements into specific and accessible requirements for digital mental health products. Additionally, the National Institute for Health and Care Excellence (NICE) are prioritising digital technology evaluations and mental health is scheduled as a speciality area.
The aim of this project is to enable access to safe and effective products, to help improve mental health care. It will do this by ensuring that digital mental health products are regulated in a risk proportionate manner and evaluated consistently. We propose to meet this ambitious aim by collaboratively working with NICE and other key stakeholders.
|
| 30/09/2022 |
£2,650,935 |
UNIVERSITY OF OXFORD |
The first iteration of the GRAM project represented the single largest assembly of global data on AMR but contained significant gaps geographically and in some cases by some infectious syndromes for example. The first priority is to consolidate the global burden estimation of AMR and integrate it into the global burden of disease enterprise so that it can be produced on a regular basis, and to make that process of integration of the estimation of AMR a sustainable ongoing process. Furthermore, better coverage of data through an expanded network of collaborators and targeted acquisition of data to fill key gaps will help produce improved estimates of the public health and clinical burden caused by drug resistant infections and help address the most important data gaps identified in GRAM-1. In order to fully utilise the data, there is a need to maximise the value of the investment and provide increasingly robust estimates on the burden of AMR, at country level over time. Continued analysis with more data will also help us better understand differences between countries, or over time regarding the impact of AMR.
This application contributes to shared activities for GRAM-2 and will be jointly funded by DHSC.
|
| 30/09/2022 |
£125,000 |
MY PLANET NOW LTD |
MY PLANET NOW is a documentary film and impact campaign leveraging first-person, "self-shot" character stories and innovative campaign strategies to improve climate literacy and build consensus for climate action among traditionally polarised and/or underserved audiences.
The project implements evidence-based communication strategies proven to engage audiences outside environmental echo chambers, and highlights narrative themes that appeal to universal values as well as self-interest, including the human health impacts of climate change. Through the careful curation and juxtaposition of stories within the film (and extrapolated throughout the campaign), MY PLANET NOW is designed to resonate with a more diverse audience than often reached through traditional climate action messaging, and to mobilise viewers around a sense of shared values and efficacy.
Although MY PLANET NOW won’t focus exclusively on the relationship between climate and health, ‘health’ is a core part of the film’s DNA. We believe that the film’s distinctive approach can make a unique and valuable contribution toward building understanding of the climate crisis as a health crisis; it can also reveal how efforts to mitigate climate change can protect and improve our health and that of future generations.
|
| 30/09/2022 |
£2,500,000 |
NATURAL HISTORY MUSEUM |
Life has evolved from a single origin to generate over 1.8 million eukaryotic species. Sequencing the genomes of all species will provide an inventory of life, transform understanding of evolution, catalogue eukaryotic gene toolkits for biology and biotechnology, and enable monitoring of ecosystems under increasing stress. The Darwin Tree of Life (DToL) project was founded to collaboratively sequence all species (~70,000 described) in Britain and Ireland to the highest quality standards to demonstrate the feasibility of large scale biodiversity genomics. We believe that these data will transform biology forever.
Our consortium of biodiversity, sequencing and analytic partners has through the last three years - and despite the covid pandemic - built systems for collection, identification, extraction, sequencing, assembly and annotation of genomes at scale, with all data released openly. We will have collected ~5000 species and released ~2000 genomes by the end of the first phase of DToL this year. With the core competencies in place, we are now seeking two years of funding to support our biodiversity and analytic partners in extending their collection and data delivery activities. During these two years we will broaden our funding base to be able to complete our goals by 2030.
|
| 30/09/2022 |
£2,674,505 |
DATACITE - INTERNATIONAL DATA CITATION INITIATIVE E.V |
To articulate the value proposition and justify open science as a norm in the research community, it is necessary to assess the impact and reach of investments made in open research data. The Make Data Count (MDC) initiative began in 2014 with the goal of creating the infrastructure for open data metrics. While different communities have yet to agree on the appropriate indicators for assessing the reach and impact of diverse research data, it is clear that standardizing and quantifying data citations is a necessary first step. Despite a growing emphasis on data citation among research stakeholders over the last five years, data citation initiatives have yet to be successful. In order to expose data citations in a reusable manner, DataCite proposes to shift focus away from relying on publisher workflows, utilizing text scraping methodologies and expanding scope beyond DOIs, developing an open data citation corpus, storing asserted data citations from a diverse set of sources. Driving the MDC initiative forward, this corpus will serve as a trusted and aggregated CC0 source of data citations from traditional workflows (Crossref), full text scraping algorithms (Meta), and biomedical/life sciences repositories (EMBL-EBI).
|
| 30/09/2022 |
£472,554 |
UNIVERSITY OF OXFORD |
We will conduct a realist review of participatory engagement – ‘REAL2’, preceded by a three-tiered, cumulative process: 1) socializing/applying the findings of an earlier realist review of community engagement with health research (REAL1), 2) consulting with diverse stakeholders about the REAL1 findings and additional work needed, and 3) scoping different ‘traditions’ of participatory practice to help focus the next realist review - REAL2. For step one we will work with KEMRI, OUCRU and MORU to consider the implications of the REAL1 findings for CE strategies in their settings and develop more focused guidance. Step two will involve consultations with stakeholder groups from different settings, thematic areas and roles (infectious diseases, mental health, climate change; funders, research leads) on the wider relevance of the REAL1 findings, and participatory engagement approaches for priority exploration in REAL2. Step three will involve a rapid scoping of key ‘traditions’ of participatory literature and practice to surface differences in the programme theories underpinning the work. These three steps will help the team – in collaboration with Wellcome – plan and implement step four: the follow up realist review REAL2. A range of accessible outputs will be developed throughout the process, to complement those produced through REAL1.
|
| 30/09/2022 |
£313,232 |
UNIVERSITY OF MINNESOTA |
Research and development (R & D) roadmaps are a valuable tool for guiding R & D efforts to prevent and control high-priority pathogens with epidemic potential. From mid-2017 through 2018, with funding from Wellcome, CIDRAP developed R & D roadmaps for Lassa, Ebola/Marburg, and Nipah viruses. From 2019 through 2021, CIDRAP developed a similar roadmap for Zika virus with funding from WHO. Draft roadmaps were submitted to WHO, but were not published owing to capacity restraints during the COVID-19 pandemic. The need for the roadmaps has not diminished and all parties involved are interested in finalizing three of them (for Lassa, Nipah, and Zika viruses); however, before they can be published, each requires thorough review and updating to incorporate recent scientific advancements and developments in the respective fields.
CIDRAP proposes to conduct an 11-month project aimed at publishing the Lassa, Nipah, and Zika virus R & D roadmaps on the WHO website. Key activities include updating the roadmaps; reinvigorating the previously established expert taskforces for each roadmap and ensuring appropriate geographic balance of members; conducting in-person taskforce consultations; finalizing and delivering the roadmaps to WHO; supporting roadmap launch activities (depending on timing and resources); and preparing manuscripts for publication in open-access journals to share results of this work.
|
| 30/09/2022 |
£983,969 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
Antimicrobial resistance (AMR) is a leading global health priority, contributing to an estimated 5 million deaths in 2019. It is a complex problem, with the potential to compromise the overall safety of healthcare delivery, from surgery to chemotherapy. AMR surveillance is described by the World Health Organisation as an essential tool to inform policies and infection prevention & control responses, however for many pathogens diagnostics and surveillance are not routinely performed. There is untapped potential for pathogen genomic data, derived from research and public health sectors, to fill gaps in AMR surveillance and inform policies and responses to the global AMR crisis. However whilst there is already an established culture of pathogen sequence data sharing, these data are essentially invisible to policymakers. This project aims to address this by making high-quality, robust and reliable genome-derived AMR surveillance data accessible to as wide an audience as possible, via a free and open-source online dashboard called AMRnet. This will be achieved by developing integrated solutions to multiple related challenges including data flow, organism-specific interpretive frameworks, and simple visualisations for complex data. Community engagement will be central to the project, to ensure its growth and sustainability.
|
| 30/09/2022 |
£670,370 |
INTERNATIONAL AIDS VACCINE INITIATIVE |
Monoclonal antibodies (mAbs) have transformed the management of many diseases from cancer to RSV (respiratory syncytial virus) over the last 30 years. However, their health impact is limited by their lack of access, especially in low- and middle-income countries (LMICs). The IAVI/Wellcome Call to action report highlighted that 85% of the world lacks access to mAbs, with few registered for use in LMICs. Currently, mAbs are developed mostly for high-income countries where the market, regulatory processes, and health needs are well understood. The market in many LMICs is not defined, nor are the diseases for which mAbs could have the greatest impact. This information gap hinders access at various stages- from development through procurement and uptake. Without knowing where the greatest need is, it’s hard to build a coordinated global response for mAb access in LMICs.
To address this key challenge, we propose to host a series of workshops to define which mAbs could have the most significant impact in LMICs in Africa. The workshops and follow-on activities will be to identify priority mAbs and understand feasibility and uptake considerations for these mAbs to help inform pathways for access in Africa.
|
| 30/09/2022 |
£203,447 |
INTERNATIONAL AIDS VACCINE INITIATIVE |
The goal of this proposal is to convene a workshop that will help define novel business models bridging across innovators, biosimilar companies, product development partners, and other global stakeholders that place access at their core from the outset, for the next generation of mAbs. The aim of the proposed convening will be to harness expert insights to define approaches that promote timely, equitable, and sustainable access to mAbs in LMICs, with a focus on infectious disease mAbs in the pipeline. The workshop is co-convened by Unitaid, IAVI, and Medicines Patent Pool, with support from Wellcome.
By convening key experts and stakeholders in a global dialogue around novel business models for mAbs access, we hope to advance several key outcomes:
Raising awareness and generating momentum around the need for alternative business models
Fostering collective dialogue and garnering expert advice in thinking through key aspects of business model innovation to inform partnership strategies and approaches
Cultivating strategic partnerships for novel business models for mAbs access
|
| 30/09/2022 |
£506,007 |
INSTITUTO DE SALUD GLOBAL DE BARCELONA |
Not available |
| 30/09/2022 |
£562,988 |
UNIVERSITY OF CALIFORNIA, SAN DIEGO |
Not available |
| 30/09/2022 |
£5,777 |
UNIVERSITY OF CAPE TOWN |
The purpose of the Showcasing African Neuroscience meeting was to facilitate a dynamic and interactive stakeholder engagement process that would: highlight the best examples of research in basic and clinical African neuroscience, explore potential for enhancing the interface between them in the African research-context, and provide a platform to highlight the significant potential for new discovery from within the continent.
Wellcome Trust supports a wide range of research, looking for potential areas of growth and opportunity, globally. Potential in the African neuroscience research-landscape was identified as one such area. Through conversations, a survey with African neuroscientists, and assistance from other groups already embedded in this landscape, the concept for a strategic meeting was born, with the aim of showcasing exciting neuroscience in African ecosystems, articulating prevailing challenges, and discussing ways to overcome them. The African neuroscience community led the engagement process, with support from Wellcome. A subsequent series of workshops drilled further into issues raised, starting discussions on how best to address them. This report builds on these discussions. In it, we highlight early advances in neuroscience research in Africa, and outline a framework for further development of African neuroscience to explore the unique challenges facing brain health and development.
|
| 30/09/2022 |
£70,482 |
REACT AFRICA |
ReAct Africa and South Centre Annual Conference 2022
Theme: Africa’s response to Antimicrobial Resistance: Accelerating One Health National Action Plans implementation for the next 5 years.
Antimicrobial resistance is a significant global threat to public health, food security, and development today. In Africa, AMR has been documented to be a problem exacerbated by a high burden of infectious diseases and weak healthcare systems. The existential COVID-19 pandemic has further complicated the situation.
The conference comes at an opportune time in July 2022. The conference offers an opportunity for retrospection where experts and key multisectoral stakeholders convene to reflect on lessons learned. The setting allows for context-specific discussions on challenges that are relatable across the region. The conference also provides a forum for sharing best practices across sectors with a one-health approach. The conference will be an opportunity to present the GRAM report results.
Leveraging on experience, insights, and tools from countries, NGOs, academia, UN agencies, continental and regional agencies, CSOs, and the private sector, the conference will explore what can be done differently in the subsequent years. Presentations will include scientific poster presentations on diverse research and exhibit best practices that contribute to catalytic action for the next five years.
|
| 30/09/2022 |
£4,999,384 |
UNIVERSITY OF GLASGOW |
The principal goal is to facilitate affordable and sustainable, locally-focused and locally-managed dengue control programmes, by releasing Ae. aegypti mosquitoes carrying Wolbachia maternally inherited symbionts to block virus transmission. The Wolbachia strain used in Ae. aegypti will be wAlbB, together with selective targeting of Ae. albopictus with other strains. Strategies will be tested in contrasting Southeast Asian, South American and African settings, to ensure broad applicability to dengue control within an operational framework. Our primary aims will be to identify mosquito backgrounds that minimize Wolbachia fitness costs; explore novel combinations of male-biased releases for suppression and replacement of Ae. aegypti and Aedes albopictus; develop guidelines for maintaining release stock quality; develop attract-and-kill traps that preferentially target wildtype mosquitoes; develop low-cost, high-throughput Wolbachia and insecticide resistance monitoring methodologies based on LAMP technology; and carry out economic evaluations to determine the optimal approaches for roll-out. The results will help improve and promote the use of wAlbB as the Wolbachia strain of choice for use in dengue control in high temperature settings, although the data obtained will also be directly relevant to other programmes using different Wolbachia strains.
|
| 30/09/2022 |
£182,164 |
REX LIFE SCIENCES LLC |
Since 2015, Dr. John H. Rex has worked to develop a digital communication platform for the antimicrobial resistance (AMR) R & D community both promotes innovative R & D and energizes policy changes to address the intertwined issues of access, stewardship, and innovation. The platform consists of a free newsletter, copies of each newsletter posted on http://amr.solutions and LinkedIn, tweets regarding newsletters, and a YouTube channel providing content related to the newsletters. As of this writing (May 2022), AMR.Solutions has 2,600+ subscribers from 50+ countries around the globe with an average of 2,500 opens and 800 clicks per newsletter. These subscribers are all heavily involved with AMR-focused projects and the newsletter is viewed as a must-read by many in the community. From a recent survey: "It provides information as well as analysis which are crucial to our thinking when tackling AMR. I am delighted that it has a wide range of topics covered from basic R & D to public health and policy." A grant from Wellcome Trust for Sep 2020 to March 2022 provided transformative supportive for the project. This grant application proposes that Wellcome Trust again support the further transformation and growth of this project via website maintenance, audience growth, and digital presence.
|
| 30/09/2022 |
£150,000 |
GENETIC ALLIANCE UK |
This application is for a final tranche of funding for Genetic Alliance UK from Wellcome, to complete our transition to sustainability.
We propose for this funding to be front-loaded, tapering over a three year period, providing support in the current financial year and the following two financial years. This would total £150,000 - matching our previous agreement.
This front-loading of the grant will provide the financial headroom necessary to move the emphasis for our fundraising activities to more substantial longer-term grants and investing in growing our income streams, while continuing progress is made in building our profile, developing our strategy and addressing our equality, diversity and inclusion priorities. We intend to use this grant as core unrestricted income which will be used to support the activities of the senior management team and the fundraising team in delivering this proposal. By the final year of the grant we anticipate that some of the growth in fundraising capacity will have been achieved, and the strategy review will be complete.
|
| 30/09/2022 |
£25,000 |
UNIVERSITIES UK |
In March 2022, we launched the findings from Phase 1 of this project. Phase 2 aims to look at the insight from Phase 1 on the coverage, adoption and influence of concordats and agreements. It also aims to explore how the agreements can be aligned in the future to increase influence, capacity, and efficiency in UK research cultures and environments.
Informed by the work so far, we are commissioning a series of activities which will do the following:
- Bring together updated insights on the agreements and concordats to explore solutions for increased influence, capacity, and efficiency.
- Run workshops to help stakeholders and representatives of the community to reflect on these insights, pulling out themes, challenges, and opportunity areas.
- Run workshops to explore these areas of opportunity and challenges, agreeing on possible future scenarios, generating ideas and to explore potential solutions for increased influence, capacity, and efficiency, taking a systems view.
- Work in collaboration with the community and stakeholders involved in agreements and concordats to refine potential solutions, and co-design a roadmap to deliver these activities.
|
| 30/09/2022 |
£9,910 |
KING'S COLLEGE LONDON |
King’s College London’s Institute of Psychiatry, Psychology & Neuroscience; the Royal College of Psychiatrists; the Association of Child and Adolescent Mental Health (ACAMH), the UK Child Psychiatry Research Society, Autistica, and the American Academy of Child and Adolescent Psychiatry (AACAP) are planning a commemorative event to celebrate the life and work of Professor Sir Michael Rutter, who sadly died in October 2021.
Known by many as ‘the father of child psychiatry’, Professor Sir Michael Rutter paved the way for developmental psychologists and psychiatrists around the world. He has made remarkable contributions to society, transforming our understanding of child development and tirelessly advocating for the health and wellbeing young people.
The commemorative event will be held from 10:00-17:00 on Monday 27th June at Bush House, King’s College London in front of an invited audience. With support from his family, we will be inviting friends, colleagues, and patients from across the globe to attend and share memories of Sir Michael’s impact, both personally and professionally. We will produce a video with highlights from the event to share his legacy more widely.
We request funding to convene the event and produce a video to share more widely Sir Michael's contribution to mental health.
|
| 30/09/2022 |
£452,707 |
WORLD HEALTH ORGANIZATION, SWITZERLAND |
Not available |
| 30/09/2022 |
£1,056,106 |
GLOBAL ANTIBIOTIC RESEARCH AND DEVELOPMENT PARTNERSHIP (GARDP) |
The lack of equitable access to essential life-saving antibiotics jeopardizes our ability to not only treat and control infectious diseases but also achieve the 2030 Sustainable Development Goals' pledge to leave no one behind. The unchecked growth of drug-resistant infections is a growing pandemic with long-term implications for global public health as it can affect anyone, of any age in any country. The SECURE project will be developed to address this challenge by facilitating access to key essential antibiotics, which are not widely accessible, for countries and populations in need, while ensuring their appropriate use. The goal is to provide long-term strategic guidance to help countries reduce mortality due to bacterial infections by ensuring access to a portfolio of antibiotics that address public health needs.
A pilot phase will be launched to learn and finetune the SECURE model to ensure greater success with global rollout. A diverse set of countries with different challenges will be enrolled in the 4-year pilot programme to inform the adaptation of the model. This approach will ensure the sustainability, flexibility and scalability of the full SECURE programme.
The objective of the proposal is to prepare the launch of the pilot phase and ensure its financing.
|
| 30/09/2022 |
£4,991,730 |
WORLD HEALTH ORGANIZATION, SWITZERLAND |
Within the overall Wellcome Trust-WHO strategic partnership on climate change and health, the project aims to bring a step change in the engagement and impact of health perspectives, evidence and voices as a strong, coherent and positive contribution to the UN Climate Change negotiations from 2022-2024. This will in turn support health resilience to climate risks, and maximize the health gains of climate mitigation actions. The project will build on WHO’s comparative advantages in leading the health community, convening world-leading expertise, providing evidence, guidance and technical support, and direct connection to national Governments. It will co-develop "demand-driven", policy-relevant global and regional research agendas, to create demand for health evidence to be integrated into international and national climate action; scale up health coverage in key UNFCCC policy mechanisms at national level, through targeted training, network building and national capacity development in the countries of the WHO African and Eastern Mediterranean; and increase health influence in the UNFCCC negotiations, through supporting participation of national health representatives on national delegations at COP27 and COP28, health pavilions running an open programme of innovative health events throughout both COPs, and a global conference to build health-enhancing national negotiating positions and alliances in advance of COP28.
|
| 30/09/2022 |
£40,621 |
INTERNATIONAL INSTITUTE FOR SUSTAINABLE DEVELOPMENT |
The objective of this project is to reverse the current trends towards environmental degradation while reducing the vulnerability of regional populations to environment-related health impacts in the Asia-Pacific region. Towards that objective, this initiative will aim toward increasing political commitment in the Asia-Pacific to strengthen both environmental and health policy via mainstreaming the environment-health nexus, as well as increasing uptake and capacity to operationalize the environment-health nexus in public policy in this region. This work aims to target the barriers to engagement on nexus issues, and support UN Member States in taking an interdisciplinary approach to intergovernmental exchanges on the environment-health nexus. We will collaborate in developing new policy products and knowledge tools on the environment-health nexus shaped to the Asia-Pacific context. In addition, we will partner in, and inform, a high-level regional dialogue on the environment-health nexus in the Asia-Pacific region. Uptake of health issues in non-health ministries through these knowledge and capacity building tools will serve to elevate health and wellbeing in intergovernmental decision-making, particularly to the desks of the negotiators making environmental decisions, at national, regional and global levels.
|
| 30/09/2022 |
£12,000 |
FUNDAçãO MéDICA DO RIO GRANDE DO SUL |
A Lancet-World Psychiatric Association Commission on Depression reflecting the work developed over three years by a group of world experts was launched in February 2022. The Commission's state of the art overview of depression provides a timely and unique opportunity for dissemination of knowledge and awareness-raising activities regarding depression. Key goals: 1) Support the organization of a global Commission launch webinar (completed February 16, 2022); 2) Organize and support regional webinars focusing on state of the art knowledge on depression involving policy makers, researchers, individuals with lived experience of depression, and clinicians; 3) Provide materials for dissemination of state of the art knowledge on depression by the World Psychiatric Association and other key partners.
|
| 30/09/2022 |
£12,695 |
UNIVERSITY OF TECHNOLOGY SARAWAK |
Not available |
| 30/09/2022 |
£12,152 |
TREND IN AFRICA GUG (UK) |
Not available |
| 30/09/2022 |
£12,695 |
H3D FOUNDATION |
Not available |
| 30/09/2022 |
£12,695 |
OPEN ENVIRONMENTAL DATA INC. |
In three virtual sessions (capped at 25 participants each), participants will come together to work on existing environmental datasets, redesigning them to be more usable to lay audiences, reusable to public needs, and inclusive of the cultural knowledge within participants’ represented communities. The target audience includes community members most impacted by environmental injustices (e.g. pollution or food insecurity) who are underrepresented in environmental data or have experienced challenges working with open datasets. |
| 30/09/2022 |
£12,695 |
OPEN COLLECTIVE FOUNDATION |
We propose to organize a free boot camp for marginalized groups in the Bioinformatics and Data Science fields, and a conference to promote and make visible the work carried out by Latin American researchers in these fields.
The WBDS LA Boot Camp offers free, intensive (virtual) training for early-career researchers, undergraduate, and graduate students interested in learning open Bioinformatics and Data Science from scratch. For the boot camp, we will create accessible and open materials, which could be reusable for future instances of this boot camp and other students. The WBDS LA Conference includes scientific lectures, posters, and oral presentations ranging from general to specific topics. This meeting encourages marginalized gender participation in these fields, providing a space of empathy, respect, trust, and comfort. The WBDS LA boot camp will provide 75 complete formation fellowships for early-career women interested in becoming Bioinformaticians or Data Scientists. |
| 30/09/2022 |
£5,714,237 |
UNIVERSITY OF EXETER |
Rare diseases affect around 6% of the population and are mostly caused by rare genetic changes. However, despite enormous investment in genomics, whole genome sequencing does not yield a diagnosis for the majority of patients. Lack of clinically-relevant genome annotation frequently prevents robust variant classification and identification of new disease-causing loci. Our proposal seeks to fulfil the bold vision of coupling functional genomics data with clinical and bioinformatics expertise to empower diagnosis and discovery in genomic medicine. We will apply machine learning and expert curation to provide new literature-derived disease models and tissue-specific gene expression maps. Focusing on two contrasting monogenic disease areas (paediatric developmental disorders and adult cardiomyopathies) we will generate long-read RNA sequencing data from fetal brain and adult heart samples to detect full-length transcript isoforms. We will then use these alongside other emerging datasets to find new causes of disease in existing patient cohorts through a combination of computational phenomics, novel pathogenic variant identification, and isoform-informed burden testing. Finally, we will provide a suite of Primary Annotated Resources to Advance Discovery In Genomic Medicine (PARADIGM), by integrating our novel high-resolution datasets into existing tools and databases that are widely used by the genomic medicine community.
|
| 30/09/2022 |
£1,882,601 |
UNIVERSITY OF DUNDEE |
Intellectual disability is a major mental health problem that affects 1-3% of the world population and is frequently caused by mutations in genes that encode poorly-studied signalling enzymes. In this ambitious research programme, we aim to employ our expertise in signal transduction to unravel how cell signalling is disrupted in intellectual disability patients, with the goal of identifying potential therapeutic targets. We have discovered a novel paradigm for intellectual disability signalling, the SRPK-RNF12/RLIM phosphorylation/ubiquitylation pathway. To identify molecular targets of SRPK-RNF12 signalling that are dysregulated in patients, we will comprehensively map SRPK-RNF12 dependent signalling processes by developing novel phosphoproteomic pipeline in a human stem-cell model of neuronal development. We will then use cutting-edge structural biology and biochemistry to unravel how the SRPK-RNF12 pathway is activated. Finally, we will determine how dysregulated SRPK-RNF12 signalling impacts on neurodevelopment and neurological functions in human stem-cell derived neurons and a mouse model, and unravel the wider role of SRPK-RNF12 within the intellectual disability signalling landscape. In summary, this bold proposal will uncover fundamental molecular and cellular principles of how signal transduction is dysregulated in intellectual disability patients, leading to new therapeutic strategies.
|
| 30/09/2022 |
£2,457,319 |
UNIVERSITY OF DUNDEE |
Modification of substrates with the small protein ubiquitin (Ub) regulates virtually all aspects of the cell. Additionally, modification with ubiquitin-like proteins (Ubls) has been implicated with important processes such innate antiviral immunity and cancer progression. E3 ligase enzymes (E3s) select specific substrates for modification and have great therapeutic importance. We have shown that novel E3s with unique mechanisms and unanticipated substrate biology remain to be discovered. Furthermore, to decipher the cellular functions of the growing complement of E3s in health and disease, a general and quantitative approach for measuring cellular E3 activity is urgently needed. In aim 1 of this proposal I will discover novel ubiquitin E3 machineries and establish their cellular functions. In Aim 2, newly discovered E3s will be carefully selected for structural characterisation and their catalytic mechanisms will be delineated at an atomic level. In Aim 3 I will develop chemical biological probes for Ubls allowing me to discover their missing E3s and gain insights into their cellular roles. In Aim 4 I will develop urgently needed global and quantitative technology that will not only expedite the study of E3s, but also accelerate the development of next generation medicines that modulate their activity.
|
| 30/09/2022 |
£3,236,010 |
IMPERIAL COLLEGE LONDON |
Immune checkpoint molecules (e.g. CTLA4, PD-1) restrain immune activation, especially at barrier surfaces where potent inflammatory cues are abundant, including trillions of commensal bacteria. This is exemplified by the microbiota-dependent colitis developing in cancer patients treated with immune checkpoint inhibitors (CPI). Mechanistically resolving the immunopathology of CPI-colitis affords a novel, experimental medicine opportunity to understand immune checkpoint regulation of the host-microbe interactome.
Using longitudinally sampled mucosal biopsies from CPI-treated patients, and novel CPI-colitis models, I will test the hypothesis that microbially-derived metabolites induce IL27-responsive, polyfunctional CXCR6+ T-cells, which are responsible for mediating CPI-colitis. IL27 regulated transcriptional modules in colonic CXCR6+ T-cells will be mapped during transitions from health to disease using parallel scRNA-seq, scATAC seq and proteome profiling. Communication networks between CXCR6+ T-cells, IL27-expressing mononuclear phagocytes, and neighbouring cells will be spatio-temporally resolved using spatial transcriptomics. The CPI-colitis associated metabolome will be longitudinally defined in patients (NMR and LC-MS). The functional impact of disease-associated metabolites, IL27 and CXCR6+ lymphocyte effector pathways will be mechanistically probed in relevant preclinical models.
Beyond informing much needed treatment strategies for patients with CPI-colitis, this study will provide novel insights into the fundamental biology of immunometabolic regulation of mucosal immune function.
|
| 30/09/2022 |
£2,652,974 |
UNIVERSITY OF SUSSEX |
Our goal is to understand the mechanisms controlling the distribution of genetic recombination during meiosis—a specialised cell division responsible for genome haploidisation during gametogenesis. We recently demonstrated that meiotic DNA breaks (DSBs) are predisposed to form concertedly, spaced periodically in a manner that suggests DNA breakage happens on the surface of a macromolecular structure—which we hypothesise is an assembly of the evolutionarily conserved pro-DSB complex "RMM". We now bring forward exciting chromosome-conformation and DSB-mapping data that support our contention.
In general terms, we aim to test how localised changes in higher-order chromosome structure shape, and are shaped by, the process of recombination. First, we will characterise the topological conformations that arise around preferred sites of DSB formation. Second, we will determine how changes in patterns of DSB formation and chromosome structure are linked in space and time, and what are the regulators. Third, we will explore how spatiotemporal control of DSB formation influences downstream patterns of genetic recombination. Finally, we will seek to integrate our findings into a generalised model of spatiotemporal regulation in meiosis that we will use to both describe—and use to derive and test predictions about—how meiotic chromosome morphogenesis and recombination behave and are regulated.
|
| 30/09/2022 |
£3,961,354 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
Symptoms of malaria are associated with cycles of host erythrocyte invasion. Merozoites, the specialised invasive parasite stages, contain a range of specific structures, secretory organelles and a molecular motor to target host receptors and invade. Proteins involved in this process are key determinants of virulence and potential vaccine candidates. The zoonotic malaria parasite Plasmodium knowlesi (Pk) is ideal for studying invasion, and our work to establish its in-vitro propagation, real-time imaging and CRISPR-Cas9 genome-editing has created an unparalleled system for malaria experimental genetics.
Invasion of red blood cells is not one process but many. Each discrete step requires distinct parasite ligand/host receptor interactions and resolving conditions, to allow progression to the next. In this project we aim to unravel the temporal mechanics of merozoite invasion through building an integrative and comparative understanding of four key processes: merozoite gliding, deformation, invasion commitment and reorientation. We will meld our pioneering Pk genetic pipeline with spatial-proteomics, detailed phenotypic screens and comprehensive functional analyses of key proteins and their molecular and biophysical role within each step. Finally, we will apply comparative biology to test key paralogs in human-infecting P. falciparum and Pk, to develop critical genus-wide understanding of invasion.
|
| 30/09/2022 |
£2,618,559 |
UNIVERSITY OF LIVERPOOL |
Urban heat raises a host of health problems. Heatwaves are torrid manifestations of how high temperatures disrupt urban life, especially for the most marginalized, and they bring issues of climate injustice into stark relief. Yet extreme temperatures are only one aspect of urban heat and health, a changing relationship that has impacted past and present communities. This project brings together a team of scholars, a community engagement manager, and a participatory artist to transform understandings of urban heat and health. It explores the history of high temperatures in the postwar era, taking three global cities as its focus: London, New York, and Paris. Drawing on and contributing to studies on climate justice, it investigates how Londoners, New Yorkers, and Parisians have experienced heat and sought to mitigate its impact on their health and well-being. Community engagement (CE) is threaded throughout the project and informs how the project team seeks to rethink understandings of urban heat by moving beyond a focus on "resilience." In seeking to create new academic and non-academic conversations on the challenging interaction between the climate crisis and cities, it will provide fresh perspectives on urban history, environmental history, the medical humanities, and emotional and sensory history.
|
| 30/09/2022 |
£3,286,571 |
BABRAHAM INSTITUTE |
Epigenetic processes create opportunities in development for safeguarding and directing cell state, particularly by the activity of Polycomb proteins and associated histone modifications. Determining how these mechanisms control cellular plasticity and lineage decisions in human embryos has fundamental biological importance with wide-reaching clinical implications. However, progress has been hampered by challenges associated with examining histone modifications over the first 14 days of human embryo development. This has led to a critical knowledge gap about how epigenetic mechanisms control the development of early human embryos, which we will directly address in this research programme. First, we will determine the epigenetic basis of developmental plasticity in preimplantation human embryogenesis by examining the dynamics of histone modification changes and by modulating Polycomb activity that we predict will disable cellular plasticity at these development stages. Second, using a novel assembloid system to support the faithful development of postimplantation human embryos, we will investigate the establishment and robustness of multilineage priming mechanisms in early postimplantation development. Third, we will test our mechanistic leads on a new role for specific Polycomb complexes in safeguarding epiblast transitions. Altogether, this programme will make vital advances in our understanding of the molecular principles that instruct early human embryogenesis.
|
| 30/09/2022 |
£1,905,426 |
BABRAHAM INSTITUTE |
Extracellular protein aggregation is a pathological hallmark associated with devastating diseases such as Alzheimer’s disease and type II diabetes. Inside cells, protein quality control (PQC) mechanisms maintain a balanced and functional proteome. In contrast, little is known about protective mechanisms acting outside cells. Until recently, only a few extracellular chaperones and proteases were shown to limit extracellular protein aggregation. We developed a Caenorhabditis elegans model to study protein aggregation in the extracellular space. We performed a systematic analysis to identify the extracellular protein homeostasis network in C. elegans and discovered 57 novel extracellular regulators of protein aggregation of which half have potential human orthologues. Building on these findings, first we propose to investigate the mechanisms of extracellular PQC by characterizing chaperone and protease activities among C. elegans extracellular regulators and human orthologues. Second, we will determine how extracellular PQC promotes healthy ageing and host defence against pathogens in C. elegans. Finally, we will translate our finding into mice and examine if extracellular regulators prevent Alzheimer’s disease associated amyloid-beta aggregation and delay mammalian brain ageing. I expect these studies to be a milestone in our understanding of how organisms keep proteins functional outside their constituent cells to maintain health.
|
| 30/09/2022 |
£2,101,790 |
UNIVERSITY OF BIRMINGHAM |
The process of DNA replication is central to life. Several proteins encoded by genes important to cancer-predisposition syndromes and human development are essential when replication forks stall, preventing DNA nucleases from degrading the paused fork. The process suppresses genome instability and may be relevant to cancer therapy by determining particular therapeutic vulnerabilities and therapy resistances. However, the role, regulation and impact of replication fork protection is poorly understood, and we currently lack the knowledge of where the opportunities for improved human health in this process may lie.
Using an integrated approach, we aim to address where and in response to what replication fork protection is most needed, how stalled protected and unprotected forks signal to recovery mechanisms, and how chromatin is regulated to promote recovery. We will reveal the molecular basis of decisions at protected and unprotected replication forks to define the opportunities for improved human health.
|
| 30/09/2022 |
£1,331,515 |
KING'S COLLEGE LONDON |
Our vision is to spread and sustain SlowMo therapy in mental health services, transforming outcomes for people with paranoia worldwide. The funding will lead to the following achievements:
1. Software code for SlowMo2 which has been co-designed with people with lived experience to support adoption by a) optimising impact on valued outcomes, b) ensuring suitability for widespread adoption across the psychological practitioner workforce and c) maintain strong user experience for a diverse range of people to support engagement.
2. Development of an e-learning package to automate workforce training. This will incorporate core training for established clinicians and an extended version specifically targeting the international need to expand low intensity psychological practitioner roles.
3. Endorsement of SlowMo’s value proposition by adopters, implementation partners and regulatory bodies, having further demonstrated effectiveness and cost effectiveness in routine care.
4. A commercialisation strategy and NHS Global Digital Exemplar Blueprint to support spread and sustainment of SlowMo, assisted by organisational support from the IoPPN’s digital therapeutics strategy and the King’s20 Accelerator.
5. Expansion of our lived experience community, collaboratively harnessing their expertise to expand SlowMo’s value proposition, including peer-led recovery college courses and product development of novel therapeutic targets.
|
| 30/09/2022 |
£2,047,586 |
UNIVERSITY OF SHEFFIELD |
Why are brains the way they are? Understanding the computational function of neuronal plasticity rules and circuit architectures is fundamental to understanding how brains work, yet it remains unclear whether or how these ‘design features’ are optimal for their behavioural purpose.
We will address these questions using the problem of stimulus-specific associative memory. In Drosophila, olfactory associative memories are stored by weakening the synapses from odour-encoding Kenyon cells (KCs) onto action-encoding mushroom body output neurons (MBONs). Our recent computational and experimental discoveries have led us to two novel, independent hypotheses for how the fly’s neuronal plasticity rules might optimise the odour-specificity of memories given other constraints in the circuit.
1. Homeostatic plasticity optimises sensory coding for stimulus-specific associative memory by compensating for inter-neuronal variability.
2. The reason learning occurs by synaptic depression (not potentiation) is that, given the constraints of downstream circuitry, this strategy makes overlap in sensory representations less detrimental to odour discrimination.
We will test these hypotheses and investigate the molecular mechanisms underlying them, by a combination of two-photon imaging, electrophysiology, behaviour, genetic manipulations and computational modelling. Revealing computational functions underlying neuronal plasticity rules will shed light on how synaptic plasticity and memory work in general.
|
| 30/09/2022 |
£3,597,079 |
NEWCASTLE UNIVERSITY |
Helicase recruitment, loading, and activation demarcates the first stage of assembling the replisome, the machinery that performs DNA replication. Within bacterial cells, helicase loading must be orchestrated at two distinct events: cell cycle mediated DNA replication initiation at the chromosome origin (oriC) and to restart replication at a repaired replication fork. Replication initiation is guided by the master initiator protein DnaA, while replication restart utilises the helicase PriA. Since DnaA, PriA, and the replicative helicase are conserved throughout the bacterial domain, it is likely that the principal events at oriC and a repaired replication fork are shared amongst diverse species. Moreover, because bacterial replication factors are distinct from their analogues in eukaryotes, the bacterial DNA replication machinery is an attractive drug target.
Despite years of study, fundamental aspects of DNA replication initiation in bacteria remain poorly understood. Specifically, the architecture of nucleoprotein complexes required to load helicase(s), and the temporal set of activities that replication initiation proteins perform during the helicase loading reaction, are unclear. This project will combine genetics, biochemistry, cryo-electron microscopy, and single-molecule fluorescence microscopy to unravel the molecular mechanisms of bacterial helicase loading, to near-atomic resolution, at both a chromosome origin and a repaired replication fork.
|
| 30/09/2022 |
£3,063,890 |
UNIVERSITY OF EDINBURGH |
Neutrophils have adapted to function in injured and infected tissues where oxygen and metabolites are limited. A proportionate neutrophil response is essential for effective immunity, with dysregulated neutrophilic inflammation contributing to the pathogenesis of inflammatory disease states. In the lung, dysfunctional neutrophilic inflammation can result in the development of acute respiratory distress syndrome, with the associated systemic hypoxia contributing to tissue hypoxia. My group has observed that not only does local hypoxia in the inflamed environment alter neutrophil behaviour, but also that systemic hypoxia can shape neutrophil responses with consequence for inflammation outcomes. We have emerging evidence that despite a short half-life, some of these changes in neutrophil physiology are long-lasting. This has led me to propose that systemic hypoxia drives central (bone marrow) epigenetic changes within neutrophil progenitors which are inherited by newly differentiated neutrophils and sustained long after the initial exposure. I further propose this central reprogramming can be informed by local cues following an inflammatory insult, with consequence for tissue effector functions and inflammation outcomes. The key goal of this proposal is to understand how activation of oxygen sensing pathways, metabolic processes and chromatin accessibility reprogram neutrophil responses and identify new targets to treat dysfunctional neutrophilic inflammation.
|
| 30/09/2022 |
£608,043 |
UNIVERSITY COLLEGE LONDON |
In2research is a high impact, scalable and evidence informed social mobility programme for socioeconomically disadvantaged people to access and progress in postgraduate study. Our mission is to drive sector change across institutions towards an inclusive research culture. We strongly believe that it is not enough to guide underrepresented people into postgraduate study, but to ensure that the culture they are entering is inclusive and a place where they can thrive. Over a year, we support participants to gain vital access to both knowledge and opportunities including a paid 8-week research placement and subject specific mentoring. Once graduated, they join our growing alumni community where we continue support throughout their career. We also provide high quality training and guidance to mentors and supervisors engaging with the programme. Through our race and cultural literacy training we aim to build understanding, providing a welcoming and inclusive environment for our participants and marginalised groups more broadly. This year we are supporting 50 participants from low socioeconomic backgrounds with 82% identifying as Black, Asian or minority ethnic. Through this funding we will expand our offer to more students and academics, shifting research culture and shaping a more diverse and inclusive workplace.
|
| 30/09/2022 |
£150,000 |
COALITION FOR EPIDEMIC PREPAREDNESS INNOVATIONS (CEPI) |
CEPI’s vision is "creating a world in which epidemics and pandemics are no longer a threat to humanity". We were established with a mission to accelerate the development of vaccines, but we know that vaccines alone are not sufficient to achieve this vision.
COVID-19 uncovered major gaps and opportunities in the therapeutics preparedness and response landscape, including:
A serious gap in end-to-end coordination
Fragility of upstream research efforts, including short-lived industry interest and insufficient access-friendly funding
Specific gaps along the value chain in: evidence generation, host-directed therapeutics, manufacturing scale-up, epidemic- and pandemic-ready policy and regulation, and advocacy for epidemic- and pandemic-specific procurement and country-readiness mechanisms
We believe the global community would be well served by CEPI expanding into therapeutics. This would maximise the benefit for global health by utilising CEPI’s well-regarded existing infrastructure, governance and processes. We propose a step-wise entry into therapeutics, starting with areas where existing CEPI capabilities can provide significant value for Therapeutics: evidence generation. Building on these entry points, CEPI will develop a longer-term strategy for how CEPI can best advance therapeutics preparedness and response, and, in doing so, help create a world in which epidemics and pandemics are no longer a threat to humanity.
|
| 30/09/2022 |
£135,640 |
IMPERIAL COLLEGE LONDON |
HIC-Vac is a collaborative MRC/BBSRC-funded network led by Professor Peter Openshaw from Imperial College London. It was established in 2017, building on the UK’s expertise in human challenge and has been remarkably successful in its aims of building a strong global team and funding seed projects in the UK and elsewhere (especially in LMICs). We now seek funding to be able to extend this success over the next 12 months, focused on work that aligns with Wellcome Trust’s current aims and goals while we look to secure a more permanent future for our very productive coalition. Our key goals in this period are to enhance the engagement and utility of the network for LMIC-based researchers, report on the establishment of an intra-pandemic challenge study (SARS-CoV-2) with a view to preparing for future pandemics, set up the management of the Smart Practises document, liaise with the EU IMI INNO4VAC human challenge initiative, hold an Annual General Meeting, support early career researchers with a mentorship scheme and to continue our very active public engagement and communication activities.
|
| 30/09/2022 |
£249,474 |
IMPERIAL COLLEGE LONDON |
There is growing international recognition that it is best practice for research funders to have sex and gender policies that require grant holders to integrate sex and gender into their research practices and outputs. In our 2021 preliminary project, we discovered that none of the 17 largest UK medical research funders and regulators has a sex and gender policy in place for the research they fund. This is to the detriment of men, women, trans, non-binary, gender diverse people, and people with intersex variations.
To ensure that evidence can be safely and reliably applied to all people, we need data to be sex and gender-disaggregated and results reported by sex and gender. Our project will – through an innovative co-creation methodology – work with UK medical research funders and regulators to produce recommendations for sex and gender policies that can be tailored to each institution. These recommendations, along with educational materials offered to research grant funders and applicants, will update the UK research landscape, which has fallen behind countries, such as Canada and the US. We intend to learn from and share this co-creation methodology to address other intersectional inequalities in research, including ethnicity, age, and socioeconomic status.
|
| 30/09/2022 |
£207,885 |
GLOBAL POLICY REPORTING |
Wellcome's strategic focus on four themes: infectious disease; climate; mental health; and discovery research covers many of the gravest challenges facing low- and middle-income countries. Translating new knowledge into policy, however, remains challenging. There remains little investment, particularly in LMICs, in independent global health media to air discoveries, channel debates, and hold policymakers accountable. Health Policy Watch provides a platform for LMIC journalists to develop and share their stories, echoing in both global North and South, and building capacity of LMIC media professionals.
A 2020-21 Wellcome Grant led to a two-fold increase in Health Policy Watch readership, including in major LMIC 'hubs', e.g. South Africa, Kenya, Nigeria, India, Pakistan. This proposal aims at solidifying gains in a sustainable model focused on:
1. Reporting from Africa and Southeast Asia around Wellcome priorities - a) Tracking countries' action on health-relevant aspects of climate commitments and health co-benefits of sustainability in under-explored themes. b) LMIC challenges battling infectious diseases, including SARS-CoV2 in an equity & health systems lens; c) preventing new pandemics in a One-Health framework; d) African & Asian discovery research.
2. Sustainable media model - recruitment of other major donors; microfinance through targeted social media appeals, media collaborations and advertising.
|
| 30/09/2022 |
£3,892,487 |
NATIONAL UNIVERSITY OF SINGAPORE |
ACORN-HAI is a large-scale multi-centre surveillance which focuses on the treatment and clinical outcomes of healthcare-associated bloodstream infection and ventilator-associated pneumonia. These severe infections are frequently caused by multidrug-resistant bacteria which have no effective treatment options. Prospectively collected case-based data of these infections are lacking and urgently needed to guide interventional trials. Our aims are firstly to establish a surveillance platform in hospitals with high burdens of drug resistance, in order to investigate target organisms and make up-to-date assessments on treatment options. Secondly through implementing the study across various regions and income settings, we aim to share expertise, optimise local engagement, and establish research teams and laboratory capacity. The enrollment criteria are based on the US Centers for Disease Control and Prevention criteria for healthcare-associated infection surveillance. Functional and mortality outcomes will be assessed on day 28. Bacterial isolates will be collected for genomic analysis to study geographical and temporal trends in resistance clones and genes. The target sample size is 500 participants per site over 30 study sites. ACORN-HAI study is a critical step towards assessing the burden of severe drug-resistant infections, and inform interventional trials to optimise treatment
|
| 30/09/2022 |
£44,049 |
UNIVERSITY OF OXFORD |
This is a joint application that will leverage expertise spanning regulatory, ethical, clinical, and laboratory to establish Shigella human infection studies (HIS) at two sites in Kenya, Kericho and Kilifi. Shigella causes a high burden of disease in low-and-middle income countries (LMICs), where 70% of all cases occur in children under 5 years who form the target population for disease prevention through vaccination. However, there are no licensed Shigella vaccines in routine use with several candidates still in various stages of clinical development. Shigella human infection studies have played a key role in the vaccine development pathway to assess vaccine efficacy. Thus, the goal is to successfully establish Shigella HISs in Kenya. This will be achieved by: (a) conducting dose-finding and dose verification Shigella studies that safely and reproducibly induce ≥60% attack rates under the guidance of experienced clinicians and scientists; (b) assessing vaccine efficacy against a Shigella serotype that is impractical in more traditional field efficacy studies; and (c) explore the ethical and social implications of conducting these studies in a LMIC setting. Once established, the model will accelerate Shigella vaccine development by facilitating the early selection of the most promising vaccines for more extensive testing in LMICs.
|
| 30/09/2022 |
£2,822,853 |
NEW VENTURE FUND |
To transform the social impact sector and enable it to truly benefit from the data revolution, we must address how we educate, train, and upskill social impact talent. data.org is launching a global Capacity Accelerator Network (CAN) program to create data science capacity hubs in the Global South that will train the next generation of data professionals with the interdisciplinary skills needed to be successful to work at the intersection of climate and health.
$6.8m (£5m) would fund CAN, launching two new Data Capacity Accelerators focused on climate and health data in the Global South (India in collaboration with J-PAL South Asia; sub-Saharan Africa in collaboration with the Global Partnership for Sustainable Development Data) and strengthening the international reach and scale of the Network of Networks model. As the central hub, data.org will serve as the point of connection and coordination and as an impact amplifier for the local accelerators by converting investment in training hundreds of climate and health data experts locally into training many thousands globally through open-source resources housed on data.org, giving the program the kind of scale and sustainability each local accelerator will not be able to achieve on their own.
|
| 30/09/2022 |
£883,161 |
INSTITUTE FOR FINANCIAL MANAGEMENT AND RESEARCH |
To transform the social impact sector and enable it to truly benefit from the data revolution, we must address how we educate, train, and upskill social impact talent. data.org is launching a global Capacity Accelerator Network (CAN) program to create data science capacity hubs in the Global South that will train the next generation of data professionals with the interdisciplinary skills needed to be successful to work at the intersection of climate and health.
$6.8m (£5m) would fund CAN, launching two new Data Capacity Accelerators focused on climate and health data in the Global South (India in collaboration with J-PAL South Asia; sub-Saharan Africa in collaboration with the Global Partnership for Sustainable Development Data) and strengthening the international reach and scale of the Network of Networks model. As the central hub, data.org will serve as the point of connection and coordination and as an impact amplifier for the local accelerators by converting investment in training hundreds of climate and health data experts locally into training many thousands globally through open-source resources housed on data.org, giving the program the kind of scale and sustainability each local accelerator will not be able to achieve on their own.
|
| 30/09/2022 |
£1,893,229 |
THE UNITED NATIONS FOUNDATION |
To transform the social impact sector and enable it to truly benefit from the data revolution, we must address how we educate, train, and upskill social impact talent. data.org is launching a global Capacity Accelerator Network (CAN) program to create data science capacity hubs in the Global South that will train the next generation of data professionals with the interdisciplinary skills needed to be successful to work at the intersection of climate and health.
$6.8m (£5m) would fund CAN, launching two new Data Capacity Accelerators focused on climate and health data in the Global South (India in collaboration with J-PAL South Asia; sub-Saharan Africa in collaboration with the Global Partnership for Sustainable Development Data) and strengthening the international reach and scale of the Network of Networks model. As the central hub, data.org will serve as the point of connection and coordination and as an impact amplifier for the local accelerators by converting investment in training hundreds of climate and health data experts locally into training many thousands globally through open-source resources housed on data.org, giving the program the kind of scale and sustainability each local accelerator will not be able to achieve on their own.
|
| 30/09/2022 |
£6,564,487 |
IMPERIAL COLLEGE LONDON |
SARS-CoV-2 continues to spread in spite of vaccination due in part to the high transmissibility of the prevalent delta variant. The factors predisposing to breakthrough infection are unknown and correlates of protection remain unclear. Human challenge studies are uniquely able to control for differences in virus strain, dose and exposure to investigate these factors. Safety in seronegative participants challenged with a D614G pre-alpha strain was recently shown and a new GMP delta challenge agent is now being manufactured. We therefore aim
To establish an optimised controlled human infection model using a GMP SARS-CoV-2 Delta (B.1.617.2) challenge agent, characterising virological and immunological readouts therein to enable further assessment and development of COVID-19 vaccines
To identify the determinants of vaccine breakthrough infection and correlates of protection in antigenically-experienced individuals
These will be achieved by challenging vaccinated individuals with Delta and optimising the attack rate by sero-screening and dose-escalation. Using these optimised conditions, 3 groups will then be compared:
vaccinated, uninfected individuals, Delta-challenged;
vaccinated, previously-infected, Delta-challenged; and
vaccinated, uninfected, pre-Alpha-challenged.
Thus, host determinants of differential disease and virological outcome will be identified in the context of pre-existing immunity by vaccination and/or infection to define correlates and mechanisms of homologous and heterologous protection.
|
| 30/09/2022 |
£17,584,518 |
UNIVERSITY OF OXFORD |
Our ten-year vision is to have local, regional and global impact on health by leading a locally driven research programme on infectious diseases in Southeast Asia.
We will deliver our vision by fulfilling four aims:
Aim 1. Reduce the burden of infectious diseases through research
Aim 2. Strengthen our research culture
Aim 3. Strengthen our networks and partnerships
Aim 4. Increase the local, regional, and global impact of our research
Our dominant activity will be research (aim 1), with its delivery, relevance, and sustainability supported by aims 2 and 3, and its impact secured by aim 4.
We will achieve our aims through a collaborative network of multidisciplinary researchers in Vietnam and Indonesia, capable of responding rapidly to escalating infectious disease threats and implementing science-led change within health systems.
Our research priorities are:
New and re-emerging infectious diseases
Drug resistant infections
Climate change impact on infectious disease epidemiology
Development and implementation of new health technologies
We will ensure that our research priorities and activities remain locally relevant and sustainable through extensive public and community engagement. We will strengthen our research culture, and nurture the careers of local researchers and operational staff, supporting their development and promoting their leadership.
|
| 26/09/2022 |
£1,043,340 |
LAGOS STATE UNIVERSITY COLLEGE OF MEDICINE |
Cognitive impairment is common in psychosis and is a great contributor to functional impairment in the illness. Interventions for cognitive and functional impairment need to be applied early during psychosis to prevent debilitating outcomes. A large proportion of first-episode psychosis (FEP) cases in need of cognitive intervention are in low- and middle-income countries (LMICs). The effective cognitive intervention programs in High-income countries (HICs) are not immediately transportable to LMICS clinical settings. There is a need for an evidence-based intervention that is culturally acceptable, paper-based, and easy to deliver by trained health workers in the routine clinical settings in LMICs. It will also be necessary to evaluate such developed interventions for effectiveness, the feasibility of implementation, and scale-up. Also, there is a scarcity of involvement people with lived experiences who are potential end-users in the intervention design and project implementation in LMICs. Using the participatory action research (PAR) approach, we aim to involve end-users to co-design, pilot test and assess the feasibility and strategies for successful implementation of a contextualized cognition intervention based that is based on the core principles and treatment techniques of cognitive remediation approaches. The 36 months project will involve 7 work packages. |
| 26/09/2022 |
£3,089,993 |
UNIVERSITY OF OXFORD |
"I have now got the motivation to go out and start showing people what I can do. I have signed up to go back to college to go back into education and learn again." Toby (after our sleep therapy) We aim to conduct the definitive test of the effects of improving sleep for people at the early stages of psychosis. Our team has pioneered the treatment of sleep problems in psychosis, conducting feasibility trials with patients at ultra-high risk of psychosis, with patients diagnosed with psychosis, and with people admitted to psychiatric hospital. In every trial our eight-session intervention has achieved large effect size improvements in sleep. We will conduct a randomised controlled trial with two cohorts: 554 patients at ultra-high risk of psychosis and 554 patients with first episode psychosis. The trial is powered to detect whether sleep therapy results in at least small improvements in cognitive functioning in each cohort. As recommended by our lived experience advisors, we will also test the effect of sleep therapy on real-world functioning, psychotic and emotional experiences, and quality of life. We will test how and for whom the treatment works, and gain further insights from patients in a peer-led qualitative investigation. |
| 26/09/2022 |
£2,981,217 |
UNIVERSITY OF OXFORD |
Cognitive deficits are a core feature of the early phases of psychosis. All licensed pharmacological treatments for psychosis act by blocking dopaminergic neurotransmission and do not improve these deficits. Independent lines of research have recently implicated several molecules with therapeutic potential that act on muscarinic, endocannabinoid, and glutamatergic signalling. All impact the balance between excitatory and inhibitory(E/I) signalling, which may be central to the pathophysiology of cognitive deficits. This proposal will use four randomised controlled trials (RCTs) to examine these non-dopaminergic interventions for cognitive symptoms in three workflows: Workflow A involves a RCT of xanomeline-trospium (KarXT) in early psychosis. Xanomeline is a muscarinic agonist with antipsychotic properties, which can be given in combination with the peripheral muscarinic antagonist trospium to ameliorate side effects without reducing efficacy. Secondary analyses suggest that KarXT improves cognitive symptoms of psychosis. Workflow B examines data from Workflow A and three other RCTs in early psychosis examining pro-cognitive interventions (cannabidiol, memantine, and immunotherapy) that act on E-I balance via distinct mechanisms. Workflow C examines subjective experience of cognitive deficits, assesses intervention acceptability, and determines how improving cognition may translate into changes in real-world functioning and quality of life in early psychosis. |
| 26/09/2022 |
£1,018,865 |
BETH ISRAEL DEACONESS MEDICAL CENTRE |
This proposal seeks to transform the assessment of cognition in psychosis through utilizing smartphones to capture momentary cognition and employing this data to create clinically actionable metrics, new targets for interventions, and novel biomarkers for mechanistic research. Today rapid and scalable cognitive assessments are not accessible for use in routine care and thus cognitive deficits, the single greatest cause of functional impairment in psychosis, remain understudied and under-treated. This proposal seeks to return a focus toward cognition through innovation in scalable, data-driven, high-dimensional, intensive longitudinal methods using smartphone digital phenotyping. Leveraging our already deployed teams in both the U.S and India combined with an already developed smartphone platform used at all sites, this proposal is designed to focus on rapid innovation and clinical results. Building off promising pilot data that demonstrate clear feasibility, we propose to create a smartphone specific suite of cognitive assessments designed to capture those domains most important in first-episode psychosis, validate its use against gold-standard measures, and explore new personalized models of cognition that can account for individual sleep and activity patterns - creating a more holistic and clinically actionable profile of each person’s cognition as it evolves across time and environments.
|
| 26/09/2022 |
£2,962,839 |
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH |
In people with psychosis, deficits in social cognition are responsible for a large proportion of the functional disability associated with illness. In a previous study, we found that social cognitive performance is comprised of two subcomponents: 1) a ‘lower-level’ factor reflecting basic emotion detection skills and 2) a ‘higher- level’ factor reflecting higher social cognitive functions referred to as the ‘mentalizing’ factor. The mentalizing factor predicted functional outcome and fully mediated the relationship between neurocognition and social function. Therefore, the mentalizing factor appears to play a major role in determining functioning in people with psychosis.
We propose a 4-week (20 session), double-blind, randomized clinical trial in 100 people with early phase psychosis to examine if repetitive transcranial magnetic stimulation, a non-invasive neuromodulatory technique, improves social cognitive performance. We hypothesize that stimulation of the dorsomedial prefrontal cortex - a key node of the mentalizing network - will alter network functional connectivity in people with psychosis and improve social cognitive performance. Neuroimaging will occur at baseline, at 4 weeks and 6 months after treatment. The primary outcome measure will be social cognitive performance, and the secondary outcome measures will include changes in within-mentalizing network functional connectivity and in long-term social functioning.
|
| 26/09/2022 |
£762,645 |
UNIVERSITY OF NOTTINGHAM |
Interventions aiming to improve cognitive functioning in psychosis are beneficial for some individuals but not others. Differences in treatment outcomes could be linked to underlying neurotransmitter systems. If functional changes in glutamate levels could predict neurocognitive treatment outcomes, it would become possible to personalise these cognitive interventions. With a reliable marker, beneficial treatments could be selected earlier.
Differences in cognitive impairments in psychosis are linked to alterations in neurotransmitters like glutamate. Our goal is to understand the potential of task-induced changes in glutamate as a marker for treatment outcomes in individuals with first-episode psychosis. We will measure alterations in brain glutamate levels with functional magnetic resonance spectroscopy (fMRS) while participants complete a cognitive task. Then, we will examine if glutamate changes can predict the cognitive effects of non-invasive brain stimulation, known to influence glutamate levels.
Simultaneously, we will work with lived experience experts to understand their view on cognitive impairments and personalised treatment options involving brain imaging and stimulation.
Our findings will provide a strong basis for a larger intervention study aiming to optimise brain stimulation parameters and to cross-validate glutamate as predictor of treatment effects. Our qualitative data will identify potential barriers to the uptake of these options.
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| 26/09/2022 |
£932,252 |
UNIVERSITY OF BRISTOL |
Large-scale psychiatric genomics studies have catalogued a suite of chromosomal deletions or duplications (copy number variants, CNVs) associated with significantly increased risk of intellectual dysfunction and neurodevelopmental disorders, including schizophrenia. How can we predict which/when ‘psych-CNV’ carriers will present with psychosis, amongst a complex spectrum of other symptoms? What are the biological routes from psych-CNV to impaired cognition?
Our recent work shows that > 60% of children carrying psych-CNVs have high risk of early-onset insomnia and restless sleep. We have also detected abnormal sleep-dependent EEG oscillations in young people with 22q11.2 deletion syndrome, which associate with cognitive impairment and clinical symptoms indicative of future psychotic disorder. We therefore propose to work with young psych-CNV carriers to map links between sleep problems and daily challenges arising from impaired memory, attention and social interactions.
Allying longitudinal, at-home monitoring of activity and EEG with clinical and cognitive assessments, MEG-based metrics of neural information processing and computational psychiatry, we aim to stratify patients according to high-resolution neurophysiological and behavioural phenotypes, embedding sleep science and patient/carer engagement in a translational framework for personalised psychiatry.
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| 26/09/2022 |
£907,255 |
RADBOUD UNIVERSITY MEDICAL CENTRE |
Cognitive impairments are frequently evident early in the course of psychosis, often before illness onset and having substantial impact on functional outcomes. However, this has not yet produced markers with sufficient sensitivity and specificity to predict outcomes at the level of the individual or facilitate early intervention.
This project will address this need by applying normative models ('cognitive growth charting') to cognitive measures derived from tens of thousands of healthy individuals and thousands of individuals with psychosis from four European countries in order to infer early risk factors and predict functioning in psychosis at the individual level. We will go beyond symptoms and assess functioning broadly using measures that meaningfully reflect the quality of life of individuals with psychosis.
We will: (i) develop deep learning technology to enable cognitive data from studies with heterogeneous cognitive data to be aggregated; (ii) map lifespan variation across multiple cognitive domains and precisely place individuals within population norms (iii) integrate these with neurobiology in order to precisely stratify cohorts, predict progression at the individual level and identify genetic and environmental factors that modulate developmental trajectories both preceding and following illness onset. Our project will be guided throughout by extensive engagement with lived experience experts.
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| 31/08/2022 |
£2,411,290 |
UNIVERSITY OF CAMBRIDGE |
The ability to know one’s direction and location in the environment is a complex cognitive function essential for survival. The brain computes spatial orientation by using both self-motion and environmental cues. One of the major gateways through which these different spatial information reach the brain's navigation system involves the connections between the anterior thalamus and retrosplenial cortex (RSP). However, due in part to their structural diversity, the functional organisation of these circuits and their specific contributions to spatial orientation remain elusive. Moreover, although both the anterior thalamus and RSP are highly susceptible to age-related changes, their contribution to spatial cognitive decline with ageing is currently unknown. To fill these gaps, the proposed research aims to determine: the specific roles that different anterior thalamus-RSP circuits play in spatial orientation the organisation of synaptic inputs to these circuits and their role in spatial orientation cellular and synaptic changes that occur in these circuits with ageing and their impact on spatial computation and behaviour Findings of this research will significantly advance our understanding of how the brain implements spatial cognition and will provide novel insights into neural underpinnings of navigational deficits in old age. |
| 31/08/2022 |
£3,218,575 |
UNIVERSITY COLLEGE LONDON |
Combining auditory and visual information to interpret the external environment is vital—whether prey, predator, or pedestrian. However, despite the ubiquity of this audiovisual integration, the underlying brain regions and circuits remain largely unclear. This is partly because the interpretation of audiovisual signals may be confounded by learning, behavioural context, or animal movements. I propose to combine behaviour, electrophysiology, and optogenetics to address these problems. First, I will generate a brainwide map of audiovisual signals before, during, and after mice learn an audiovisual localization task, using high-throughput chronic electrophysiology. This will identify which brain regions combine auditory and visual information, whether this changes throughout learning, and the neural computations involved. Second, I will causally test which intracortical and subcortical projections are required for behaviour with a novel combination of non-invasive laser stimulation and inhibitory opsin expression. Finally, I will determine which of the identified audiovisual computations and circuits are task-specific, and which represent general mechanisms that apply to other tasks, like audiovisual navigation. The results will identify fundamental principles of audiovisual integration that generalize across behaviours, are likely applicable to other sensory combinations, and provide a foothold to understand why failures in this process are associated with cognitive disorders. |
| 31/08/2022 |
£2,453,045 |
UNIVERSITY OF YORK |
The mucus lining of large colon forms a protective barrier between the bacterial community that inhabits the colon and the epithelial layer. Both experimental elimination, or excessive degradation of this mucus layer by colonic bacteria, leads to inflammation and thus chronic disease of the colon. Inflammation of the colon also increases the risk of colon cancer as well as being a precursor to it. Colonic mucin is a glycoprotein which is ~80 % carbohydrate by mass with these carbohydrates being heavily sulfated. The bacterial community in the distal colon are essential to human health, and metabolism of mucin, acts as a key nutrient and colonistaion factor but excessive degradation leads to disease. Carbohydrate sulfatases have been identified as key enzymes for bacteria to utilise colonic mucin. Furthermore, key sulfatases have been identified as exo acting and both cell surface exposed and periplasmic making them excellent drug targets to inhibit and thus, control mucin metabolism in individuals with inflammatory bowel disease. Here we propose an integrated molecule-to-function approach to: 1) Define structural features of bacterial carbohydrate sulfatases that determine substrate specificity 2) Identify which carbohydrate sulfatases elicit digestive tract disease 3) Identify small molecules that modulate sulfatase function. |
| 31/08/2022 |
£1,642,980 |
UNIVERSITY OF MANCHESTER |
Mammalian microbiomes are dynamic ecosystems, composed of hundreds of taxa whose populations continuously rise and fall, shaped by interactions microbes have with their host and one another. Understanding the forces driving microbiome dynamics is critical if we wish to engineer them, however, the vast complexity of most microbiomes renders this a formidable challenge. I will address this challenge, developing interdisciplinary tools to understand and predict microbiome dynamics, focusing on the poorly understood role of the host in controlling microbiome dynamics.
First, I will use innovative sequencing tools to quantify the impact of host immune background on the assembly and stability of the gut microbiome, then develop new computational tools to identify the specific host-to-microbe interactions causatively driving these differences. Concurrently, I will develop new computational tools to identify microbe-to-host interactions shaping host immune development. Finally, I will build a new body of theory to understand how these interactions integrate to shape overall microbiome dynamics.
Throughout, I will focus on one key host adaptation: Immunoglobulin A. However, by combining targeted experimental and computational approaches with novel theory I will build an interdisciplinary platform for investigating the role of any host mechanism. Together this will transform our understanding of microbiome dynamics.
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| 31/08/2022 |
£1,642,475 |
UKRI-MRC |
Telomeres cap the ends of eukaryotic chromosomes and are essential for maintaining chromosome stability, cell viability and setting long-term proliferative capacity. Telomere dysfunction has been implicated in cancer and premature aging. Our work aims to understand how mammalian cells overcome the problems of (i) shortened telomere length caused by incomplete genome replication, and (ii) chromosome ends being subject to fusion and repair. These problems directly impact telomere maintenance and chromosome integrity, and are ameliorated by two large complexes, telomerase and shelterin, respectively, in mammalian cells. We will use a combination of in vitro biochemical reconstitution, cryo-electron microscopy (cryo-EM) and functional studies in vivo to dissect the molecular mechanisms of these complexes. We will also take advantage of recent developments in cryo-electron tomography (cryo-ET) to investigate high-order telomere structures and their role in telomere maintenance. The proposed research will provide detailed insights into these two fundamental problems of telomere maintenance in mammalian cells, and explain how telomere dysfunction gives rise to human diseases.
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| 31/08/2022 |
£2,499,972 |
UNIVERSITY OF OXFORD |
Micronutrient deficiencies are common in Africa and cause about 745,000 deaths annually. Some studies indicate strong associations between micronutrient deficiencies and life-threatening infections, but findings are inconsistent. Moreover, causality has not been established for most micronutrient-infection relationships and underlying biological mechanisms are poorly understood, preventing the deployment of clear data-driven interventions. My project will bring together cutting-edge human genetics with detailed phenotypic follow-up to identify causality and elucidate biological mechanisms. To infer causality, I will apply a Mendelian randomization approach. This will involve a) identifying and validating genetic variants that predict zinc, iron, folate, and vitamins A, D and B12 status in African populations; and b) testing whether these variants influence risk of severe malaria, tuberculosis, bacteraemia, pneumonia, diarrhoea, and mortality in large case control studies involving available samples and data. As proof of concept my career re-entry fellowship work has identified novel Africa-specific genetic variants, which predict iron and vitamin D status, and show that a novel genomic locus controlling cellular iron intake influences susceptibility to severe malaria. To discover the mechanisms underpinning causal micronutrient-infection relationships, I will conduct detailed phenotyping using a recall-by-genotype approach. Understanding these mechanisms will help to inform the development and targeting of effective interventions.
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| 31/08/2022 |
£2,131,247 |
UNIVERSITY COLLEGE LONDON |
This proposal will build upon the principal applicant’s experience of 15-years’ research work in Lima, Peru. The province of Callao, Lima, has a tuberculosis incidence above 150 per 100,000 population whilst Peru has the highest burden of multidrug-resistant tuberculosis in the Americas. Mycobacterium tuberculosis is the focus of this work, although the concepts are equally applicable to many pathogens.
This proposal has three key aims:
To apply hybrid genome sequencing to understand tuberculosis transmission.
To quantify the clinical impact of tuberculosis pre-resistance.
To define the association between pathogen genotype and the host transcriptomic response to tuberculosis infection and disease.
Comprehensive population level surveys of Mycobacterium tuberculosis combined with prospective household cohort studies and the latest in genome sequencing technology will address these aims.
The potential for hybrid deep sequencing to unravel tuberculosis who-infected-whom transmission chains has never been evaluated. Similarly, pathogen pre-resistance – first described by the principal applicant - has never been evaluated in a clinical setting.
The association between the pathogen genome and gene expression following tuberculosis infection has never been adequately addressed. Understanding the importance of pathogen lineage and the trajectory of the host transcriptome following infection could improve prediction of tuberculosis progression from latency to disease.
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| 31/08/2022 |
£810,985 |
KEMRI-WELLCOME TRUST RESEARCH PROGRAMME |
Multiple reinfections are characteristic of many respiratory viruses and a critical determinant of endemicity in human populations. However, there is a paucity of data on the rates and determinants of reinfections, and the importance of reinfections in chains of transmission. This project will investigate reinfection for three common respiratory viruses - SARS-CoV-2, influenza, and respiratory syncytial virus - within the household setting. I will determine the frequency and timing of reinfections independent of clinical presentation; identify viral genomic and host immunological characteristics of reinfections; and determine the factors that influence the transmission potential of reinfections. My proposal includes a three-year household cohort study in coastal Kenya, with intensive respiratory sampling for RT-PCR and genomic sequencing, and bimonthly blood samples to assess immune status and serological responses relating to reinfection. I will estimate the rate of immunity loss and reinfection infectiousness in relation to age, virus load, symptoms, and host immunity, and use mathematical models to explore the transmission dynamics and intervention impact building on the new understanding from this research.
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| 31/08/2022 |
£1,340,881 |
KEMRI-WELLCOME TRUST RESEARCH PROGRAMME |
Multiple reinfections are characteristic of many respiratory viruses and a critical determinant of endemicity in human populations. However, there is a paucity of data on the rates and determinants of reinfections, and the importance of reinfections in chains of transmission. This project will investigate reinfection for three common respiratory viruses - SARS-CoV-2, influenza, and respiratory syncytial virus - within the household setting. I will determine the frequency and timing of reinfections independent of clinical presentation; identify viral genomic and host immunological characteristics of reinfections; and determine the factors that influence the transmission potential of reinfections. My proposal includes a three-year household cohort study in coastal Kenya, with intensive respiratory sampling for RT-PCR and genomic sequencing, and bimonthly blood samples to assess immune status and serological responses relating to reinfection. I will estimate the rate of immunity loss and reinfection infectiousness in relation to age, virus load, symptoms, and host immunity, and use mathematical models to explore the transmission dynamics and intervention impact building on the new understanding from this research.
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| 31/08/2022 |
£2,107,681 |
UNIVERSITY COLLEGE LONDON |
Background. Incidence of adolescent depression, anxiety, self-harm, and eating disorders has increased in the past 20 years. During this time, adolescent body dissatisfaction has also soared. Body dissatisfaction is a key risk factor for eating disorders, but robust longitudinal evidence on whether it is also a risk factor for depression, anxiety, and self-harm, that trans-diagnostic universal preventative interventions could target, is limited. There is also limited longitudinal research on risk factors - and their underlying mechanisms - for body dissatisfaction in general population adolescent samples. This evidence is needed to adapt existing school-based interventions and increase their effectiveness.
Aims. To:
Investigate the causal role of body dissatisfaction in the aetiology of adolescent mental illness.
Identify novel risk factors for adolescent body dissatisfaction.
Understand aetiological mechanisms underpinning body dissatisfaction.
Methods.
Aim 1: I will triangulate robust methodological approaches for causal inference in large twin cohorts and UK electronic health records.
Aims 2-3: I will conduct a four-year school-based cohort study co-produced with adolescents, teachers, parents. I will collect observational, experimental, and digital data to gain a novel understanding of aetiological mechanisms unpinning adolescent body dissatisfaction.
Implications. My research will inform policy recommendations and lead to the development of new preventative interventions.
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| 31/08/2022 |
£3,342,680 |
UNIVERSITY COLLEGE LONDON |
During brain development, the birth, specification, differentiation, and survival of diverse cell types are coordinated to generate circuits spanning neural fields, yet we understand little of how this is achieved. My proposal will address how development is coordinated at multiple levels to build functional circuitry using the well-characterised and tractable Drosophila visual system. Recently, my lab discovered that photoreceptors regulate the neuronal diversity of their target field, the lamina, through a Hedgehog signalling gradient. Unlike other known morphogen gradients, which emanate away from the source, here the gradient forms along the lengths of photoreceptor axons. Aim 1 will determine how photoreceptors establish this unique instructive gradient. While Hedgehog signalling specifies lamina neuron identities, MAPK signalling drives neuronal commitment. Aim 2 will define the downstream molecular mechanisms that underpin and coordinate neuronal specification and commitment. Finally, based on our findings that developmental coordination often relies on intercellular signalling, Aim 3 will systematically survey and validate receptor-ligand pair expression from single cell transcriptomic datasets to uncover novel intercellular communication that coordinates neural development. Achieving these aims and addressing developmental coordination will fill a gaping hole in our understanding of nervous system development, with far-reaching implications for basic biology and medicine.
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| 31/08/2022 |
£735,867 |
UNIVERSITY COLLEGE DUBLIN |
The period 1700-1900 saw the development of many new constructions of "problem" drinking signified by terms such as "intemperance," "inebriety," "dipsomania" and "alcoholism." During this period Ireland was under British rule and the perception that Irish people were excessively fond of alcohol raised questions about their capacity for self-governance and rationality. This cultural context meant that new alcohol-related medical frameworks became implicated in an existing socially-biased and politically-charged discourse. The health impacts of this medico-cultural interaction have been observed in Ireland into the twentieth century (Mauger; Cox). However, the mutually constructive nature of this relationship demands scrutiny of the understudied cultural dimension. As the first large-scale examination of the cultural side of this medico-cultural interrelation, this project will proceed in three phases: 1) the project will assemble a corpus of alcohol-related medico-scientific texts. 2) The project will then track their circulation in Irish culture through contemporary library catalogues and records to gauge their cultural penetration. 3) The project will synthesise this circulation information with an analysis of representations of disordered drinking in a wide range of literary sources (fiction, non-fiction, periodicals, private letters, and life-writing) to reveal the changing nature of this interchange at a formative time in Ireland’s history.
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| 31/08/2022 |
£1,555,394 |
KING'S COLLEGE LONDON |
Ovarian cancer is a deadly disease with a substantial unmet need for more targeted therapies. Changes in epithelial organisation and tumour microenvironment (TME) alter cellular communications and influence patient response to treatment. However, the exact mechanisms involved are not well understood because of the complexity of tumour-TME interactions, and the difficulty in modelling them using current approaches. The overarching goal of this fellowship proposal is to build integrative AI models of how the diverse cell types in the TME interact and how epithelial organisation influences these interactions. I will use multiplexed tissue imaging to tag tens of proteins in the same tumour simultaneously to visualise spatial protein activities across millions of cells. Building on my highly interdisciplinary background in AI, cancer biology, and image-based modelling, I will characterise TME phenotypes and their therapeutic relevance from multiplexed images. Novel methods will be developed to integrate single-cell and spatial transcriptomics data to determine genetic and molecular factors underlying these phenotypes. I will further identify biomarkers and phenotypes that stratify patient responses to therapy using AI. The developed methodologies will provide new conceptual frameworks for modelling the TME, and cellular interactions and greatly advance our understanding of their role in resistance and relapse.
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| 31/08/2022 |
£910,667 |
UNIVERSITY OF CAPE TOWN |
The social drivers of antimicrobial resistance (AMR) remain understudied.(1) The burden of AMR is greatest where resources are least available. Across structures within society, including healthcare, power manifests itself according to gender, socioeconomic status, race, ethnicity, and class influencing infection-related health-seeking and health-providing behaviours.(2) I will investigate how and why social determinants influence how people seek, experience, and provide healthcare for (bacterial) infection prevention and control (IPC) and antibiotic use in South Africa and India. Applying an innovative lens and mixed methods of:
ethnographic research, sociograms, and semi-structured interviews with healthcare providers, patients, and carers;
quantitative analysis of clinical practice in hospitals measuring the various predictors of AMR using bi-variable and multivariable regression analyses
this research will provide empirical, high-quality evidence on how social determinants intersect with health, social well-being, and vulnerability in IPC practices and antibiotic use. Using this knowledge I will: 1) design, implement, and measure effects of interventions accounting for these factors; 2) provide a toolkit for advocacy for actors in AMR and health to assist them to promote dialogue and policy on this issue. This work directly benefits communities most affected by AMR, reframing healthcare structures and practices in participating sites with potential for wider translation.
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| 31/08/2022 |
£3,246,052 |
KING'S COLLEGE LONDON |
Many of the brain’s important functions engage computations across multiple brain regions, but the ways in which different regions collaborate remain poorly understood. The goal of this proposal is to identify the organizing principles and functional roles of long-range circuits between the cerebellum and the forebrain.
The cerebellum’s role in sensorimotor learning is well established, while its contributions to cognitive behaviours, such as processing of reward, have only recently been appreciated. Here, I aim to create a unified understanding of these seemingly distinct functional roles by defining common principles of multi-regional computations performed by cerebellar circuits and their partners in the motor cortex and basal ganglia, which may facilitate sensorimotor and reward-related functions, respectively. To achieve this goal, I will utilise a combination of cutting-edge techniques in mice to (1) map the organizational logic of connections between the cerebellum and forebrain, (2) uncover shared activity patterns in these long-range circuits, and (3) define causal contributions of the cerebellum to computations in partner regions and to behaviour.
This work will generate new insights into the cerebellum’s diverse roles and provide a rigorous foundation for quantitative, multiscale theories of learning and computation that can be applied throughout the brain.
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| 31/08/2022 |
£3,179,329 |
KING'S COLLEGE LONDON |
Our brain is floating in the cerebrospinal fluid (CSF): a source of signaling factors, hormones and nutrients. The CSF is secreted by a single layer of cells called the choroid plexus (ChP), which forms the blood-CSF-barrier.
The dynamic regulation of CSF signals delivered to the neural stem cells is critical for brain development. CSF abnormalities can lead to diseases such as microcephaly, autism and schizophrenia. My plan is to use the new model I recently developed of ChP organoids to better understand the dynamic changes in early ChP and CSF and how they influence brain development.
First, using single-cell RNA sequencing and proteomics, we will study the origin of cellular diversity in the ChP and the contribution of different cell subtypes to the CSF proteome. We will validate these findings with foetal ChP tissue.
Next, using ChP-cortical organoid, we will explore how CSF signals influence cortical development. We will investigate the effect of temporal secretion of CSF components on the neuroepithelial cell proliferation and differentiation using synchronised trafficking assays.
Finally, we will investigate the role of the barrier in transport of immune cells across the ChP epithelium, characterise the trafficking mechanisms in health and diseases such as multiple sclerosis (MS).
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| 31/08/2022 |
£3,343,288 |
UNIVERSITY OF OXFORD |
Wnt signalling pathways are essential in embryonic development and have important functions in tissue regeneration and overall maintenance of tissue homeostasis throughout the lifespan of multicellular organisms. Furthermore, dysregulation of Wnt signalling is associated with many human diseases, most prominently cancer. Understanding how these pathways function at the molecular level is therefore of great importance.
Dissecting molecular mechanisms governing the different steps in this pathway has proven difficult, to a large extent due to pathway complexity and absence of suitable research tools able to reduce such complexity. Recent advances 1 demonstrate that a reductionist approach would provide a well-controlled biochemical system to gain detailed functional insights to elucidate the molecular mechanisms governing pathway activation and termination.
In this proposal I will address how: (i) the destruction complex is inactivated upon Wnt signalosome formation; (ii) the Wnt signal is transduced across the plasma membrane; (iii) the Wnt signal input at the plasma membrane is terminated. Answers to these questions will deepen our mechanistic understanding of the pathological activation of the Wnt/beta-catenin pathway at the plasma membrane, which contributes to various cancers 2. How the pathway is modulated in normal physiology is of great interest for stem cell therapy and regenerative medicine.
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| 31/08/2022 |
£2,140,669 |
KING'S COLLEGE LONDON |
Worry is the cardinal symptom of generalised anxiety disorder, which affects 6% of the population at any time. Worry may arise from altered functioning of the neurocomputational processes that simulate the future to adaptively avoid danger. My goals are to 1) characterise the neurocomputational processes that use "simulation" to enable avoidance, and 2) determine how changes in these processes are linked to pathological worry.
I will use computational modelling, combined with neuroimaging, to reveal how simulations, supported by neural state reactivation, are used to guide decision-making in gamified avoidance tasks. Using state-of-the-art transcranial ultrasound stimulation and pharmacological manipulation, I will determine the causal role of neural circuits and their reliance on core neuromodulators. Finally, I will investigate the origins of aberrant simulation strategies, determining the influence of genetic risk and early-life stress, and testing the influence of real-world stress in adulthood. Later, I will link simulation processes to clinically significant worry, both in the lab and the real world, and investigate how to train more positive simulation strategies.
Together, this work will provide insights into the processes supporting avoidance of danger, and indicate how these processes underpin pathological worry. Ultimately, these findings could inform the development of more targeted treatments.
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| 31/08/2022 |
£1,040,692 |
CENTRE FOR RESEARCH IN INFECTIOUS DISEASES (CRID), CAMEROON |
Global temperatures are increasing due to climate change, allowing insects such as the malaria-transmitting Anopheles mosquitoes to expand into new habitats. Temperature impacts Anopheles' life traits; it accelerates development rate, modifies longevity and fecundity, and regulates malaria parasite development rate. High temperatures have been shown to reduce the efficacy of several public health insecticides in Anopheles. However, temperature extremes harm/kill mosquitoes, forcing them to evolve genetically to tolerate high temperatures (thermotolerance) or to exhibit plastic (phenotypic) responses, such as aestivation and long-distance migrations, to survive. As the evolutionary/genetic changes can have pleiotropic or linkage-based effects on the life traits of Anopheles, such as behaviour, Plasmodium susceptibility, and resistance to insecticides, adaptation to climate change is likely to impact malaria control and elimination efforts. This project will (i) establish molecular/functional mechanisms of thermotolerance and its markers in the major African malaria vectors, An. coluzzii and An. gambiae, (ii) identify how thermotolerance and its markers modify their epidemiologically important ecological traits, and (iii) establish the operational impact of thermotolerance adaptation on the efficacy of major malaria control tools - the long-lasting insecticidal bed nets and indoor residual spraying ingredient. This will promote evidence-based malaria control measures and resistance management by decision-makers.
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| 31/08/2022 |
£1,456,512 |
UNIVERSITY OF OXFORD |
Anti-inflammatory therapies do not stop or reverse fibrosis progression in Crohn’s disease (CD), leaving patients with the only remaining option of surgery. Research to reveal alternatives has been impeded by the unique tissue stiffness and location of fibrotic lesions in deeper layers of the intestine; and by the lack of in vivo models that would both recapitulate small intestinal fibrosis and allow mechanistic studies.
I propose to use cutting-edge spatial profiling to study full-thickness CD patient tissues in situ. The platelet-derived growth factor alpha (PDGFRA) pathway drives small intestinal fibrosis in mice closely resembling CD fibrosis, and enables targeting of pro-fibrotic fibroblasts at the same time. In vivo disruption of the pro-fibrotic fibroblast pathways that we identify in CD patient tissues will enable studying the impact on fibrosis progression. I created an in vitro system to persistently polarise intestinal fibroblasts towards a phenotype that mirrors pathologic patient fibroblasts. Notably, this state is reversed by epigenetic modulation, representing a novel avenue for treating established fibrosis which will be explored in vitro and in vivo.
By this, fundamental insights into fibroblast-driven mechanisms of intestinal fibrosis will be generated. This will enable rational drug design, including epigenetic fibroblast reprogramming.
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| 31/08/2022 |
£2,331,512 |
UNIVERSITY OF OXFORD |
I aim to understand brain mechanisms of flexible behaviour in complex environments, focusing on how predictive models of the environment’s structure are used for action selection. The key questions are:
- What is the computational structure of the model used for planning? Does it store local relationships between locations and use step-by-step simulation to evaluate options, or store long-range relationships allowing rapid action selection at the cost of reduced flexibility?
- What is the differential contribution of, and interaction between, medial frontal cortex and hippocampus in model-based action? Do these regions represent different levels of hierarchically organised behaviour?
- How does information in the model get translated into action? Do dopaminergic reward prediction errors, or short-term memory by recurrent cortical activity, store the output of model-based evaluations to guide choices?
I will answer these questions using a novel behavioural assay for mice, in which they choose among goals, and plan routes, in a complex maze environment ideally suited to mathematically modelling planning computations. I will characterise activity in frontal cortex and hippocampus using high density silicon probes, and in the dopamine system using photometry, including simultaneous recordings to study interaction between regions, and optogenetic manipulations to test causality.
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| 31/08/2022 |
£1,887,230 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
In utero exposure to infectious diseases may set the stage for long-term health outcomes. There may be no evidence of the infection when the chronic condition is diagnosed. This proposal aims to investigate whether infectious diseases during pregnancy can increase the risk of the offspring developing a non-infectious chronic condition during childhood and adolescence. Specifically:
1. Do infectious diseases during pregnancy increase the offspring's risk of non-infectious chronic conditions?
2. Do infectious diseases during pregnancy affect the offspring's growth pattern?
3. Is the relationship between maternal infectious disease and non-infectious chronic outcomes mediated by conditions such as preterm birth?
Using an unparalleled longitudinal Brazilian resource derived from linked data, I will compare health outcomes and growth trajectories of children and adolescents born to mothers with and without specific infectious diseases during pregnancy using a variety of epidemiological approaches and decompose the direct and mediated effects of maternal infection on chronic disorders.
The results from this study will advance our understanding of the relationship between infectious diseases during pregnancy and chronic disorders, with widespread implications enabling targeting of critical points along the path from in utero exposure to outcomes to avoid or mitigate illness and disability over the life course.
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| 31/08/2022 |
£1,484,174 |
UNIVERSITY OF OXFORD |
A new generation of Magnetic Resonance Spectroscopy (MRS) tools promise to deliver powerful, novel, in vivo imaging of cell-type-specific microstructure and functional metabolism in the human brain. However, these new generation tools require a re-engineering of data acquisition and analysis methods to overcome low signal and a lack of spatial specificity. Therefore, I will advance these novel MRS methods by delivering techniques to simultaneously spatially- and temporally-resolve functional brain metabolism and cell-type-specific microstructure. This will unlock non-invasive, quantitative imaging measurements of metabolism underlying major healthy brain processes: plasticity, aging, development; as well as disease pathophysiology.
This research will:
develop novel simultaneous spatially- and dynamically-encoded MRS in the human brain with high spatial and temporal precision.
enable these technological leaps by creating a dedicated spectroscopy analysis toolset to overcome the low signal-to-noise.
translate this technology to widely available commodity hardware and cement its use by tracking pharmacologically induced functional and structural plasticity.
I will create a powerful platform to explore novel spectroscopic signal mechanisms and share it through a well-established, open-source, neuroimaging package (FSL). This will enable critical, but previously unanswerable, clinical and basic science questions to be addressed.
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| 31/08/2022 |
£2,412,721 |
UNIVERSITY OF EDINBURGH |
Insults to the intestinal tract such as infections with pathogenic organisms, excess inflammation, or chemotherapy treatment cause significant damage to the epithelial barrier and increases in regulated mammalian cell death. Regulated mammalian cell death is an important host defense mechanism; however, I uncovered a previously unappreciated mechanism during my postdoctoral fellowship in which intestinal bacteria directly exploit the metabolites released by dying intestinal epithelial cells to promote growth.
My findings have launched a novel line of research within the realm of host-microbe interactions. The primary focus of my research program is to understand the cellular and molecular processes at the host-microbe interface that originate within the dying mammalian cell, fuel bacterial growth, and culminate in intestinal disease. Going further, my lab will focus on the added interplay with tissue repair and regeneration. I will combine the power of bacterial and mammalian genetics to:
Determine the impact of metabolites from pathogen-induced lytic cell death on bystander bacteria and immune cells.
Define the bacterial inducers of intestinal mucositis.
Interrogate the factors responsible for prolonged susceptibility to infection following intestinal injury.
Ultimately, I seek to identify death-dependent mechanisms that influence bacterial outgrowth and modify the repair of injured tissue in the intestine.
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| 31/08/2022 |
£2,130,543 |
UNIVERSITY OF CAMBRIDGE |
One of the biggest challenges of this century is to understand how the brain computes, transmits and stores information at single-cell resolution. Which neurons are active when a certain task is learned or at different stages of an organism's development? Is it possible to manipulate neurons to retrieve a particular memory? The lack of molecular technology currently hinders our understanding of the complex processes by which our brain moves from simple signals to complex tasks such as sleep or memory formation.
The main goals of this research proposal are to visualise, map and manipulate the active neural circuits underlying specific behaviours and to encrypt into DNA the neuronal firing history . These fundamental questions will be addressed through the development of: Ca2+-activated luciferases, light- and activity-driven transcription factors (engineered by artificial proteases and photocontractable proteins) coupled to transcriptional readout, and Ca2+-activated CRISPR-Cas9 systems. These new molecular tools are being developed through a synergy between synthetic chemistry and powerful synthetic biology techniques such as directed evolution to optimise the performance of the different systems.
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| 31/08/2022 |
£828,198 |
UNIVERSITY OF CAPE TOWN |
The population aged 60 years or older in sub-Saharan Africa is increasing at a more rapid rate than any other region of the world. Long-term care for older people in the region is primarily provided by families. Southern Africans are ageing in a region characterised by inadequacies in private care (families and communities), vulnerability to poverty, and exclusion from health services and the inappropriateness of existing health services to older persons. A growing burden of noncommunicable diseases increase levels of ill-health and disability amongst older persons particularly in low-income settings. Yet policy development in this area has been slow. While empirical data is quite limited, there are indications that the availability and quality of care provided to older people has been impacted by changing family structures brought about by migration, the HIV/AIDS epidemic, COVID pandemic, high rates of poverty and unemployment and changing norms around filial and community commitment to older people. This research programme aims to develop a wider theoretical understanding of the family care of older people in a Global South context, and provide frameworks to assist leaders, bureaucrats, donors and technical experts in the process of policy making to support the wellbeing of older persons.
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| 31/08/2022 |
£2,371,053 |
UNIVERSITY OF EDINBURGH |
A fundamental feature of cellular growth is that global protein and mRNA amounts scale with cell size. This ensures constant concentrations of key enzymes and reactants for the biochemical reactions that underpin core cellular processes.
The precise scaling of mRNA content with cell size is achieved by two mechanisms: increased transcription due to limiting RNAPII and feedback on mRNA decay to stabilise transcripts in larger cells. However, this size-scaling of biosynthesis is only sustained within a limited size range; above which mRNA concentrations decrease, the cytoplasm becomes diluted, and many aspects of cellular physiology decline – including stem cells’ capacity to self-renew.
I propose to elucidate the molecular mechanisms responsible for these size-dependent changes by identifying the mechanism for size-dependent mRNA decay feedback (Aim 1) and determining the molecular events responsible for the upper cell size limit for efficient biosynthesis (Aim 2). We will also address the open question of how cellular physiology is impacted by extreme small cell size (Aim 3).
Initially using yeast as a model system, this will combine quantitative genomics, proteomics, and imaging. Molecular insights from yeast will then be tested in embryonic stem cells to determine how size impacts stem cell function (Aim 4).
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| 31/08/2022 |
£2,791,338 |
ROSALIND FRANKLIN INSTITUTE |
Alzheimer’s disease involves a complex cascade of aberrant protein processing leading to aggregates of Abeta and Tau. Despite being hallmarks, aggregates do not necessarily result in cognitive decline. Approaches enabling the imaging of intermediates responsible for cytotoxicity within native brain tissue are needed. This will facilitate understanding of the molecular landscape underpinning protein dysfunction, cell death and disease.
The cutting edge of structural biology is cellular. New instrumentation harnessing plasma ion sources allow tissues to be prepared for electron cryo-tomography (cryoET). However, new methodology is needed to robustly streamline tissue specimen preparation for this challenge. This is because a throughput of electron transparent specimens is needed to produce reliable insight. I will deliver a workflow combining reproducible vitrification of brain tissues, optimised sculpting of brain tissue by plasma ion beam milling and high-resolution TEM analysis. This will uncover the molecular changes in mouse disease models and human clinical samples.
The organisation of macromolecules in healthy and disease mouse and human tissues and structures of disease-relevant intermediates of Abeta and Tau will be determined within their subcellular context. This will lead to a molecular understanding of mechanisms for cell disruption in native tissue, and a greater understanding of Alzheimer’s disease pathogenesis.
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| 31/08/2022 |
£2,606,632 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
The world’s population is ageing rapidly, especially in Asia and Latin America. Maintaining brain health into older age is a major challenge: depression and dementia affect 7% and 5% of adults aged over 60 years respectively. Infections are potentially important, under-recognised, modifiable contributors to poor brain health, whose effects vary across settings.
My research aims to analyse relationships between infections and key components of brain health (mental health, cognitive health and sensorimotor function) in older age by applying robust causal inference methods to large, longitudinal datasets. Using a combination of electronic health records from the UK and US, harmonised longitudinal surveys from Mexico, India, the UK and US and multidimensional genetic, social and health data from UK Biobank, I will address three key research questions:
What risks do acute infections pose to brain health in UK and US populations?
Do relationships between infections and brain health differ in India or Mexico compared to the UK and US?
What mediates relationships between infections and brain health?
I will supplement epidemiological approaches with Mendelian randomisation and causal mediation analysis to generate fundamental insights into the infection-brain health relationship across populations, with the ultimate goal of improving brain health worldwide.
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| 31/08/2022 |
£2,049,125 |
UNIVERSITY OF CAMBRIDGE |
When considering whether an exposure is a causal risk factor for an outcome, evidence from randomized trials is reliable but typically slow or impractical to gather, whereas evidence from conventional observational studies is often unreliable, as it is subject to bias from confounding and reverse causation. Mendelian randomization (MR) is an example of a quasi-experimental approach: it is analogous to a randomized trial, but relies on nature doing the randomization for us. MR can be implemented rapidly for a range of exposures to provide insights about causal relationships that can prioritize or deprioritize exposures for further investigation. The aim of our research is to develop methods that enable detailed MR analyses to inform policymakers and drug developers about the nature of causal effects: enabling trial interventions to target the right mechanism in the right population group at the right time.
We will develop methodology for MR that informs us on how causal effects occur, when interventions are most effective, and which population groups they are strongest in. We will also apply our methods to address questions of key biomedical importance, and provide resources and training so that others can apply our methods to their research questions.
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| 11/08/2022 |
£150,000 |
INSTITUT DE RECHERCHE EN SCIENCES DE LA SANTé DIRECTION RéGIONALE DE L'OUEST |
Title: Public engagement tools for a participatory development of gene drive technologies in Africa
The social science studies and preliminary stakeholders’ engagement described in our main proposal will identify ethical and social considerations that may affect the adoption of gene drive technologies for public health action in Africa. The current Research-Enrichment-Public-Engagement (REPE) project will build on identified knowledge gaps to co-create gene drive governance in Africa by connecting scientists and end-users through a two-way dialogue platform. Specifically, the REPE ambitions are to: i) develop an information and exchange platform that will maximize interactions between scientists and various stakeholders to ensure co-development and ownership of gene drive technologies (GDT) by potential beneficiaries of its use, ii) build an interactive social science database on genetic vector control to guide policy, iii) improve scientists’ skills to communicate their findings and aspirations with general audiences. This open-access engagement approach will help to gather relevant information to feed our main research pathway, and to provide a robust framework for the introduction of gene drive applications in Africa. Such roadmap will guide scientists, inform the public on the progress and guide policymakers to make an informed decision. The project is primarily focused in the West and Central African regions, already involved in our initial project, but the platform will be opened to potential stakeholders beyond these regions.
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| 11/08/2022 |
£18,062 |
UNIVERSITY OF CAPE TOWN |
My research is embedded within two South African birth cohorts with numerous risk factors for poor child development including food insecurity, malnutrition, and anaemia. Preliminary work indicates a 31% prevalence of maternal anaemia. Given that iron deficiency is the most common global cause of anaemia, nutrition is recognised as a health priority to target in educating and empowering communities.
I have developed a three-tier public engagement project. The first objective is to run interactive workshops with mothers from study communities. The aim is to identify practical ways to improve research processes, to gain insight into community perceptions and challenges around nutrition, to collaboratively develop key messages and strategies for improved iron intake, and to discuss prospective methods for sharing study outcomes with the wider community.
The second objective will focus on using workshop feedback to create accessible, informative, and culturally appropriate resources for dissemination at study sites and more broadly to the South African public. Resources will include posters, pamphlets, and a video aimed at raising awareness and providing practical guidelines around the importance of a nutritious, iron-sufficient diet. The goal is to make these resources accessible via antenatal clinics, study sites, community resource centres, institutional websites, social media platforms, and government endorsed mobile healthcare platforms.
Tier three involves sharing research results through academic platforms and community meetings for feedback and discussion with study participants. I also aim to prepare an article for a popular science magazine that is accessible to the general public including the South African youth.
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| 11/08/2022 |
£32,000 |
UNIVERSITY COLLEGE LONDON |
Iranians top the number of asylum seekers in the UK, many of whom suffer from mental health problems. While social support is a protective factor in mental health, political divisions alongside refugee- and mental health-related stigmas impede emotional support in Iranian communities, thus amplifying the isolation of refugee torture survivors. A meaningful engagement of Iranian communities is therefore paramount to my main project.
The project: Building Bridges - Solidarity and Healing amongst Iranian Diaspora
In collaboration with award-winning Iranian artists, UCL-Culture, KCL, and Counterpoint Arts, I will engage three UK-based Iranian community organisations. Through creative workshops we will explore strategies to overcome internal community tensions and stigmas that negatively impact the psychosocial wellbeing of Iranian refugees. The discussions with my collaborators and the evidence from literature confirm that the Iranian New Year Nowruz maintains its high value amongst all groups of Iranian diaspora.
The seven symbolic objects found on Haft-sin (seven ’S’s), a table around which families gather during Nowruz, is the backbone of our activities. Community members are encouraged to explore challenges to solidarity with trauma survivors and refugees and participate in the making of artefacts that will become part of a public exhibition during Nowruz.
The achievements:
Research: Main study will be enriched through data surrounding refugee and mental health stigma reduction.
Community and Artistic Collaborators: Developing relationships to express their work and experiences in new ways.
Public: Communities will have an opportunity for self-reflection and consciousness- raising on mental health issues and internal dynamics.
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| 11/08/2022 |
£99,927 |
KING'S COLLEGE LONDON |
Our proposed Research Enrichment activity will focus on social contact-based public engagement to support the SCOPE project goals of achieving earlier and better care for people with psychosis in Ethiopia. We will target 5 groups identified as playing a key role in rights-based care pathways and recovery from psychosis in the SCOPE study sites: police, religious leaders, university and high school students, general health workers, and journalists.
Our approach will be participatory and geared towards achieving ongoing engagement that endures beyond the timescale of the project. Proposed activities over four years: 1) equipping service users and researchers to co-develop social contact interventions, 2) participatory planning/co-development of engagement materials and strategies with target group members, and 3) delivering three engagement activities per target group with iterative learning and refining of the approach through participatory action research.
What we will have achieved:
5 members of the Ethiopian Mental Health Service User Association trained as trainers in empowerment methods and evidence-based social contact approaches.
24 Ethiopian researchers and 24 people with psychosis empowered and equipped to co-develop and conduct social contact-based engagement.
5 distinct packages of social contact-based, multi-media engagement activities co-developed with members from each target group.
15 engagement activities with approximately 400 participants from target groups, identification of mental health champions and creation of a forum for ongoing dialogue about how to achieve earlier detection and better care for people with psychosis, and facilitate uptake of SCOPE findings
Evidence on the acceptability, feasibility and potential impact of our engagement activities.
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| 11/08/2022 |
£84,984 |
UNIVERSITY OF GLASGOW |
Deforestation is widely linked to disease emergence, requiring land management solutions that support health, conservation and economic goals. We aim to increase awareness of planetary health and potential disease impacts from land use decisions in local communities and secondary schools. Using a range of Earth Observation (EO) data, such as drone and satellite data, we will explore how EO data can be used as a platform to communicate health risks and stimulate discussions on health and landscape.
We will conduct a series of participatory mapping workshops within local communities living in Malaysian Borneo. We will work closely with community organisations to involve a wide range of stakeholders living and working within forest, plantation and village areas. Maps and images will be used as tools to discuss local land uses, health challenges and perceptions, recording stories from different community members using multimedia approaches. These co-created materials will be used to develop a wider programme of activities for secondary school students highlighting the links between landscape and health. We will develop web-based tools for students to explore EO data and the stories of people living within these areas. Activities will be piloted in secondary schools within Sabah, Malaysia and used to develop lesson plans distributed through educational organisations across Malaysia and the UK.
Together, these activities will highlight links between environment and health and develop new methods using EO data as a tool for health communication and community empowerment. This will serve as a model approach for planetary health public engagement.
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| 11/08/2022 |
£186,399 |
UNIVERSITY OF BRISTOL |
Planned activities will give older people a voice to express their opinions about ageing and musculoskeletal disability, in settings where older people are not currently heard. We will conduct this work in Zimbabwe and The Gambia, the two study sites with the least healthcare infrastructure. Older people have extensive life experience. The programme will promote action, innovation and positivity about wellbeing in older age, combating ageism; aims align with the WHO Healthy Ageing 2021-30 strategy.
This programme is informed by previous public engagement successes led by collaborators in Zimbabwe. We will co-produce a film on ‘Ageing well’, scripting four personal stories reflecting a collage of snippets of real-life stories gathered and developed through participatory workshops, structured around key health themes, sensitive to diverse health beliefs and medical pluralism. We will run National ‘Art of Ageing’ Competitions, with expert mentoring for short-listed entrants and winning entries celebrated at national festivals. Using stories and images from these two activities, we will co-design a ‘Story of Ageing’ brochure to encapsulate the health and wellbeing agendas of ageing in Africa.
The project will be delivered in partnership with local community-based organisations (CBOs), Ministries of Health and stakeholders. The team bring together expertise in research in older people and musculoskeletal disability, film and media production, public engagement and impact evaluation. Project evaluation and lessons learned will be shared with stakeholders through a variety of channels. The project will provide a voice to older people who are (and who feel) deprioritised by current healthcare delivery models.
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| 11/08/2022 |
£25,273 |
UNIVERSITY OF WARWICK |
In collaboration with our partners, Fuel, our proposed project will produce a series of three 10-minute audio pieces, drawing on our research and conversations between the project team and the artists who will be commissioned by Fuel to script and produce the pieces. These audio pieces will engage audiences with women’s experiences of narrating their own illness and agency in their recovery in the past and present, with the aim of increasing knowledge and understanding of maternal mental illness. The project will provide experience to the two Postdoctoral Fellows (with the PI’s guidance) of working closely with partners in the arts to develop original pieces of work that highlight and enhance their research in creative and impactful ways.
The audio pieces will be shared through a physical installation which will be deployed at music/performance festivals/venues and universities/mental health settings, and digitally via Fuel and the project website. The project team will attend these events to discuss the research and development of the audio pieces with audiences, engage in panel discussions, and to collect feedback. The venues will be selected to encourage engagement with diverse audiences in terms of age, ethnicity, disability, sexuality and gender, including women who have experienced postnatal mental illness and their support networks. Our press offices will contact Woman’s Hour, with the view to including a feature on the audio pieces prior to the work being made accessible on Fuel Digital (https://digital.fueltheatre.com/) and our project website (launching July 2022) as streamable podcasts in Autumn 2023.
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| 11/08/2022 |
£154,327 |
KING'S COLLEGE LONDON |
A major concern for parents with mental health problems is the transmission of risk to their children. Even in families without mental health issues, there is a desire to understand how parents influence child wellbeing. We propose creating a mental health dialogue between parents and researchers focussed on understanding the intergenerational transmission of psychopathology. Collaborating with Bethlem Gallery (art gallery based at Bethlem Royal [Psychiatric] Hospital) and the Centre for Mental Health (CMH; charity with extensive PE and PPI experience) we will run creative workshops with parents, exploring beliefs surrounding the intergenerational transmission of risk for mental health problems. Workshops will be facilitated by artists with lived experience of mental illness. Bethlem Gallery will support engagement with patients at Bethlem Royal Hospital, while CMH will support engagement with parents from diverse socio-cultural groups across the country.
Workshops will explore themes around mental health, genetics, scientific literacy, cultural influence, and the effects family members have on one another. We will establish a list of key questions that parents want answers to regarding mental health within the family. These will feature in an arts-led PE response by Bethlem Gallery designed by artists and curators. We will also explore how parents want researchers to share findings. Where robust research already addresses key questions, we will share findings in accessible formats. Where it does not, questions will be disseminated within the scientific community, to guide future research. CMH will support us in sharing with policy makers and mental health professionals, for sustained impact.
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| 11/08/2022 |
£21,687 |
UNIVERSITY OF LEEDS |
This project aims to consolidate work that has been happening across the globe, creating an introductory curriculum on health research and, pivotally, engaging with and representing key concepts of capacity, consent and autonomy making them accessible objects of knowledge and discussion to this population.
Without further capacity building to support them to understand what research is, how it is designed, funded, reviewed and carried out, they will be unable to engage with discussions of capacity, consent and autonomy which are the conceptual foundations of their exclusion. They will also be unable to understand where they can engage with research and affect change in it.
By the end of this project we will have:
Appointed an expert by experience to co-produce the project collaboratively with me.
Reached out to all interested parties to share their experiences of, and resources for, engaging people with an intellectual disability about health research and key project concepts of capacity, consent and autonomy.
Consolidated the resources into one package to be delivered, engaged with and evaluated in a series of workshops.
Led a series of workshops and given life/visual representation to the reflections of the participants on capacity, consent and autonomy through creative methods.
Identified target audiences and key knowledge transfer locations to host resources.
Created guidance for the delivery of the resources.
Launched the resources, delivery guidance and creative representations, further widening the reach of the resources & seeking feedback.
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| 31/07/2022 |
£271,702 |
YORK UNIVERSITY (CANADA) |
The COVID-19 pandemic demonstrated the value of epidemiological models in battling against the disease. However, modelling is not a trivial task. It requires time, effort and continuous maintenance to address the evolution of the disease and of the countermeasures. On one hand, this requires a systematic and robust development process to ensure the effectiveness and the quality of the produced models. On the other hand, it also implies the need for a change management process that will handle the maintenance and the evolution of the models. Furthermore, infectious diseases have to be studied in conjunction with other affecting parameters, include climate and sociodemographics. Therefore, modellers need to be able to consider multidimensional and hybrid models to better study the phenomenon. In this project, we propose the application of software engineering and model-driven engineering principles to aid the design, development and simulation of climate-sensitive infectious disease models. More specifically, we propose a integrated development platform that will support (a) the definition and design of models, (b) the simulation of scenarios based on these models, (c) the automatic validation and verification of models and code generation, (d) the control of model versions, and (e) the merging of models from different domains. |
| 31/07/2022 |
£483,759 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
The frequency and scale of extreme hydro-meteorological events (heavy rainfall, storms, floods, drought) is predicted to increase due to climate change. These events, of which flooding is the deadliest, disproportionately affect those in low socio-economic groups in low- and middle-income countries. In Southern Malawi, the geographical focus of this proposal, the most recent flooding event (Jan 2022) resulted in one million people requiring humanitarian assistance, displacing approximately 200,000 people, and devastating vital infrastructure. Flooding is known to also impact vector-borne diseases exposure; however, the nature of this relationship is understudied, and there is a lack of guidance on how to use this association to guide risk mitigation activities. The primary goal of this proposal is to develop an enhanced vector-borne disease digital surveillance platform for forecasting transmission risk in areas vulnerable to extreme hydro-meteorological events. Using a spatio-temporal statistical modelling framework to gain insights into how flooding affects malaria within Southern Malawi, we will work closely with key governmental and humanitarian agencies in Malawi to design a user-centric, sustainable, and scalable digital platform to demonstrate how risk information can be used to guide both proactive and responsive vector-borne disease control policy and practice in flood-prone areas.
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| 31/07/2022 |
£553,752 |
UNIVERSITY OF CALIFORNIA, DAVIS |
Arenaviruses are featured in the World Health Organization’s list of priority diseases with specific concerns around endemic arenavirus infections in Africa and emerging arenavirus threats in South America. The risk of these zoonotic viruses is driven by the distribution and ecology of their rodent reservoir species which are highly sensitive to landscape changes. In the coming years, our changing climate could impact the risk of arenavirus spillover from rodents through various mechanisms such as drought, frequency of fires, and adaptive agricultural practices. We aim to develop climate-sensitive models for individual arenaviruses by closely collaborating with regional public health experts to create a pipeline of validated data that feeds into predictive models. Models will be based on reservoir rodent distribution, human cases, and bioclimatic factors that influence the ecology of arenaviruses will be also used to predict future risk based on specific emission scenarios and projected local climate data (2.6/4.5/6.0 IPCC-GISS). Furthermore, models will be presented on an online platform for public and policy analysts to explore with clear validation around model uncertainties. The tool will also become a resource for researchers as a centralized database and knowledge center for arenaviruses in addition to a home for predictive scenario-based modeling activities.
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| 31/07/2022 |
£566,937 |
UNIVERSITY OF TEXAS AT AUSTIN |
Climate-sensitive infectious diseases more often than ever pose a threat to humankind with pandemic potential (1). The Wellcome Trust has identified 37 tools with a climate component used for the analysis of infectious diseases, most of which (81%) are focused on vector-borne diseases. Furthermore, most tools available are for areas where the disease is already endemic.
Soil and water-borne infectious diseases outbreaks are linked to seasonal weather patterns and extreme weather conditions in the coastal areas, such as coastal flooding and storm surge, which will be becoming more frequent and persistent due to the predictive climate change. To better understand the dynamics of the relationship between soil and water-borne infectious diseases with climate and more importantly predict outcomes in the future, particularly in areas with potential emerging situations, we are proposing the development of an openly accessible computational tool that would be accessible to non-expert users, i.e. researchers and health professionals, and allow them to use available climate inputs and epidemiological information to facilitate analysis, prediction and visualization of data relevant to infectious disease studied, as a means of informing policies in disease management.
1.Baker, R.E., et al. Infectious disease in an era of global change. Nat Rev Microbiol (2021).
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| 31/07/2022 |
£508,827 |
PLYMOUTH MARINE LABORATORY |
This proposal focusses on India, which carries a heavy burden of multiple waterborne diseases, where medical infrastructure is poor, and where clinical data on diseases are difficult to access. We aim to develop a multi-layered digital tool to map sanitation conditions and occurrence of diseases that can be rapidly updated, especially in the event of natural disasters, such as floods, or changes in environmental conditions, notably monsoon rainfall. The required data will be collected through a smartphone application aimed at local citizens and primary health workers, for direct uploading of data without external intervention, thereby filling an acutely-felt gap in information. Crowd-sourced data products on sanitation and diseases will be publicly and freely available. This will be complemented by routinely-updated satellite-based maps on risks from the presence of pathogenic environmental bacteria (notably Vibrio cholerae) in natural water bodies, and on environmental threats from heavy rainfall and floods. Public engagement activities will ensure uptake of products by the general public and decision makers. The goal is to create a marked step down in the diseases burden through improved technology and citizen scientist participation. The design strategy allows for translation of the methods to other localities and other diseases.
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| 31/07/2022 |
£514,355 |
FUNDAçãO GETULIO VARGAS |
For 40 years, Brazil has witnessed the emergence of diseases transmitted by the mosquito Aedes aegypti: DENV-1 (1986), DENV-2 (1991), DENV-3 (2001), DENV-4 (2010), Chikungunya (2014), and Zika (2015), with severe human and economic costs. Viruses at risk of introduction are Nhong-nhong, Mayaro, and Oropouche. Misdiagnosis is common, and emergence of new viruses can go largely unnoticed. New tools are needed to increase the precision of arbovirus surveillance and control in preparation for climate change. Mosqlimate is a multi-disease tool with two main goals: 1) estimate probabilities of change in pattern of disease transmission in response to climate and land use changes; 2) identify circulating viruses during outbreaks when information is incomplete. Mosqlimate will detect signs of expansion of arbovirus transmission areas, as well as signs of outbreaks potentially linked to new arboviruses. The tool will flexibly feed on climate and epidemiological data whenever available. Another tool, OviCounter, will fill in the mosquito data gap by providing digital technology to improve the use of eggtraps for mosquito surveillance at large scale. As output, Mosqlimate will deliver measures of risk to integrate into the Brazilian early warning system "Infodengue" and its mature community of practice.
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| 31/07/2022 |
£460,648 |
INTERNATIONAL CENTRE FOR DIARRHOEAL DISEASE RESEARCH, BANGLADESH |
Not available |
| 31/07/2022 |
£393,393 |
UNIVERSITY OF LEICESTER |
The ability to predict risk of climate-driven, vector-borne and zoonotic diseases, at fine spatial resolutions, is important for directing public health policy, such as optimal targeting of vaccinations and managing health interventions. With disease cases commonly reported at a coarse county or state level, such high resolution predictions are crucially not often available. Disaggregation regression is a validated method that can address this gap, but is restricted due to the lack of user-friendly tools. Here, we aim to create an online app that reads in case data, fetches environmental data, fits disaggregation models and finally summarises predictions in policy-relevant ways. Importantly, we have agreements in place to co-design this tool with public health bodies working on vaccination programmes, and in countries affected by high-burden zoonotic and vector-borne diseases. We will use Lassa fever, a climate-sensitive, zoonotic disease as a case study, to demonstrate a user-friendly workflow that predicts fine-scale cases from areal level case data in Nigeria, in order to optimise vaccine distribution. We will then showcase the potential public health outcomes that can benefit from our tool, across a wide variety of diseases and geographical locations.
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| 31/07/2022 |
£534,931 |
WAGENINGEN UR |
Our vision is to create WaterPath: an open-source modelling toolkit that can be used to quantify and visualise the impact of climate change and socio-economic development on waterborne pathogens and AMR bacteria in surface water and consequent disease risk. The Toolkit will be based on an existing mechanistic water quality model that will be extended to generate climate-sensitive projections and disease risk estimation.
We envision that the WaterPath Toolkit becomes the main point of reference for modelling population exposure to waterborne diseases in future climate scenario analysis. To achieve that, we will target a diverse audience of users: scientists, modellers and data scientists, software engineers and policy makers. By utilising past work and existing connections with global initiatives, we will create a unique community of practice that will participate in the conceptualization and testing of the toolkit, while also disseminating our work to create space for future extensions and open-source contributions.
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| 31/07/2022 |
£504,479 |
UNIVERSITY OF TEXAS MEDICAL BRANCH |
Arboviral diseases are critical climate-sensitive infectious diseases and increasing global public health threats. Arboviral epidemics will continue to occur as urban growth and globalization expand; however, predicting where and when the next arbovirus epidemic will occur remains challenging. Therefore, investigating and understanding the environmental determinants associated with arboviruses’ (re-)emergence are essential to developing the most cost-effective and sustainable strategies to prevent outbreaks and reduce arboviral disease burden. Currently, there are three major research gaps to anticipating, preparing, and mitigating outbreaks and epidemics caused by arboviruses, including: (i) data about the global diversity of arboviruses remains unsynthetized, (ii) lack of knowledge about the global distribution of arboviruses, and (iii) some potential generalized patterns and drivers associated with (re-)emergence of arboviruses remain poorly investigated. In this study, we will create a user-friendly data-driven platform that provides open access to knowledge about arboviruses in a broad context (Aim 1). Them, we will evaluate the impact of macro-ecological traits (e.g., climate change, deforestation, urbanization, and human mobility) on the (re-)emergence of arboviruses and determine the potential hotspots for arbovirus discovery (Aim 2). Overall, our results will improve understanding of arboviral emergence and provide tools to mitigate them, with direct implications for global public health.
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| 31/07/2022 |
£519,891 |
IMPERIAL COLLEGE LONDON |
The impact of climate change on mosquito-borne diseases are highly uncertain and will vary regionally as people and mosquitoes adjust in different ways. Estimates of how climate influences mosquitoes’ ability to spread disease are scarce, with experiments typically conducted in artificial environments with inbred-laboratory strains. High-quality entomological data from disease endemic areas will be essential to produce meaningful future projections. This project proposes to develop a flexible user-friendly interface to allow policymakers, stakeholders and researchers to explore the epidemiological consequences of the changing environment. The tool will empower primary data collection by translating user defined estimates of how mosquito bionomics may change over time into disease projections in their local environment given existing and future control interventions. Users can also input projections of disease burden from statistical models and investigate the public health measures needed to mitigate the effects of climate change. The project will focus on malaria and the arboviruses dengue, zika and chikungunya. It will build on the existing malaria interface (https://mint.dide.ic.ac.uk/) to include climate sensitive mosquito bionomics inside established disease-specific mechanistic models. Situations ranging from disease introduction to increasing mosquito abundance will be explored to allow future scenario planning including economic evaluations across spatial scales.
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| 31/07/2022 |
£533,798 |
BARCELONA SUPERCOMPUTING CENTER |
Interacting and successive extreme climatic events, such as droughts and floods, can trigger outbreaks of multiple infectious diseases. These compound hazards can devastate communities if risk reduction plans are not implemented to protect vulnerable populations. Recent methodological advances in climate-sensitive disease modelling have allowed the quantification of the combined impact of hydrometeorological extremes on disease risk. However, this research has not been developed into user-friendly and sustainable tools to serve anticipatory action planning of a diverse set of users. Our goal is to develop an infectious disease modelling tool called IDExtremes within an existing open-source framework for climate science, to predict the probability of outbreaks using observed and forecast hydrometeorological indicators. The flexible design will allow users in different settings to input observed (long-lag) and forecast (short-lag) hydrometeorological indicators, such a drought and flood indicators, and output the probability of an outbreak of a given climate-sensitive disease (e.g., dengue, malaria or cholera) several months in advance. IDExtremes will be integrated in existing communities of practice, as a new health service for the Barbados Meteorological Service, a new climate service for the Brazilian Ministry of Health and an early action trigger tool for humanitarian agencies operating in Asia and Africa.
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| 31/07/2022 |
£524,866 |
THE CYPRUS INSTITUTE |
The risk of vector-borne disease emergence will increase in the northern hemisphere in response to a warming climate, which drives the suitable habitats and distribution ranges of many species. Developing predictive, reliable, and widely applicable models of disease risk requires accurate representation of the physiological dependencies of vectors and pathogens. VEClim aims at vector-borne disease prediction and management by employing data-driven climate-sensitive large-scale mechanistic modelling to represent vector populations and disease transmission. An operational model service will provide access to a vector-pathogen model repository and enable customisation and evaluation of control strategies and future climate scenarios. Short, medium, and long-term predictions of local, regional, and global vector activity and outbreak risk will be delivered through a user-friendly interactive web-based geographic information platform. Model outputs and analyses will be optimised for clarity and utility, targeting wide adoption by scientists, decision makers, and the general public. With the vector-pathogen model repository, comprehensive risk assessment web-platform, and an active user community, VEClim will aid the adoption of predictive tools in integrated management plans for vectors and vector-borne diseases.
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| 31/07/2022 |
£470,546 |
PIVOT WORKS, INC |
Few empirical models of infectious diseases have been operationalized into decision support tools on the ground. Even fewer have been evaluated for their ability to improve health system readiness. Madagascar is particularly vulnerable to climate-sensitive infectious diseases due to low investment in its health system and the population’s widespread poverty and high exposure to rising temperatures and extreme precipitation events. We will create an infectious disease forecasting tool to inform an adaptive health system strengthening intervention on how to respond to local disease burdens in a rural health District of Madagascar. This will include empirical models, a multi-pathogen predictive dashboard, and an associated R package that will be integrated into an existing health information system. The dashboard will include predicted and historical indicators for three major climate-sensitive infectious diseases prioritized by local health actors: malaria, diarrheal disease, and acute respiratory infections. The complete set of tools will be co-created using methods based in participatory modeling to ensure their applicability, usability, and sustainability. In addition, we will measure the impact of integrating this tool on health outcomes and health system readiness.
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| 31/07/2022 |
£556,300 |
ECOHEALTH ALLIANCE |
Rift Valley Fever (RVF) is a complex disease with devastating public health and economic costs. It is transmitted directly from livestock to people and is maintained via mosquito transmission in livestock populations. As a zoonotic disease with a vector component, outbreaks of RVF are tightly linked to climatic and environmental conditions. Statistical modeling approaches have been developed to forecast RVF in Africa, but performance has been inconsistent across regions, with higher predictive accuracy in East Africa than in Southern Africa. Current continent-wide models, which use the Normalized Difference Vegetation Index (NDVI) to predict RVF activity, do not capture local attributes, such as livestock density and land cover, which may explain differing performance. We have assembled a team that includes local South Africa (RSA) government stakeholders, and co-created a tool for RSA that builds on previous work to create an RVF Early Warning System for RSA. Our goal is to package this new, open, locally customizable tool developed for RSA for deployment to other impacted regions. The intent is that end-users (farmers, farmer associations, others) would be forewarned when to vaccinate their livestock against RVF, a month to three months in advance of potential RVF activity.
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| 31/07/2022 |
£176,005 |
UNIVERSITY OF WARWICK |
For a range of diseases, changes in climate variables such as temperature, precipitation, and humidity are altering the geographical distribution of disease prevalence and the risk of outbreaks. Previous studies have forecast future trends of vector-borne diseases based on climate projections under anthropogenic climate change. However, future disease risks depend on the effects of both anthropogenic climate change and natural (or internal) climate variability. Natural climate variability is even important for intervals as long as the next 100 years.
The key goal of this project is to develop flexible open-source software for estimating future epidemic risks in different locations while accounting for anthropogenic climate change and natural climate variability. This involves pairing climate models and epidemic risk models. While we focus initially on vector-borne diseases, the computational framework will be built with a modular structure, enabling adaptation for other types of pathogen (e.g. respiratory viruses) straightforwardly: this will simply involve replacing the epidemiological model module with computing code for an appropriate transmission model. Similarly, using different climate models will involve replacing the climate data module. To ensure usability by other scientists and policy advisors, we will run a workshop to train potential users to generate results with the software tool.
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| 31/07/2022 |
£565,228 |
UNIVERSITY OF MINNESOTA |
Increases in frequency of severe weather events are a hallmark of climate change and impact the effectiveness of malaria control programs. Mozambique is already experiencing these and does not have the capacity to respond to the infectious disease challenges that co-occur. Digital technology will be used to integrate climate and malaria data to identify areas at risk of malaria in the aftermath of severe weather in a much more comprehensive manner. A time-series model will be used to determine geographic areas of increased malaria risk following severe weather. This will provide the basis of a software platform to quantify and visualize these areas for delivery of malaria control measures. The overall objective is to improve the response to malaria risk, increase the efficiency of control programs, and decrease morbidity and mortality. The specific goals are to: 1)create a time-series model that determines geographic areas of increased malaria risk due to severe weather events in Mozambique; 2)develop and pilot a software platform that predicts geographic areas of high risk following severe weather; and 3)integrate this platform into the Mozambique malaria control and disaster management programs. This platform will directly inform the preparation and delivery of malaria control activities after severe weather.
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| 31/07/2022 |
£509,905 |
UNIVERSITY OF OXFORD |
Dengue is the most rapidly expanding arboviral disease in the world. Epidemics of varying size occur yearly in endemic settings during rainy seasons, yet real-time and highly spatially resolved predictions of the locations, duration, and size of dengue outbreaks within cities are not currently deployed. An integrated single software package that provides probabilistic and actionable forecast information about the locations and intensity of dengue outbreaks would enable the public and decision makers to take preventative actions, better target limited resources, anticipate surge capacity in hospitals, and prioritise and evaluate vector and disease control interventions. We bring together an interdisciplinary team of weather and climate scientists, epidemiologists, clinicians, public health policy makers, and engineers to build a scalable, flexible and automated forecasting system that can integrate diverse and complex datasets collated across two cities in Vietnam, and produce forecasts at sub-city scales in Hanoi (emerging) and Ho Chi Min City (endemic). A mobile and desktop application will be built where weather and disease forecasts are integrated to establish enhanced understanding of the link between them. The platform will deliver new science evaluating disease mitigating interventions as they are deployed and provide a tool for local predictions of dengue in cities.
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| 31/07/2022 |
£378,925 |
MASSEY UNIVERSITY |
We propose the creation of a searchable, interactive and participative database for modelling parameters for climate-sensitive zoonotic diseases, which are responsible for 80% of global outbreaks. The tool will be for multiple pathogens and relevant worldwide, at all scales from local to global. It aims at facilitating and harmonising modelling in the absence of directly relevant observational data, which usually requires the use of parameters extracted from the literature. This tool will allow faster, more reproducible models, with less bias due to the source of parameters.
To do this we will:
Organise a modeling experts workshop to identify the relevant pathogens and parameters
Conduct a systematic review of literature and media reports to identify relevant sources
Use Natural Language Processing to extract information, compile and summarise the data, after validation against manual literature scanning and data extraction
Create a web-based interface that allows searching the database, and summarises key information about the relationship between climate and health using a One Health approach for a general audience
Add a collaborative feature by which authors can add their own research to the database, and automate the addition of results from common literature search engines to ensure the sustainability of the tool
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| 31/07/2022 |
£509,875 |
UNIVERSITY OF LIVERPOOL |
The overall aim is to develop and build capacity in the use of an innovative user-friendly digital CLIMate SEnsitive DISease Forecasting Tool - CLIMSEDIS
CLIMSEDIS will allow end-user stakeholders to utilise forecasts and delineate sub-national risk of multiple climate sensitive diseases to inform timely and targeted intervention strategies in eight countries across the Horn of Africa.
The project comprises six phases with key deliverables:
Conduct a scoping review to identify climate risk factors associated with spatial-temporal distribution of priority climate sensitive diseases in the Horn of Africa, and datasets available for the development of CLIMSEDIS
Identify key multidisciplinary stakeholders, and conduct a needs assessment and gap analysis for the development of CLIMSEDIS for priority climate sensitive diseases in selected countries
Develop forecasting system models for selected diseases working across different spatial and temporal scales to inform the design and development of CLIMSEDIS
Pilot the functionality, user-friendliness, and stakeholder acceptability of CLIMSEDIS in selected countries, and develop the final version of CLIMSEDIS
Develop and implement a strategic roadmap for scaling up the use of CLIMSEDIS to all stakeholders in the Horn of Africa
Develop and implement a maintenance and monitoring protocol for the sustainability of CLIMSEDIS in the Horn of Africa
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| 31/07/2022 |
£513,372 |
UNIVERSITY OF CAPE TOWN |
A barrier to entry for Climate Sensitive Infectious Disease (CSID) modelling is access to local, well-documented data. In this project we will develop an open-source web based platform in which we collate, curate and transform data to catalyse CSID modelling. The tool can be used to explore data across a range of diseases in several countries. To develop the foundational tool, we will focus on data related to malaria transmission in Botswana, Eswatini, Namibia and South Africa, owing to data availability through multiple sources and research and political interest in malaria elimination. Data usability is further increased by responsible documentation and contextualisation with guidance to enable CSID modelling. The digital tool will incorporate health, climate, transmission, entomological, economic and demographic data. Extensive dissemination and co-creation will enable the tool to be sustained by a growing community of local, African CSID modellers and analysts.
Though the digital tool may eventually be extended beyond malaria and into other geographic regions, the principal goal remains the same: to enable the development of CSID models calibrated to operationalisable datasets that are responsibly sourced, where the data characteristics and geographic context are well incorporated.
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| 05/07/2022 |
£3,058,019 |
THE FRANCIS CRICK INSTITUTE |
Our proposed WWW Consortium brings together three prospective cohort studies of healthy adults in receipt of COVID-19 vaccination in West Africa, the West Indies, and West London to answer fundamental questions in the immunology of SARS-CoV-2 variants. Given the diverse outcomes of COVID-19 in our respective locations, despite many overlapping characteristics such as shared genetic ancestry and AZD1222 vaccination, we have power to make a significant contribution to understanding the mechanisms underlying the apparent heterogeneity in our cohorts. We have 3 aims:
Harmonise our studies to determine the breadth of immunity to SARS-CoV-2 variants by transferring assay and modelling capacity between sites, while also genotype participants to enable comparison across our mixed-ancestry populations;
Test four hypotheses that may contribute to breadth within and between our cohorts: exposure to prior SARS-CoV-2 variants, to other bat & human coronaviruses, to malaria, and to host immunoreactivity; and
Build models of immune responses to variants that incorporating individual-level data and are applicable in LMIC settings with limited datasets.
Together, our work will provide insights into the factors that drive the complex immunology to SARS-CoV-2 variants that can also inform future pandemic response in regions currently underserved by both research and surveillance capacity.
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| 05/07/2022 |
£3,055,943 |
IMPERIAL COLLEGE LONDON |
SARS CoV-2 continues to evolve. Novel variants are driven by high levels of global transmission and viral replication, sustained selection pressures imparted by existing immunity acquired through natural infection and vaccination, and increasing use of antivirals. Building on G2P-UK, established working partnerships between teams in the UK, Africa and India, and an ethos of free knowledge exchange, we outline 4 inter-related aims that will enable and prepare G2P-Global to evaluate the significance of emerging viral variation across 3 continents. We will: 1) Implement standardized methodologies that enable rapid in-country risk assessment of the biological and antigenic properties of SARS-CoV-2 variants of concern (VOCs), providing real-time data for guiding infection control and vaccination policies; 2) Undertake discovery-led molecular, cellular and in vivo (hamster) analyses of variant phenotypes to address the mechanistic basis for how the virus can evolve while balancing immune escape with the maintenance of efficient respiratory transmission; 3) Assess the potential for spill-overs into domesticated and wild animal species and subsequent reservoir seeding; 4) Establish communications networks and laboratory resources that will build technical and logistical preparedness enabling G2P-Global partners and additional collaborators to undertake in-country virological assessments of future respiratory virus outbreaks, and associated virus variants.
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| 05/07/2022 |
£3,203,346 |
AFRICA HEALTH RESEARCH INSTITUTE |
SARS-CoV-2 evolved variants that could escape previous immunity and transmit better. This process so far culminated in the Omicron variant, which led to a global infection wave of unprecedented scale. To ensure an effective response to variants, their biology, evolution, and mechanisms of escape must be better understood. It is critical to rapidly determine cross-protection afforded by vaccination or previous infections against emerging variants and understand the mechanisms for that protection or lack thereof. This will require understanding B and T cell targets, as well as how these relate to emerging variation, to quickly model/predict new viral escape mutations. Such a high-resolution response is only possible by combining immunology, virology, T and B cell biology, antibody mapping, and structural biology, and will need to be done for increasingly hybrid-induced immunity. The effort must also benefit young investigators.
Specific Aims
1. Perform immunological surveillance of current and emerging variants and predict future mutations which impact antibody and T cell immunity
2. Determine how increasingly complex hybrid immunity functions against current and emerging variants
3. Determine how immune impairment mediated by co-infection with HIV modulates response to variants
4. Promote the next generation of African scientists through cutting-edge research and scientific exchange
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| 05/07/2022 |
£2,687,616 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
Coinciding with > 70% seroprevalence in Malawi and > 75% vaccination coverage in the UK, the omicron variant has had lower mortality than the delta variant. Both prior infection and vaccination protect against severe COVID-19, and vaccination combined with infection induces highly cross-reactive hybrid immunity. Pre-existing cross-reactive T cells targeting highly conserved replication proteins abort SARS-CoV-2 infection before PCR positivity or antibody seroconversion, leading to protection against COVID-19. Our unpublished data suggest that this rapid immune-surveillance is attributable to pre-existing cross-reactive SARS-CoV-2 T cells that are highly enriched in the human airways. Furthermore, lung-resident B cells elicit antibodies that cross-neutralise influenza variants and recent work has highlighted the protective potential of mucosal IgA against COVID-19. These data suggest that cross-reactive airway immune responses could be critical in defence against emerging variants. We hypothesise that airway-compartmentalised T and B cells provide an enriched long-lived reservoir of cross-reactive immunity against emerging variants than can protect against COVID-19, and we postulate that is impacted by background exposure, vaccination status and pre-existing HIV infection, in Malawi and UK adults. An understanding of tissue-resident long-lived, broadly cross-reactive immunity is vital for development of next generation mucosal-targeted vaccines and for future studies predicting susceptibility to novel variants.
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| 05/07/2022 |
£2,268,260 |
KEMRI-WELLCOME TRUST RESEARCH PROGRAMME |
We propose to augment our well-established genomics surveillance infrastructure with a well-structured and coordinated platform for continuous immunological surveillance and characterization of emerging SARS-CoV-2 variants within Kenya and the Eastern Africa region. We will assemble a network of collaborating health facilities across Kenya and the Eastern Africa region to contribute genomic and immunology samples. Our current status as an Africa CDC/WHO-AFRO regional genomic reference laboratory has facilitated bidirectional sample and data sharing with Ministry of Health teams from Eastern Africa and will be a key feature of the immunology work.
We will determine whether newly emergent variants exhibit substantial changes in their sensitivity to neutralization by antibodies induced by vaccination and natural infection, and consequently predict the likely impact on vaccine effectiveness. In addition, we will establish a monoclonal antibody discovery pipeline to rapidly identify variant specific or cross-neutralizing monoclonal antibodies. The network will therefore produce directly actionable health intelligence to support local and international public health policy adjustments to curtail the negative health and economic impacts of the virus.
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| 05/07/2022 |
£3,059,984 |
UNIVERSITY OF OXFORD |
Southeast Asia (SEA) represents a weakness in global COVID-19 pandemic response because many countries do not have the required capacity to conduct advanced analysis to determine the potential threat of SARS-CoV-2 variants. Our aim is to develop and apply a multidisciplinary research platform for rapid assessment of the biological significance of SARS-CoV-2 variants, thereby supporting local policy makers with evidence-based decision. We will deliver our proposal through four Objectives:
Establish a new SEA research platform that supports locally-led investigations evaluating the biology of emerging SARS-CoV-2 variants.
Employ state-of-the art structural biology to provide rapid prediction of the ability of new variants to evade host immunity and drugs.
Evaluate the impact of circulating variants of concern on antibody and T-cell responses in SEA populations, and the clinical consequences of infection.
Create a framework for effective communication and engagement with policy makers and the public concerning new virus variants and their potential to threaten public health.
Our proposal will be delivered by the Vietnam and Thailand Wellcome Africa Asia Programmes, bringing together a multidisciplinary team in SEA (Indonesia, Singapore, Thailand and Vietnam), the UK and the USA. It will strengthen regional scientific capacity that can be rapidly deployed for future outbreak responses.
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| 24/05/2022 |
£4,393,868 |
UNIVERSITY COLLEGE LONDON |
Despite left-right asymmetry being a universal feature of animal nervous systems, we understand little about how such asymmetries arise, how they are encoded in circuits and what roles they play in nervous system function. Our programme of research will elucidate all these aspects of brain asymmetry through the implementation of a comprehensive genetic, developmental, physiological and behavioural platform to study habenular lateralisation in zebrafish. Our first aim is to resolve the developmental processes that establish habenular asymmetry. One focus will be on Cachd1, a transmembrane Wnt-receptor binding protein that modulates asymmetric neurogenesis; additionally, we will perform a large-scale Crispr/Cas9-based screen to identify novel genes that influence habenular asymmetry. Next, we aim to understand how lateralised neurons diversify and will combine functional calcium imaging with spatial transcriptomics to explore the emergence of neuronal diversity in terms of transcriptional and physiological profiles of left- and right-sided habenular neurons. To understand the functional consequences of normal and disrupted brain asymmetry, we will characterise a range of innate behaviours, including context-dependent exploration, in wild-type and mutant animals. Finally, by subjecting our multimodal datasets to methods including canonical correlation analysis and directly manipulating circuit activity, we will determine how neural asymmetry impacts behavioural outcomes.
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| 24/05/2022 |
£2,124,864 |
UNIVERSITY OF CAMBRIDGE |
During development tissues wrapped in extra-cellular matrix (ECM) undergo well-defined deformations to build an embryo. How morphogenetic provides mechanical forces to control the shaping of adjacent tissues is unknown. However, a clear understanding of multi-tissue mechanics is essential to engineer the morphogenesis of organoids in vitro if we wish to use these structures to accurately model their in vivo counterparts. Vertebrate posterior body elongation exemplifies the problem of multi-tissue morphogenesis as the shaping of the notochord, spinal cord and somitic mesoderm must be coordinated together generate a proportioned body axis. We will measure how mechanical forces impacting upon the zebrafish pre-somitic mesoderm alter when spinal cord and notochord expansion is disrupted and characterize the impact on tissue elongation and signalling. A second aim will model pre-somitic mesoderm elongation in aggregates of mouse embryonic stem cells or gastruloids. By modulating the stiffness and ECM composition surrounding the organoid, we will assess their impact on mesoderm progenitor self-renewal. Finally, we will recapitulate in vivo multi-tissue mechanics by encapsulating gastruloids in matrix and applying compressive forces using micro-cantilevers and microfluidics. It will enable a reciprocal interaction between developmental biology and bioengineering in developing new approaches to engineer improved morphology of multicellular systems.
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| 24/05/2022 |
£1,991,223 |
UKRI-MRC |
Almost all bacteria, including several major human pathogens are naturally found in multicellular communities termed biofilms, wherein cells are embedded in an extracellular matrix of polymeric molecules. The presence of an extracellular matrix is the hallmark of all bacterial biofilms, which protects cells from a wide range of environmental stresses including antibiotic treatment.
I will investigate the bacterial biofilm matrix using advanced biochemical and structural biology techniques in conjunction with high-resolution cryo-EM imaging. This research builds on in situ and in vitro systems that my laboratory has developed over the last few years. This project will reveal at the molecular level how bacterial cells bind to each other, and how they are stably held within biofilms by components of the extracellular matrix. Furthermore, this research will investigate key molecules in the biofilm matrix, which render bacteria tolerant to high doses of antibiotics.
Insights from this work will shed light on a fundamental aspect of bacterial biology related to the biofilm matrix that remains poorly understood due to a previous dearth of techniques available to study this problem. The basic knowledge generated in this work will be used to develop novel strategies for therapeutic intervention against bacterial infections.
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| 24/05/2022 |
£3,144,276 |
UNIVERSITY OF GLASGOW |
Malaria parasite transmission is a uniquely vulnerable to intervention with the simple goal of reducing R below 1. Informed strategies to achieve this require in-depth knowledge of the parasite biology behind transmission - currently impeded by a paucity of tools to study human non-falciparum parasites. Transmission is initiated (commitment) by expression of a transcription factor, AP2-G that directs new transcription programmes that generate male and female gametocytes in the blood ready for ingestion within the female mosquito blood-meal. Expression of ap2-g is tightly regulated through epigenetic mechanisms and responsive to the environment.
However, to date we are ignorant of:
the mode of action of the sex-specific developmental programmes initiated by AP2-G
environmental factors that stimulate gametocytogenesis
how and when a sex-specific genome is configured
In a ground-breaking programme supported by a wealth of published and unpublished data, we propose to gain unprecedented insights into these issues by establishing a new human infectious model of transmission, Plasmodium knowlesi, in London, Malaysia and Glasgow building on paradigm-shifting research from our existing rodent and human models.
Exploiting the gametocytogenesis discovery pipelines in the sophisticated P. berghei and P. falciparum models will permit a comparative integrative approach to understanding and ultimately blocking malaria transmission.
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| 24/05/2022 |
£1,831,364 |
IMPERIAL COLLEGE LONDON |
Tissue wound healing is a normal consequence of injury but if dysregulated, can lead to pathology, as seen in idiopathic pulmonary fibrosis (IPF). IPF is a chronic debilitating lung disease with no cure, characterized by deposition of excessive extracellular matrix in the lung parenchyma. Macrophages are key components of lung defence with central roles in resolution of inflammation and repair. My published and preliminary work indicates that pulmonary macrophages are metabolically rewired during fibrosis and furthermore, that these metabolic phenotypes are related to disease severity. I hypothesise that metabolic alterations underlie pulmonary macrophage profibrotic phenotypes and that targeting macrophage metabolism is a tractable therapeutic strategy. This project aims to answer the following key questions (Figure 1A);
What are the metabolic phenotype and nutrient dependencies of macrophage subsets in the fibrotic lung?
How does macrophage metabolism influence stromal phenotypes in the fibrotic lung?
Can targeting lipid metabolism in macrophages ameliorate lung fibrosis?
Using innovative tools and therapeutics I will define the role of lung macrophage metabolism using robust animal models, primary human cells, and unique clinical cohorts. Together, these studies will delineate the pathways that define balance between health and disease, revealing novel approaches for therapeutic intervention.
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| 24/05/2022 |
£7,790,614 |
UNIVERSITY OF OXFORD |
Global health is defined by narratives of a clearly discernible and singular end. Official announcements of ‘the end’, however, are often arbitrary and unstable. Furthermore, they can distract from important counter-narratives and undermine social, environmental, political and epistemic justice when those ‘left behind’ are excluded from discussions of whether the end has been achieved, or is achievable, and if so when and how.
Today, uncertain trajectories, the ‘slow violence’ of environmental degradation, passive attrition of many diseases, and drug resistances question ideas of a singular extinction event and finality. Drawing on an interdisciplinary approach involving historians, sociologists, epidemiologists, psychologists, bioethicists, literary and legal scholars, philosophers and policymakers, this timely and important research has two synergistic empirical and normative aims to:
1. Explore lived experiences of time and temporality of endings of crises, to capture counter-narratives and their implications for future practices, responses and policies
2. Provide an account of the moral and ethical obligations and responsibilities of global health institutions in the aftermaths of crises to health
From detailed comparative research in three countries, including ethnographic, cognitive time-perception and archival methodologies, we will foreground the people, places, processes and policies to capture everyday experiences of endings and aftermaths in context.
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| 24/05/2022 |
£3,110,994 |
UNIVERSITY OF EDINBURGH |
In mammals, genome methylation is erased and reset during germ cell development. The PIWI-interacting (piRNA) pathway directs de novo DNA methylation of young, active transposable elements (TEs). This is a highly precise process that safeguards the genomic integrity of the germline. piRNAs tether the PIWI protein MIWI2 to nascent TE transcripts, triggering events that culminate in DNA methylation. The underlying mechanisms have remained mostly unknown because they occur in a tiny population of developing germ cells and the methylation process is not conserved in other model organisms. Our technical advances have overcome these challenges, leading to our recent discovery of the first nuclear effectors of MIWI2 function. We will harness these advances to discover the factors and mechanisms that mediate piRNA-directed TE co-transcriptional silencing, transcriptional silencing, and DNA methylation. Our recent data suggest that specific licencing steps and multi-factor authentication are required for TE methylation. We will define how constituents of the pathway work together to discover the basis of its exacting precision. In summary, our goal is to provide a mechanistic understanding of this previously intractable process that lies at the heart of mammalian germline immortality.
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| 24/05/2022 |
£3,374,818 |
UNIVERSITY OF GHANA |
Solidarity is an often-invoked concept in global health. Appeals to solidarity at national and international levels have multiplied in the wake of the Covid-19 pandemic. Yet, at the international level, the results have failed to ensure equity in the production and allocation of resources for combating and mitigating the devastating effects of the virus. Historically, solidarity has proven to be an efficient tool in driving social change; ranging from the rights of workers to struggles for independence and emancipation. Solidarity discourse in global health reveals three critical gaps that must be addressed to move beyond rhetoric: conceptual ambiguity; epistemic injustice; and lack of tools for enactment and accountability. Our project addresses these gaps by engaging in an exercise of pluriversality that captures the multiple conceptualizations of solidarity, especially from historically marginalized groups: Latin America, Asia, Africa, Indigenous communities, and non-English speakers. Through an approach of incompletely theorized agreements, we interrogate the various conceptions to arrive at a set of core solidarity goals for global health. From these goals, we co-create, with key stakeholders and actors in global health, a solidarity index and ranking that enables actors to self-examine, transform, and be held accountable by stakeholders and the public.
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| 24/05/2022 |
£8,748,933 |
UNIVERSITY OF LEICESTER |
We have led advances in the genetic epidemiology of lung function, but the causal genetic variants and causal genes, and the mechanisms by which they influence lung function, chronic obstructive pulmonary disease (COPD) and other respiratory diseases remain incompletely understood.
Through a new collaborative interdisciplinary endeavour, we will accelerate discovery of genetic risk factors for lung function impairment, and define the mechanisms and biological pathways underpinning the observed associations.
To achieve this, we will use new genomic data from population studies, building on the cross-ancestry studies of the SpiroMeta consortium, and integrate with new multi-omic datasets using improved statistical genetic methodologies. To prioritise pathways we will undertake high-throughput functional genomic screens using CRISPR, perform lung digital spatial transcriptomic profiling and utilise informative mouse models. This will inform in-depth mechanistic assays at the cell, tissue and organ scales to identify the key mechanisms underpinning regulation of lung function in health and disease.
The complementary strengths in each contributing centre will enable a co-ordinated approach for efficient prioritisation of key pathways. This programme of research will improve the diagnosis, treatment and prevention of respiratory disease through mechanistic discoveries that identify new drug targets and biomarkers, and that highlight drug re-purposing opportunities.
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| 24/05/2022 |
£3,738,985 |
UNIVERSITY OF OXFORD |
Our proposal is an ambitious plan of multidisciplinary research combining cutting edge genomics and Machine Learning (ML) technologies to map the regulatory wiring of the human genome in unprecedented detail. Its outputs will provide immediate gains in decoding non-coding disease genetics, as demonstrated by our recent decoding of a locus associated with COVID-19 severity enriched in South Asian populations. We will leverage these unique maps to develop highly validated predictive ML methods to identify which variants are causal, which cells types they affect and importantly the identity of the genes and pathways that underlie the genetics of common and rare diseases. We will recursively train these networks using single-cell epigenetic data from previously inaccessible cell types, such as the human brain, to overcome the current barriers to decoding disease genetics in these tissues. Finally, we will thoroughly validate these approaches via worldwide collaboration as part of ICDA and within our own programme in haematological primary cell types solving many of the common variants associated with infection and autoimmunity. Our ultimate goal is to make sequence changes in the non-coding genome as interpretable as in the coding genome.
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| 24/05/2022 |
£2,368,846 |
UKRI-MRC |
Poly-adenosine (poly(A)) tails are found at the 3'-end of almost every eukaryotic mRNA and play essential roles in regulating gene expression. Poly(A) tails are required for export of mRNAs from the nucleus, for efficient translation and for mRNA stability. They are added by the evolutionarily-conserved cleavage and polyadenylation factor (CPF/CPSF), a megadalton multi-subunit complex that cleaves pre-mRNAs, adds a poly(A) tail of specified length and promotes transcription termination. The activities of CPF (endonuclease, polymerase and phosphatase) must be intimately coupled with each other and with transcription but the molecular basis for this remains unknown. In this proposal, I will use an integrated approach to obtain a molecular understanding of eukaryotic mRNA 3'-end processing. Specifically, I aim to:
1) Determine the sequence specificity of the 3'-end processing machinery;
2) Understand the molecular basis of pre-mRNA recognition, cleavage and polyadenylation;
3) Understand how dynamics and conformational changes contribute to CPF activities;
4) Determine how CPF is coupled to transcription.
In addition to cryoEM, X-ray crystallography, biochemical reconstitutions and functional studies, we will employ NMR and single-molecule studies to investigate the dynamics of this process. Together, this will define the molecular basis of mRNA 3'-end processing.
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| 24/05/2022 |
£3,069,718 |
UNIVERSITY OF DUNDEE |
Protein secretion is an essential process that delivers a diverse array of proteins to the extracellular milieu. We study the conserved cellular machinery that mediates the first step of protein secretion, export from the endoplasmic reticulum. We aim to understand how cells maintain selectivity when handling a vast diversity of protein sequence and structure. Here, we aim to dissect the molecular mechanisms by which cargo proteins are selectively captured into nascent vesicles. We then aim to leverage redundancy in this step to specifically abrogate a subset of interactions using small molecules, thereby inhibiting secretion of a subset of proteins. Our aims encompass a blend of mechanistic studies that dissect protein-protein interactions for two export receptors, chosen for their conservation and medical relevance (Aims 1 and 2), complemented by cell-based approaches to reveal the spectrum of proteins that engage these machineries in diverse cell types (Aim 3), and small molecule screens for modulators of these interactions (Aim 4). At the completion of our studies, I anticipate having a molecular understanding of how key medically important cargoes engage their receptors, how such interactions drive unique secretion signatures in diverse cells, and a set of tool compounds that perturb interactions to impact secretion.
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| 24/05/2022 |
£1,374,764 |
UNIVERSITY OF EDINBURGH |
Our recent work revealed that circadian rhythms exist in the intracellular concentrations of key ions fundamental to cellular life: magnesium and potassium. We now propose a creative research programme around the central hypothesis that fluxes of ions provide key regulatory functions in the circadian organisation of the cellular landscape.
Objective 1 is to delineate ion concentration rhythms at the sub-cellular level and use multi-omics techniques to reveal how these integrate into the rhythmic transcriptome, proteome, and metabolome over the diurnal and circadian cycle. Objective 2 will reveal the full cellular magnesium transport machinery of a eukaryotic cell and use gene editing and live cell imaging to visualise the dynamics subcellular magnesium fluxes, as well as long-term adaptation experiments to identify those cellular functions that are sensitive to magnesium rhythms. Objective 3 will investigate the functional effects of potassium concentration rhythms in progression of the cell cycle, in gatekeeping glycolysis and primary metabolism, and in facilitating regulated cellular proteostasis throughout the cell and circadian cycles.
Overall, the program will deliver systems level understanding of spatiotemporal ion fluxes and their key roles in the rhythmic orchestration of cellular properties that are fundamental to the health of a eukaryotic cell.
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| 24/05/2022 |
£3,943,192 |
UNIVERSITY OF OXFORD |
The neocortex mediates cognition, encompassing a diverse set of abilities including sensation, perception, decision making, planning, and movement. Dysfunctions of neocortex are thought to underlie numerous neurological and psychiatric disorders. All neocortical areas share a common laminar architecture, with stereotyped patterns of connectivity linking any given layer with another layer or with other nervous system structures. The computational and behavioral roles of the different layers have largely remained enigmatic.
We will combine sensory discrimination tasks with cutting-edge approaches for manipulating, recording, imaging, and analyzing neuronal populations to investigate how cortical circuitry flexibly performs multiple task. This study will investigate the computational, behavioral, and plastic properties of layers in somatosensory cortex. Our first goal is to test the theory that upper layers create high-dimensional representations to flexibly support multiple complex tasks which deep layers balance with low-dimensional representations to enhance generalization. Our second goal is to understand cellular and circuit mechanisms by which cortex acquires task-dependent contextual representations during learning. Our study will contribute to new frameworks for understanding how all neocortical areas enable behavior and how various disorders disrupt cognitive processing.
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| 24/05/2022 |
£1,736,753 |
UNIVERSITY OF OXFORD |
Chronic hepatitis B is one of the world’s unconquered diseases and presents as a spectrum of liver disease, reflecting a dynamic interaction between the virus and immune system. Although current treatments suppress hepatitis B virus (HBV), they are not curative and patients are at risk of developing progressive liver disease. The persistence of the HBV DNA genome and inadequate host immune responses limit progress towards a cure. HBV replication varies spatially within the liver and temporally between disease phases, suggesting localised hepatocyte-intrinsic and liver-resident immune resistance mechanisms. We have shown that oxygen levels influence HBV replication, leading to the hypothesis that hypoxia is a central unifying pathway regulating hepatocyte susceptibility to HBV infection and local immune control. We have developed single-molecule sensitive methods to visualise HBV RNA molecules, offering unprecedented sensitivity to quantify viral transcription in situ and new insights into the behaviour of individual cells that are masked in population-based studies. Combining this with spatial transcriptomics provides an integrated approach to study both viral and immune parameters in the liver and a step-change in our understanding of this chronic disease and paving the way for new therapies.
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| 24/05/2022 |
£4,832,016 |
UNIVERSITY OF OXFORD |
Memory and motivation provide life with direction and purpose. Our studies using Drosophila have discovered that heterogeneity of the dopaminergic system is a fundamental organising principle of mnemonic networks. Identifiable parallel combinations of dopaminergic neurons reinforce valence- and reward-specific memories, and control state-dependent expression. Opponency provides an update function when learned expectations are not met. A recent synapse-level connectome, or wiring diagram, reveals unprecedented additional complexity of memory networks that needs to be deciphered. We will use single-cell transcriptomics to discover the ‘wireless’ neuromodulatory network – the information that connectomes lack. With cell-type specific genetic interventions we will determine how internal motivational states engage the wireless network to orchestrate and select activity within wired subcircuits of the dopaminergic system - to instruct appropriate formation and expression of different kinds of memory. We will also establish how breakdown of control in the dopaminergic system produces inappropriate compulsive reward-seeking. These experiments and approaches will transform our understanding of the molecular, cellular and network-level operating principles that permit diversity in the dopaminergic system to coordinate parallel state-dependent memory networks. Dysfunction within a heterogeneous system is likely to underlie the diversity of roles implicated for dopamine in numerous neurological and psychiatric disorders in humans.
|
| 24/05/2022 |
£713,657 |
QUEEN MARY UNIVERSITY OF LONDON |
Autism research increasingly highlights social networking sites/SNS as the means of establishing connections for adolescent users. However, by focusing on psychosocial outcomes rather than practices in their situated contexts this literature does not address how SNS engagement is driven both by users and algorithms; nor does it aim to understand autistic users’ communicative strategies. The project will close this gap through a novel theoretical approach that brings in perspectives from sociocultural linguistics to provide description and understanding of how young people participate in ‘affinity spaces’ created around SNS users’ common interests.
Combining techniques from corpus-assisted discourse analysis and visual participatory methods I will develop a methodology that re-orients the focus from speech pathology to the agentive and creative adaptation of discursive and technological resources. This is a needed leap in research on social practices of young autistic people that have grown up with SNS presence. Focusing on both public and private SNS accounts, the project will carry out a longitudinal analysis of observed user actions, user-generated posts, interview and workshop data to identify contextual features facilitating interest-driven communication and interaction. The results will lead to support initiatives that are inclusive of young people’s focused interests and communicative abilities.
|
| 24/05/2022 |
£824,067 |
UNIVERSITY OF CAMBRIDGE |
The proposed research will investigate an entirely novel aspect of the biology of the human malaria parasite, Plasmodium. Epigenetic marks such as histone acetylation and methylation play important roles in the biology and virulence of this parasite. I propose to study a new epigenetic modification, histone lactylation, which was recently discovered in human cells, where it can promote gene expression. I have shown that the mark is present in Plasmodium as well. Lactyl epigenetic marks could be particularly important in Plasmodium because malaria parasites are exposed to high and fluctuating lactate levels in their human host environment, and hyperlactataemia is characteristic of severe malarial disease. This project will fully characterise the spectrum of histone lactylation in Plasmodium and assess its sensitivity to varying levels of exogenous lactate. It will map the presence of histone lactylation throughout the genome, and identify the enzymes responsible. It will then explore the idea that histone lactylation could modulate parasite virulence and stress-resistance in vivo, using isolates obtained directly from African malaria patients as well as laboratory lines. The research will significantly improve our understanding of an entirely novel epigenetic mark, which may affect virulence in a very important human pathogen.
|
| 17/05/2022 |
£3,273,631 |
KING'S COLLEGE LONDON |
Sex impacts the maintenance of hearing over the life course. Onset, severity, and prevelance of age-related/adult-onset hearing loss (ARHL) are not equivalent in men and women, so why should we presume the genetic drivers and the molecular pathways are equivalent?
Estrogen-related receptor gamma (Esrrg), a transcription factor, is the only gene identified to date which shows a sex-specific association with ARHL in women of post-menopausal age. In this proposal, I will adopt a cross-disciplinary approach encompassing auditory electrophysiological recordings and single-cell transcriptomics in genetically modified/ovariectomised mice to understand if we can use the transcriptional signature of Esrrg and/or estrogen-signaling to maintain hearing. Pilot data shows that loss of Esrrg in development leads to an auditory neuropathy. Here, I will establish if the molecular pathways regulated by Esrrg early in cochlear development are those by which Esrrg maintains hearing, and how sex impacts these pathways. Subsequently, I will determine if Esrrg and/or estogen-signaling are pivotal for cochlear synaptic and myelin health over the life course, the dysfunction of which, are both associated with early pathological changes in hearing. Finally, I will conduct proof-of-principle studies to determine if manipulating Esrrg and/or estrogen-signaling can be used to rebuild synapses/remyelinate the cochlea.
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| 17/05/2022 |
£1,053,292 |
IMPERIAL COLLEGE LONDON |
The brain is composed of complex networks of neurons, which underlie its adaptive and versatile functionality. Recent neurotechnological developments have provided new tools for probing network function through optogenetic perturbations, enabling investigators to go beyond observational techniques. The overarching aim of this proposal is to develop a unifying computational framework that can accompany and guide experimental perturbational interrogation of neural circuits. This is pursued by simulating and analysing biologically detailed models of neuronal networks to study how neuronal connectivity, dynamics, and plasticity can be probed with optogenetic perturbations. The models are used to explore and quantify the high-dimensional properties of neural activity space and input-output transformations through parametrized perturbations. The insights obtained from the computational modelling will guide the design of experiments, where it is only feasible to test a small number of parameters. The models will provide hypotheses and predictions, and offer a conceptual framework to interpret and organize the large-scale datasets resulting from perturbation studies. By filling the gap between neurotheory and neurotechnology, this work will take us closer to the fundamental goal of understanding how neuronal networks represent and process information, and pave the way to more effectively probe the functional and dysfunctional properties of brain circuits.
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| 17/05/2022 |
£2,101,262 |
UNIVERSITY OF MANCHESTER |
Cells within biological tissues must respond to internal and external mechanical forces to maintain tissue structure, ensure tissue homeostasis and coordinate embryonic development. Mechanical regulation of cell division is emerging as a key route to control proliferation in tissues, but our knowledge of the mechanisms involved is still in its infancy. This is important considering the
mechanical strains experienced in proliferating tissues during embryonic development and in common diseases, such as cancer. A major gap in our understanding is how the speed of mechanical change impacts mechano-regulation. Most studies expose cells to fast, instantaneous, changes in mechanical strain but in vivo tissues frequently experience a much slower build-up of strain, such as during morphogenesis or fibrosis. Crucially, in preliminary work, we find a marked difference in division response when tissue is stretched at different speeds. We will use a combination of tissue-stretch and tailored mathematical and computational modelling to determine how the speed versus strength of strain regulates cell division in complex tissue environments. Unravelling how tissues respond to strain rate provides a new window into the fundamentals of mechano-regulation not previously explored and will reveal mechanisms vital to tissue function that can be exploited in regenerative medicine.
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| 17/05/2022 |
£1,129,118 |
UNIVERSITY OF EDINBURGH |
Adolescence is both a critical period of development for mental health and a time of rapid change. To illuminate the evolving influences on, and manifestation of, mental health issues over this period thus necessitates creative methodologies that capture rich data on multiple timescales. The current study will use a multi-timeframe measurement burst accelerated cohort study to capture rich data on the daily life experiences of adolescents in relation to their mental health over 5 years. This will allow us, for the first time, to understand how daily life experiences coalesce into long-term changes in mental health, as well as how long-term developmental changes impact the daily life manifestations of ,and proximal influences on, mental health issues. This can inform better preventive interventions by identifying new and optimal ‘daily life’ targets at different developmental stages. It can also provide invaluable information for the further development of promising and increasingly popular ecological momentary (smartphone-based) interventions at these developmental stages.
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| 17/05/2022 |
£2,172,766 |
UNIVERSITY COLLEGE LONDON |
The brain’s capacity to make and break habits affects every domain of our life and depends on the ability to detect and transform sensory inputs into appropriate actions. How neuronal circuits regulate this process is major open question in neuroscience. In mammals, cortical and subcortical sensory circuits are involved, but their relative contributions to the making and breaking of habits remain elusive. To address this issue, I will study the circuit mechanisms underlying visually guided actions in the mouse as a genetically tractable mammalian model organism by combing large-scale in vivo electrophysiology and two-photon imaging to monitor brain activity with viral approaches to perturb defined circuit elements. This powerful approach will enable me to discover (1) how cortical and subcortical visual circuits control goal-directed and habitual actions, (2) how fluctuations in neuronal activity in these circuits contribute to moment-to-moment variability of behaviour, and (3) how aberrations in these circuits contribute to behavioural impairments in genetic mouse models of autism spectrum disorder. Overall, this research will provide a deeper understanding of brain circuit mechanisms that underlie the making and breaking of habits and may point to convergent circuit dysfunctions that potentially underlie negative symptoms in neurobehavioural disorders.
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| 17/05/2022 |
£3,121,151 |
UNIVERSITY OF DUNDEE |
Group A Streptococcus (StrepA) kills > 500,000 people globally each year. New therapeutic options are urgently required. We will elucidate the mechanisms by which Group A Carbohydrate (GAC) is built into the bacterial cell wall and acts as a critical virulence factor in host–pathogen interactions.
We will apply, and expand, our innovative techniques in carbohydrate biology to answer three major questions:
What are the molecular and structural details of the GAC biosynthesis machinery?
What is the role of GAC biosynthesis during cell division?
What is the role of GAC in host-pathogen interactions?
We will provide detailed understanding of the GAC biosynthesis machinery on a mechanistic, structural, and cellular level by applying immunoprecipitation, proteomics, and structural studies. The role of GAC biosynthesis during cell division will be investigated using microscopy and genetics, coupled with biochemical approaches. Finally, we will define, the GAC-dependent mechanisms utilised by StrepA to colonise humans. We will identify molecular details of GAC’s role in host–pathogen interactions, the GAC-dependent immunological responses initiated and the resulting contributions of GAC to pathogenesis.
We anticipate that our results will lead to the development of novel therapeutic approaches to combat StrepA and closely related pathogens and enable studies on other important bacterial carbohydrates.
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| 17/05/2022 |
£1,250,763 |
UNIVERSITY OF SUSSEX |
Dysregulation of DNA replication and consequent chromosome segregation are strongly associated with birth defects, ageing and cancer. While chromosome segregation is crucial for genome preservation, it can also result in chromosome instability, particularly when DNA replication is incomplete. Cells growing under replication-stress (RS) conditions therefore face increased risk of chromosome mis-segregation because of elevated levels of late replication intermediates (LRIs) that escape into mitosis, persistently interlinking sister chromatids and compromising their disjunction. It remains elusive how cells tolerate these aberrant conditions and suppress chromatin breakage and/or imbalanced chromatin transmission. We and others previously identified highly spatially and temporally organised LRI-associated and ultrafine-DNA bridge (UFB)-binding protein complexes that associate specifically with replication intermediate structures during mitotic progression. In this proposal, we will employ recently developed 3D Expansion STED (3D ExSTED) super-resolution nanoscopy and genome editing technologies to address the roles of, and regulatory mechanisms governing, these mitotic complexes. We aim to understand how they function in the protection and segregation of chromosomes and the pathological consequences of their deficiency. Using ExSTED, we also aim to reveal DNA folding of mitotic chromosomes in human cells. Our goal is to understand how cells maintain stable chromosome structures under normal and stressed conditions.
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| 17/05/2022 |
£2,123,803 |
UNIVERSITY COLLEGE LONDON |
Modern life has granted increased life expectancy. Yet, living longer means that we are more likely to develop and die from dementia, for which there is no cure. The development of an effective treatment is hampered by the late stage of detection. It is therefore critical to identify novel targets for diagnosis and therapy that are important drivers of disease progression earlier in life.
The blood-CSF-barrier is thought to play an important role in the development of age related neurodegenerative disease and recent analysis of human post-mortem samples has found marked derangement to occur during middle age.
I have recently developed the first non-invasive technique to assess blood-CSF-barrier function, using MRI. This now enables measurement every few seconds to dynamically capture the functional response to drugs in addition to longitudinal assessment across the aging process.
Here we seek to leverage the unique advantages of this new technology to characterize the causal role of blood-CSF-barrier dysfunction in age-related cognitive decline. We will employ longitudinal multi-parametric imaging with comparison to gold-standard measures of CSF-secretion and CSF-mediated brain-clearance together with targeted pharmacological intervention.
Together, therefore, this programme of work will greatly enhance our understanding of the role of the blood-CSF-barrier in dementia.
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| 17/05/2022 |
£495,786 |
QUEEN'S UNIVERSITY BELFAST |
Subcellular mRNA localisation regulates multiple biological processes, from neuronal plasticity and cell migration to acquisition of cell fates. Although the asymmetric distribution of mRNAs has now been reported in multiple cell types, precise mechanisms of mRNA localisation and the consequent implications for tissue formation, maintenance and homeostasis are less understood. Preliminary data showed that proteins classically known for their roles as actin adaptors can bind RNAs in endothelial cells, hinting towards a potential link between cytoskeletal reorganisation and mRNA distribution. Together with the support of robust collaborations, we will develop an innovative experimental programme demonstrating the relevance of spatial control of gene expression for complex biological systems. Firstly, we aim to investigate how actin-binding proteins regulate subcellular mRNA localisation and local translation in the context of endothelial cell motility and blood vessel formation. Secondly, we will uncover novel RNA-protein interactions during endothelial barrier disruption and study the impact of asymmetric mRNA distribution in endothelial cell-cell junction during vessel remodelling. Finally, using murine models of retinal vascular development, we will explore in vivo roles of mRNA localisation. Altogether, our work will expose how unappreciated mechanisms underpinning subcellular mRNA compartmentalization shapes mechanisms of tissue biology.
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| 17/05/2022 |
£2,927,541 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
The health and environmental challenges posed by unhealthy and unsustainable diets, and the food system underpinning those, have emerged as key public and planetary health concerns. Whilst there is broad consensus on the long-term need for dietary and food-system change, adequate policy responses are lacking.
My aim is to improve decision-making for human and planetary health by addressing two major obstacles: the lack of consistent attribution of food-related health and environmental impacts to dietary changes, and the lack of representing those impacts in the comparable monetary terms that are relevant for policy appraisals and decision-making.
My key goals are to:
Estimate and attribute the health and environmental impacts of dietary changes at scales relevant for decision-making.
Estimate the monetary and economic value of the health and environmental impacts of dietary changes.
Co-create and analyse policy options for integrating the health and environmental impacts of dietary changes into decision-making.
In my methodological approach, I will follow a systems perspective and extend and link health, environmental, and economic models. The focus in the first five years will be the health impacts of climate change and air pollution that are linked to diets, and the impacts diets have on biodiversity and ecosystem services.
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| 17/05/2022 |
£2,595,915 |
IMPERIAL COLLEGE LONDON |
Innate immune responses are tightly regulated to protect the host from invading bacteria without inducing detrimental inflammation and tissue damage. Inhibitory receptors of the leukocyte immunoglobulin-like receptors (LILRs) family are expressed by human innate immune cells and are negative regulators of their activation and immune responses. Thus, the inhibitory LILRs are proposed to have a critical role in orchestrating immunity and resolving inflammation. However, whether these receptors have a role during invasive bacterial infections remains elusive. In this grant, we will test the hypothesis that bacterial pathogens have evolved sophisticated mechanisms to interact with inhibitory LILRs to suppress innate immune responses for immune evasion and to promote infection. The key goals are to 1) analyse the structure-function relationship of bacterial ligand and inhibitory LILR interactions, 2) measure the capacity of bacteria-inhibitory LILR interactions to suppress antibacterial responses, 3) assess if these interactions promote bacterial infection, and 4) characterise how LILR variation impacts ligand recognition and antibacterial responses. Using bacteriological-, biochemical-, cell- and in vivo- approaches to address these goals, the project will lead to a significant shift in our understanding of how inhibitory LILRs regulate infection and uncover the therapeutic potential of targeting inhibitory LILR-ligand interactions in future antibacterial therapeutics.
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| 17/05/2022 |
£2,203,400 |
UNIVERSITY OF EXETER |
Cryptococcus causes one of the most impactful fungal diseases in humans and is responsible for > 220,000 cases and > 130,000 deaths per year. Mortality is amplified by both innate and evolved drug resistance by this fungus and its ability for morphogenesis. I recently discovered a new genetically-distinct lineage of Cryptococcus through whole-genome sequencing of environmental isolates from Zambia, which has a reduced ability to cause disease in the murine model of infection and very high levels of antifungal resistance. In this project I will exploit this new lineage to gain mechanistic insight into fungal pathogenicity and drug resistance. I will perform comparative transcript profiling of all Cryptococcus lineages following infection of macrophages and antifungal drug exposure to identify genes responsible for those crucial phenotypic differences. Using the new lineage, I will construct a gene deletion library of unique gene differences and experimentally test them in relevant animal models to characterise novel drivers of pathogenicity. The genetic basis for pathogenicity and drug resistance will be complimented by delineating epigenetic determinants of those traits by constructing a comprehensive chromatin atlas across pathogenic morphotypes. This project will deliver new knowledge to address the important human health issues of cryptococcal infection and microbial drug resistance.
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| 17/05/2022 |
£2,564,693 |
UNIVERSITY OF OXFORD |
The malaria-causing Plasmodium parasite relies on its invasive organelles to enter host cells. These organelles, the rhoptries and micronemes, must cluster at the apical end of the parasite and discharge their contents at specific times during invasion. The shape and localisation of these organelles are determined by filamentous assemblies. Helical filaments in the rhoptry and microneme lumens template their shape, but the protein which forms these filaments remains unidentified. The parasite’s microtubule array is implicated in the transport of micronemes to their functional location. However, how microtubule-binding proteins organise this array is not understood and the proteins that transport micronemes have yet to be established. Here I propose to investigate how the Plasmodium invasive organelles are organised using a combination of cryogenic electron microscopy, mass spectrometry, CRISPR/Cas9 and biochemical assays. I will identify the luminal helices and dissect their shape-determining mechanism. I will solve the structure of the microtubule array and characterise the links to other structures in the cell. Finally I will identify the proteins responsible for microneme transport. My research will uncover principles of organelle organisation and transport relevant across eukaryotes, and will reveal unique aspects in Plasmodium that could be targeted by novel therapeutics.
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| 17/05/2022 |
£2,404,610 |
SWANSEA UNIVERSITY |
Autistic people - accounting for 1-2% of the population - have worse physical and mental health outcomes than their neurotypical peers, but Autistic adults have been neglected in health research. Furthermore, reproductive health, including menstruation, maternity, and menopause, are under-researched. Using a Critical Autism Studies paradigm within a community-led project, this study aims to generate significant shifts in understanding of Autistic reproductive health experience. First, this ambitious participatory research project includes establishing Wales’ first participatory Autistic Research Community Council to oversee the project. Second, qualitative longitudinal methods will be used to understand Autistic people with wombs’ (women, non-binary and trans men) reproductive health experiences across the life course, including their interaction with healthcare services and their unmet needs. 100 participants from four life course stages (young; non-mothers; mothers; peri-menopausal) will each take part in up to 10 in-depth visual methods facilitated interviews over a five-year period (total n=1,000). Third, in collaboration with the Autistic Research Community Council, a new quality improvement intervention for reproductive health services will be co-produced with health professionals. In doing so, the study has strong potential for wide-reaching impact, both in relation to improving gynaecological and obstetric healthcare, but also in Autistic community capacitation.
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| 17/05/2022 |
£4,109,069 |
UNIVERSITY COLLEGE LONDON |
Dementia affects more than half of patients with Parkinson’s disease (PD) but the underlying mechanisms are not understood. I have previously shown that PD dementia is linked to changes in brain networks, but the causes of network dysfunction are not known. Specific gaps are: the link between network dysfunction and accumulation of pathological proteins such as alpha-synuclein, amyloid and tau; relative importance of feedback versus feedforward signaling within circuits; the role of neurotransmitters such as acetylcholine and noradrenaline on PD dementia; and the sequence of events leading to PD dementia.
In this proposal I will use advanced MRI combined with PET imaging, plasma markers and pharmacological manipulation to transform our understanding of PD dementia.
My goals are to:
Relate network changes in early PD dementia to underlying neural pathology using tau and amyloid PET and fluid biomarkers
Characterise changes in feedback and feedforward brain networks in early PD dementia using high-field MRI and magnetoencephalography
Understand the link between neurotransmitters and network changes in PD dementia through pharmacological manipulation
Determine the sequence of events leading to Parkinson’s dementia using computational modelling
This will shed light onto pathological mechanisms, provide targets for intervention and guide development of effective biomarkers for PD dementia.
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| 17/05/2022 |
£988,234 |
UNIVERSITY OF YORK |
In vitro tissue models are a workhorse of biomedical research, providing invaluable tools to study disease and screen new treatments. However, it remains difficult to produce effective models that can accurately recreate native tissue biology. This leads to models with poor predictive power and the potential to generate misleading insight, a continued prevalence of animal models, and a severe obstacle to biomedical progress. In this research programme, we will address the urgent need for innovative biomaterials able to scaffold the growth of effective models via enhanced biochemical signalling complexity. This will be achieved through a chemistry-driven approach, developing:
1) Materials able to sequentially enrich key bioactive proteins at relevant stages of tissue development;
2) Strategies to reversibly functionalise materials with biochemical signalling ligands, providing precise spatiotemporal control over signalling cascades;
3) Novel cyclic and bicyclic peptides able to potently mimic the signalling activity of high cost, low stability growth factors and cytokines.
The highly modular platforms developed within this programme will enable a step-change in our ability to engineer accurate in vitro models of healthy and diseased tissues, accelerating biomedical research and the development of clinically-relevant technologies.
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| 17/05/2022 |
£543,096 |
UNIVERSITY OF MANCHESTER |
How can we understand the different forms of medical uncertainty, their interplay, the debates that surround them and the linkages with socio-economic vulnerability? Using qualitative in-depth interviews with patients, clinicians and researchers, documentary analyses and hashtag ethnography, this project will explore four conditions characterised by multi-layered medical uncertainty (i.e. simultaneous uncertainty about aetiology and diagnosis alongside the scarcity of specific treatments) both in their historical developments and in everyday experiences. The four conditions that will be explored are fibromyalgia, ME/CFS, Long Covid and chemobrain. The project will explore how patients contend with the illness experience, the often difficult processes of obtaining a diagnosis and having it recognised by other medical professionals and society at large, and the scarcity of specific treatments. The project will further analyse how clinicians and researchers manage the everyday uncertainty in their work, and the debates, negotiations and conflict between them and the patients surrounding the definitions of these conditions. The result will be an understanding of medical uncertainty that is multi-dimensional, dynamic and social. Finally, this project will include a public engagement component that aims to increase awareness of these conditions and of their under-diagnosis and under-recognition, particularly among primary care professionals.
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| 17/05/2022 |
£1,183,946 |
UNIVERSITY COLLEGE LONDON |
The research aims to link national datasets containing clinical, environmental, and social information to address gaps in our knowledge of the health impact of non-fossil fuel air pollution. The three exposures of interest are 1) regular use of underground electrified transport (the London Underground), 2) mineral extraction sites, and 3) domestic wood burning. The outcomes of interest are respiratory health, mental health, cancer incidence, and mortality. My team and I will geographically link national datasets on these exposures with health outcomes from a representative sample of the UK. We will assess short-term symptoms (breathing difficulties, mental health) using primary care electronic health records from the Clinical Practice Research Datalink with around 45 million people. Longer-term outcomes (cancer incidence, death) will be quantified using the ONS-Longitudinal Study of ~1 million people with 40-year follow-up. We will also send questionnaires to 250,000 participants of UK Biobank on London Underground use and exposure to domestic wood combustion and analyse the association of these exposures with lung function. The findings will help the public, health care professionals, government advisors, and other UK/International authorities to make informed decisions to maintain air quality and population health as we transition from fossil fuels.
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| 12/05/2022 |
£86,465 |
UNIVERSITY OF KENT |
This award will challenge preconceptions about children and young people with various forms of health and social care involvement including those in care, with insecure immigration status, with a disability and with mental health issues. With its emphasis on co-design and peer-to-peer outputs, the award provides opportunities for young people from these marginalised groups to tell their personal stories, to highlight the issues they feel are vital, and to engage creatively with their lived experience.
The design and performance of stories developed by children and young people with creative professionals will offer an avenue into understanding children’s varied life experiences. The live theatre and filmed YouTube performances, and social media engagement will bring the stories to wider audiences. The educational packages support learning and offer points of reflection on some of the issues affecting children today to provoke discussion amongst young people and facilitate growing awareness of the challenges some of their peers face.
The on-line gallery offers a legacy of some of the ways that children engage creatively with their life experiences of care, immigration and citizenship, disability and challenges to mental health including bullying. Themes devised by young people place their concerns front and centre, and provide stakeholders and the wider public more capacity to understand young people’s life experiences.
Young people will benefit from training and development opportunities from in-person and online classes, being part of focus groups, engaging in the development and contribution of creative outputs, research materials, and evaluation tools.
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| 12/05/2022 |
£47,201 |
UNIVERSITY OF BRITISH COLUMBIA |
Smart Triage represents a significant shift in the care provided at Ugandan health facilities. Previously, children were seen on a first-come, first-serve basis. With Smart Triage, children are stratified by severity of illness to guide prioritization of care to the sickest children. This change in practice is unexpected for families. Sustaining impact beyond our research award will require acceptance and cooperation from caregivers and family of children who present to health facilities and the general public who become participants within this new system.
Here we aim to sensitize caregivers and community members to Smart Triage and its impacts on the care provided at Ugandan health facilities. We will host community dialogues with caregivers, community leaders, and Village Health Teams (VHTs) to provide details of the motivation for Smart Triage and outcomes to-date and gain feedback the system. These discussions will inform the development of educational materials on the role of Smart Triage and the importance of triaging in reducing death and improving outcomes for vulnerable children in Uganda. We will engage with VHTs to broadly distribute these materials to caregivers across one district in which we operate. VHTs are trusted community members that serve as link between caregivers and the formalized health care system. We will monitor caregiver awareness of Smart Triage when they arrive at health facilities before and after our campaign to assess impact, and host additional community dialogues to help refine our approach. This approach will then be replicated in more districts.
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| 12/05/2022 |
£81,434 |
UNIVERSITY OF EXETER |
We will hire natural history artists, Rebecca Jewell and Sandy Ross Sykes, to help run a two-day public engagement training workshop for our team, in addition to thirteen public-facing workshops across our partner institutions: Fishbourne Roman Palace, Museum of English Rural Life, Powell-Cotton Museum, National Museums Scotland and Edinburgh Zoo. At these workshops we will explore debates about animal feeding whilst co-creating artworks and linked exhibitions. The resulting visual and intellectual outputs will be incorporated into a highly illustrated Modern Bestiary.
Our Modern Bestiary will update received wisdom about animal behaviour and diet, which has been in circulation for millennia, most famously in the form of medieval bestiaries. These richly decorated manuscripts presented contemporary understandings of animals and the natural world, interwoven with Christian allegories. They were used as accessible and visual tools for ministers to engage their congregations and disseminate moral teachings, and were a precursor to modern natural history texts.
Whilst our Modern Bestiary will not espouse morality tales, it will challenge popular ideas about ‘good’ animal feeding (e.g. feeding garden birds) and ‘bad’ animal feeding (e.g. feeding feral pigeons). It will also interrogate assumptions about animal feeding (e.g. rabbits should eat carrots, squirrels should eat peanuts, cats should eat fish, giant pandas should eat bamboo, ducks should - or should not - eat bread) – to stimulate wider reflection and debate.
Through this process our whole team will develop public engagement and evaluation skills that will extend beyond the life of the project.
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| 12/05/2022 |
£30,742 |
UNIVERSITY OF YORK |
Successful public engagement activity will have connected publics with novel empirical and theoretical aspects of the project. It will have changed ways of thinking and talking about caring and dying across species boundaries.
Shared exploration of materials for sale at the ‘Care-Full Pop Up Petshop’ will have engaged the public with concepts of care which extend beyond familiar understandings of the term. Extending post human theoretical care work into lived experiences in interspecies family settings, our shopping list activity grounds new materialist and feminist care theories though drawing out both practical and emotional meanings of pet ‘care’. Attendees now question accepted commercialised framings of animal ‘care’ and can legitimately express the deeper meanings and implications of emotional caring for both human and animal family members.
Through The Wake of Granny Wolf we have permitted interspecies family members to explore post human ideas of death and dying, outside the constraints of rigid existing medical frameworks. The empirical findings of the project include the significant barriers to attempted interspecies care conversations which exist in professional end of life settings. Through playful and speculative engagement with the death of a human-animal hybrid character, we have learnt where the resisted conversations which are being started in the clinic might ultimately take us. Through travelling together beyond the frustrated end of life conversations encountered in reality, these speculative cross species end of life conversations can direct the project and the public towards an ultimate goal of imagining a post human end of life care setting.
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| 12/05/2022 |
£14,877 |
NORTHUMBRIA UNIVERSITY |
"Understanding and Re-Imagining Sleep and its Disorders" consists of a workshop series and a website hosting an exhibition and resources. Building a mutually beneficial partnership with The Sleep Charity, the project co-produces knowledge of sleep and its disorders, stimulates public understanding and empathy, and fosters wellbeing.
The workshop series is co-designed with The Sleep Charity and facilitated by the applicant (a literary/cultural studies scholar), psychologists from the Northumbria Centre for Sleep Research, and an artist. Participants from the Newcastle area having difficulties sleeping come together with researchers and the artist to share stories, explore sleep and wellbeing knowledge, and express their lived experiences of sleep/sleep disorders creatively. Insights from workshop discussions feed into the collaborators’ research and practice.
The creative outputs produced at the workshops are collected into an online exhibition accompanied by resources, which ensure the project’s legacy and generate further public engagement. The exhibition features creativity prompts inspiring a wider audience to delve into their experiences of sleep. Responses submitted to these prompts are added to the exhibition, creating an ever-expanding archive. The online resources—podcasts/videos/blog posts co-created by the researchers with The Sleep Charity—bridge the literary/cultural side of sleep and the psychology of sleep, engaging new audiences with multidisciplinary research.
The resources and exhibition’s prompts, accompanied by graphics suggesting ways of drawing on this content to facilitate individual reflection and independent workshops, ensure the scalability of the project, empowering organisations like The Sleep Charity by providing them with further tools in their mission to help people sleep better.
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| 12/05/2022 |
£30,488 |
CARDIFF UNIVERSITY |
Previous consultations with young people, youth workers, and teachers in a disadvantaged area of Wales have highlighted a need for resources to aid young people’s sleep. These resources need to recognise the diverse experiences and challenges that can impact the sleep of young people.
We will empower young people, especially those from disadvantaged backgrounds, to share their experiences of sleep and influence sleep advice given to teenagers in their community. We will achieve this through workshops which will support young people to share their stories using zines – small booklets using art and text to express underrepresented and marginalised voices in society. These will be exhibited online, in their local secondary school and community. Young people will also work with artists and researchers to create engaging and inclusive sleep lesson resources that will be used in health education lessons in their local school and community centre. The project outputs will be disseminated online and at a community event, where researchers and young people will showcase and discuss their work with educators, policymakers and community members.
The project will provide young people with more sleep resources, provide an avenue to amplify their voices in research and education, and increase awareness of how adults can support them. It will improve our understanding of the factors influencing young people’s sleep and what they believe should be prioritised in research. Empowering young people to share their experiences will improve our skills in two-way public engagement and how to use public engagement to change policy.
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| 12/05/2022 |
£201,165 |
IMPERIAL COLLEGE LONDON |
This engagement programme will change perceptions about asthma, revealing the diversity and complexity of the condition and associated health inequalities, through sharing stories, knowledge and experiences in creative ways. We will generate new understanding by bringing together women with lived experience of asthma and asthma researchers to conceptualise, express and exchange their unique perspectives using creative tools and techniques. Partnering with four UK women’s groups with a focus on arts/craft/creativity, we will explore asthma in a programme of in-person and online workshops including textiles, knitting, ceramics and photography. Workshops will explore asthma biology, the experience of asthma and connected health inequalities. Visualisations of cell interactions generated through the main award will be used as inspiration, alongside personal and professional stories. Following the workshop programme, participants will take part in a participatory process, using their creative exploration to inspire the development of engagement activities to share their collective stories and experiences with public audiences. We will produce this second phase of engagement in collaboration with participants and focus on reaching women, people of colour and people living in deprived communities, all of whom have an increased risk of asthma. By engaging these groups we will create a deeper understanding of asthma in the communities where it is most prevalent. We have kept the second phase of the engagement programme purposefully open to allow the results of the creative collaboration and cross-pollination of research and lived experience perspectives to emerge and drive the objectives of the wider public engagement activities.
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| 12/05/2022 |
£86,820 |
UNIVERSITY OF CAMBRIDGE |
Humans have much to learn from honeybees, particularly about immunity mechanisms deployed under attack from viral infections. Previously, the artist Lily Hunter Green and I created a science-art installation, ‘Silencing the Virus’, that reflected an individual-level antiviral defence of honeybees. Here, we apply for a Research Enrichment to communicate new findings on social immunity in honeybees, aiming to enhance our research by gaining insights from communities that had to bear and resist a viral pandemic.
We recently demonstrated that honeybees share antiviral RNA among members of the hive through the ingestion of jelly provided by worker bees to young generations, indicating that RNA transfer plays a role in social defence in honeybees. We propose to creatively communicate our research on ‘RNA cooperation’ with the public.
We will develop a 2-year programme of workshops and performances using a competitive game approach. The game challenges collaborating ‘workers’ teams to control a visualised infectious ‘digital’ disease that spreads by proximity and exposure time, yet can be cleared by an "RNA healing bee-cell". Game performance is scored by the number of survivors. Workshops conclude with a discussion summarising the experience, nominating winners, and proposing strategies to improve game performance. Applying our research findings to a game-based project will give participants renewed agency to overcome viral infections.
Our project will provide new knowledge enabling young people and the public to connect with the nature of the honeybee, inspiring them to propose new ideas that could impact our research on RNA cooperation between organisms.
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| 12/05/2022 |
£243,713 |
UNIVERSITY OF CAMBRIDGE |
Despite consultation prior to the launch of Spectrum 10K, the public response to this study revealed a depth of feeling previously unseen within the field. This offers an opportunity for an in-depth, exciting and reciprocal community engagement process that will be of great value to the autism community, the study team, the wider Autism Research Centre, and autism researchers globally. This proposal is to request funds for community engagement, to ensure enough people are included from across all sectors of the autism communities, with voices loud and quiet, including users of Alternative and Augmentative Communication (AAC), with and without learning disabilities, supportive and critical, and as many points of view in between as possible. It is an opportunity to work with autistic people to find out how this ambitious aim can be achieved, develop new ways of working, and to share them with the wider autism research community. Note that we use ‘autism community’ and ‘autism communities’ interchangeably as we recognise there is considerable diversity within these.
Outcomes
Increased trust between the Autism Research Centre (ARC) and the autism communities.
An understanding of what can and should be changed in Spectrum 10K.
A detailed, published description of the autism communities’ opinions about autism genetics research. This will be a resource for the entire community (including autistic people, carers, policymakers, clinicians and researchers).
Enhanced team skills in the specifics of engagement with autism communities, in science communication, and in navigating complex ethical issues.
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| 12/05/2022 |
£27,525 |
LIVERPOOL JOHN MOORES UNIVERSITY |
The research enrichment activity is a 90-minute "dance soiree". This consists of professional dancers performing a 25–30-minute dance that expresses the project’s themes and is followed by informal public discussion of issues around ageing. The non-verbal aspect is important for presenting the project’s research to an audience of older age people in Liverpool (where the project is based) and in Kyiv (where the Soviet Institute of Gerontology and Geriatrics was based, and where its Ukrainian successor is based). The purpose is to initiate dialogue with the older age public and to discuss attitudes to ageing and older people. Older people from the local area (via an Eventbrite invitation circulated to university networks and Age Concern in Liverpool and Institute of Gerontology and personal networks in Kyiv) will be invited to the dance soiree - a live dance performance in Liverpool and a film screening in Kyiv. Before leaving the audience will complete a questionnaire that asks them how they related to the dance as well as their experience of ageing. They will also be invited to leave their impressions in a comment book. This broader dialogue will be important for contextualising the Soviet experience of growing old. The experience of collaborating on a dance and engaging with older age audiences will enrich the project by deepening the team’s understanding of the key challenges for older people. Its other achievement will have been to get members of the public to reflect on their own experience of growing old.
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| 12/05/2022 |
£99,995 |
IMPERIAL COLLEGE LONDON |
Our activities will cover participatory local action, national media, and global communication. This engagement will generate knowledge and awareness among target groups in vulnerable communities in Dhaka with the aim of motivating them to engage with and adopt better solid waste practices. This, in turn, will reduce waterlogging issues and mitigate the spread of associated diseases. Student ambassadors and their teachers, alongside journalists and civil society leaders, will use the co-produced knowledge to continue sharing and co-creating solutions with community residents in the years to come to improve people’s waste practices, reduce waterlogging and mitigate other hazards, such as the incidence of vector-borne diseases.
Outcome 1: Awareness and knowledge about municipal waste and health will have increased in the selected areas, led by youth and community leaders, through dialogue and co-creation of knowledge about everyday practices and public health.
Outcome 2: Local waste management solutions, supported by scientific evidence, local context and knowledge, will have been co-produced by communities and researchers.
Outcome 3: Students are expected to change waste practices following the engagement activities and they will act as ambassadors to promote these activities to the broader community.
Outcome 4: Infographics, policy briefs, visual and audio materials will have been co-produced to represent issues, solutions and findings and will be freely available to schools and local authorities.
Outcome 5: Media coverage about municipal waste, water and health will have increased through engagement with journalists and communication of scientific data.
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| 12/05/2022 |
£65,309 |
CARDIFF UNIVERSITY |
We will develop a 3-step public engagement activity on curiosity-based learning for upper-key-stage-2 children in underserved schools in the Cardiff Capital Region. First, children will learn about the neuroscience of curiosity-based learning via a school assembly science show. Second, selected classes will collaboratively build a Curious Brain in the video game Minecraft to critically evaluate and deepen their understanding of the brain mechanisms underlying curiosity-based learning. After initiating this project in schools, children can continue to work on their projects at home. Third, the Curious Brain projects will be exhibited at the science museum Techniquest Cardiff. All participating school classes along with their parents/carers will be invited for a celebratory event. Other museum visitors will be able to attend the science show on curiosity-based learning and interact with the exhibited Curious Brain projects. Prior to and after the set of engagement activities, short questionnaires/interviews will be conducted to measure teachers’, children’s, and parents’ perceptions and attitudes around curiosity-based learning, and any potential changes due to the engagement activities.
Important outcomes: (1) Children, teachers, and carers learn specifically about the nature and importance of curiosity-based learning and generally about the process of science. (2) In terms of research enrichment, we will understand better the conceptions about curiosity in a specific age group in which the promotion of curiosity is key for successful learning. (3) We will learn which interventions will be most promising for the refinement/development of further public engagement programs with a wider age range and national reach.
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| 26/04/2022 |
£1,082,977 |
UNIVERSITY OF MANCHESTER |
Patients with melanoma liver metastases have inferior response to checkpoint inhibitors (CPI) compared to those without, resulting in decreased survival. The liver plays a regulatory role in the immune system. Its unique cell populations modulate local and systemic immune tolerance.
Goals
1. To examine how liver stromal/parenchymal cells interact with melanoma cells resulting in changes in signalling/metabolic pathways and production of inflammatory mediators
2. To assess how factors identified in Goal #1 drive changes in immunosuppressive cell types and/or T-cell dysfunction both within the liver and at extrahepatic sites
3. To leverage mechanistic understanding of liver-directed immune tolerance to develop new treatment strategies and biomarkers.
I have developed reductionist in vitro co-culture assays and a syngeneic mouse model of concurrent liver and subcutaneous tumours, which recapitulates resistance to anti-PD-1 therapy seen in patients. I will use functional assays to explore how stromal, parenchymal and immune interactions drive immune tolerance and resistance to CPI in liver metastases. To assess clinical relevance, I will correlate these observations with analyses in human samples.
This work will inform novel liver-directed strategies to target CPI resistance in patients with liver metastases.
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| 26/04/2022 |
£691,956 |
THE FRANCIS CRICK INSTITUTE |
Although most neurogenesis occurs during embryonic periods, dedicated neural stem cells persist in specialised niches of the mammalian brain (dentate gyrus and subventricular zone). Here, maintaining the correct balance between quiescent and active states ensures lifelong neurogenesis. In contrast to the brain, neural stem cell niches have not been identified in the gut. However, in adult zebrafish enteric glia are able to undergo neurogenesis. Moreover, although adult mammalian glia do not give rise to neurons at homeostasis, we find they can undergo efficient neurogenesis in culture, without the addition of reprogramming factors.
We propose that the differential neurogenic activities of these cells is a consequence of their distinct environment. To explore this hypothesis we will perform high-resolution spatial transcriptomics across time (embryonic and adult samples), species (mouse and zebrafish) and organs (brain and gut). This will allow us to decipher how cell-cell contacts impact on the transcriptomic state and neuronal output of the cells, and to infer downstream signalling pathways that control the bidirectional transitions between "activated" and "quiescent" states. We will then validate these findings by manipulating the environment in cell culture models.
Findings from this research could advance fundamental knowledge and the development of therapies for neurodegenerative diseases.
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| 26/04/2022 |
£565,828 |
UNIVERSITY COLLEGE LONDON |
While it is normal to experience fear in certain situations, we can adjust our fear responses depending on our knowledge and circumstances. Many brain regions are known to be involved in processing perceived danger and mediating fear reactions, nevertheless the mechanisms of how these reactions are controlled are still unclear. Such control is crucial since its impairment can lead to anxiety disorders such as phobias or post-traumatic stress disorder, in which the circuits in the brain associated with fear and anxiety are thought to become overactive, leading to pathologically increased fear responses. Brain circuits in the ventral lateral geniculate nucleus (vLGN) have been shown to have strong control over fear reactions. I will test the hypothesis that the vLGN is a crucial hub for integrating external sensory signals with the internal state and knowledge of an animal, in order to regulate fear-related behavior depending on the perceived threat level. I will determine how information about sensory signals, present circumstances and previous knowledge converge on and are integrated by vLGN circuits, and what information is conveyed by neuromodulatory inputs. This will allow me to elucidate the neural circuit-mechanisms of how the level of perceived threat can regulate fear responses.
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| 26/04/2022 |
£597,372 |
THE FRANCIS CRICK INSTITUTE |
Gametocytes are the only stage of the malaria lifecycle that can be transmitted from humans to mosquitos to sustain disease transmission. Prior to being taken up by mosquitos, immature gametocytes sequester to the bone marrow where they extensively remodel the host cell in which they reside. For example, gametocytes can infect nucleated erythrocyte precursors, leading to a delay in erythroblast maturation. There is also evidence that parasite proteins exported onto the host cell surface are critical for mediating cell-cell interactions leading to the secretion of cytokines involved in angiogenesis, leading to remodelling of the bone marrow microenvironment. However, the parasite effectors responsible for these critical remodelling events remain to be identified.
The aim of this proposal is to describe the mechanisms underlying the key remodelling events in gametocyte infected host cells and determine which parasite effector proteins are responsible for mediating them. Using state-of-the-art single-cell approaches I will identify what erythroblast developmental pathways are perturbed upon gametocyte infection. I will also use a combination of reverse genetics and mass spectrometry to identify which effectors are responsible for host cell subversion and mediating cell-cell interactions. Overall, this work will identify key regulators of host cell remodelling required for malaria parasite transmission.
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| 26/04/2022 |
£692,950 |
KING'S COLLEGE LONDON |
Autism spectrum disorder (ASD) involve synaptic deficits leading to excitatory-inhibitory imbalances in cortical circuits. My proposal focuses on how disturbed synaptic RNA localisation and localised translation could act as a convergent pathophysiological mechanism across 2 mouse models with haploinsufficiency of ASD risk genes. I previously demonstrated that long 3’UTRs of synapse-localised mRNAs are structured scaffolds which recruit RBP components of neuronal RNA granules. Notably, misexpression of longer 3’UTR isoforms has been proposed as an ASD hallmark. Therefore I hypothesise that regulation of synaptic mRNA localisation and translation is disrupted in ASD due to aberrant 3’UTR RNA structure and RBP binding. There are three main aims:
Investigate the RNA localisation and translation signatures contributing to presynaptic deficits in 2 ASD models.
Describe the regulatory code of RNA structure and RBP binding on 3’UTRs, and at full-length and single-molecule resolution for selected presynapse-localised mRNAs encoding key proteins overlapping ASD risk (ASD-mRNAs).
Monitor the precise outputs of localised translation for these ASD-mRNAs, their dysregulation in ASD and the regulatory importance of cis-elements (RNA structures and RBP binding sites) encoded on the 3 ‘UTR.
Collectively I aim to uncover the regulatory code of synapse-localised post-transcriptional regulation and their contribution to synaptic dysfunction in disease.
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| 26/04/2022 |
£725,269 |
UNIVERSITY OF EDINBURGH |
Cancer-causing mutational processes leave distinct footprints in the DNA, detectable using the computational approach of mutational signatures. While DNA replication and DNA polymerases are involved in practically all mutational processes, the mechanisms of how different polymerases contribute to individual mutational processes remain largely unknown.
Here, I propose an interdisciplinary project to understand the role of polymerase errors in mutational processes, combining our new experimental technique for polymerase error measurement, computational method development, and analyses of sequencing data from ca. 40,000 cancer patients, several animal models, and cell lines.
I aim to elucidate how the major replicative polymerases Polepsilon and Poldelta contribute to mutational signatures found in cancer patients deficient or proficient in post-replicative repair and to understand the role of translesion synthesis polymerases in mutational processes and treatment resistance. I will combine our results with publicly available data sets to build computational methods for polymerase signature detection in patient sequencing data and to create models for patient risk stratification and prediction of treatment response. This interdisciplinary approach will be used to bring mechanistic insight into the role of DNA polymerases in different mutational processes, predict personalised treatment plans, and lay foundations for development of novel treatments in the future.
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| 26/04/2022 |
£575,642 |
UNIVERSITY OF GLASGOW |
Apicomplexan parasite Toxoplasma gondii’s ability to sense and regulate iron levels is critical to its ability to cause disease. Yet, little is known about how these parasites coordinate responses to the dynamic iron environment in their hosts. Translational regulation, mediated by mRNA-binding proteins (mRBPs), of iron acquisition/storage proteins appears conserved across the tree of life. As such, I propose to investigate the role mRNA-binding proteins in regulating T. gondii iron content.
Many organisms use aconitase to regulate cellular iron. Under iron starvation, aconitase binds short sequences in mRNAs, called iron response elements (IREs), regulating translation according to IRE position. Using genetic techniques, I will determine whether T. gondii uses aconitase/IREs to regulate iron content.
Other, less conserved, mRBPs have been implicated in iron homeostasis in other model organisms. To identify novel post-transcriptional regulators of T. gondii iron homeostasis, I will characterise all mRNA-protein complexes whose abundance changes according to iron availability using enhanced RNA-interactome capture. I will use genetic techniques to validate and characterise iron-responsive mRBPs.
To uncover how shortlisted mRBPs regulate cellular iron, I will identify their target transcripts using immunoprecipitation and RNA-sequencing. Using molecular techniques, I will determine the consequences of mRBP-binding on transcript stability, localisation and translation.
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| 26/04/2022 |
£698,646 |
UNIVERSITY COLLEGE LONDON |
Animals are endowed with the capacity to execute a large spectrum of motor behaviours. Numerous motor tasks result from changes in joint angles through contractions of flexor or extensor muscles. However, many motor behaviours, such as holding an object, require joint stabilisation, produced by co-contraction of flexors and extensors. And others, such as the follow-through when throwing a ball, may require co-inhibition of both. To allow the simultaneous control of multiple muscles, the motoneurons innervating them must receive synchronised inputs from as yet unidentified premotor circuits. We recently discovered that a fraction of premotor spinal interneurons are divergent, i.e. innervate more than one synergist or antagonist motor pools. Therefore, these neurons form an anatomical substrate for mediating joint stabilisation or relaxation. In this project, I aim to build a taxonomy of spinal interneurons innervating pairs of synergist or antagonist motor pools based on their molecular, anatomical, and physiological properties. I will then compare the synaptic strengths of the innervation of synergist versus antagonist motoneurons by divergent interneurons. Lastly, I will manipulate divergent premotor interneuron activity to determine their roles in movement. Thus, this project will shed light on the identity of these neurons and their functions in motor behaviour.
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| 26/04/2022 |
£216,991 |
LANCASTER UNIVERSITY |
Social prescribing, and specifically, the prescription of community-based activities such as walking groups and choirs, is envisaged as a means to improve the health and wellbeing of people with common mental disorders (CMD) such as anxiety and depression. Little is known, however, about what it is like to participate in prescribed activities.
By bringing together auto-phenomenology, in the form of my own participation in socially-prescribed activities, and semi-structured interviews with others engaged in these activities, I will capture phenomenological (embodied, emotional, and affectual) accounts of emergent experience. These accounts will provide insight into experiential complexity that will inform the development of social prescribing services and improve outcomes. Specifically, this insight will influence how activities are developed, selected, and understood, and moreover, how they are presented to service users.
This proposal builds upon, and advances, my novel ‘therapeutic landscapes’ research (the study of places and activities associated with being good for health and wellbeing). By attending to experience emerging when independent choice is disrupted, and within landscapes not typically considered as ‘therapeutic’ (e.g. community centres), it will contribute to my efforts to conceptualise ‘therapeutic landscape’ experience as a spatially-unbound process; a conceptualisation that will broaden the scope of ‘therapeutic landscapes’ research.
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| 26/04/2022 |
£609,935 |
UNIVERSITY COLLEGE LONDON |
This interdisciplinary project will integrate public health and crime science frameworks with complexity science methods to advance new approaches to evidence-based violence prevention research. It will combine realist approaches, empirical mixed-methods, Bayesian causal models, and advanced social simulation techniques to identify intervention causal mechanisms and dynamics in silico. These empirically-based models will inform human trafficking prevention, while demonstrating the profound capabilities of these methodologies for all violence prevention research. In3 will advance realist complexity approaches to address how interventions work, for whom, in which contexts, and why.
In3 integrates three primary aims:
Empirical discovery: identify and interrogate intervention causal mechanisms for primary prevention of trafficking and tertiary prevention of mental ill-health among survivors in the UK
Theory development and methodological innovation: adapt complementary interdisciplinary theoretical frameworks and complexity-appropriate methods for violence prevention and response research
Capacity building: forge new interdisciplinary links between public health, crime science, and complexity science approaches to violence research
Outputs will include key insights and recommendations for those who develop and implement UK human trafficking interventions, novel interdisciplinary violence prevention theoretical frameworks, new techniques for integrating causal inference and simulation methods for intervention research, inclusive training materials on the theoretical, and methodological developments for violence researchers.
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| 26/04/2022 |
£720,220 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
More than one million people die every year from tuberculosis (TB), an infectious respiratory disease caused by Mycobacterium tuberculosis (Mtb), a human-adapted bacterial pathogen which exhibits resistance to many currently available antibiotics. Understanding the physiological and metabolic processes enabling the success of Mtb is critical to eradicate TB. Nutrient acquisition is an important component of host defences against Mtb infection and, therefore, is a promising but underexploited area for new drug development. Coenzyme B12 (B12) is an essential cofactor in at least three metabolic pathways in Mtb, including methionine biosynthesis, nucleotide pool maintenance, and fatty acid metabolism. However, during its evolution to specialist pathogen from an environmental ancestor, Mtb lost the ability to produce B12 de novo and must therefore obtain the cofactor from its host. The mechanism(s) for B12 acquisition remain unknown, but could have significant implications for understanding the adaptation of Mtb to human colonisation and refractoriness to clearance. The study proposed here aims to identify and functionally characterise the proteins involved in B12 transport in Mtb, elucidate their cellular organisation, and investigate the regulatory mechanisms underlying their expression. These investigations will reveal the unique aspects of Mtb B12 transport that could be exploited for anti-TB drug design.
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| 26/04/2022 |
£429,596 |
UNIVERSITY OF CAMBRIDGE |
This project explores the effects of industrial mining in the reproductive lives of humans, animals, and the land to expand our understanding of reproduction beyond the narrow model of the individual and biological human reproductive cycle that has traditionally constrained this body of scholarship (Ginsburg & Rapp 1991, 1995; Franklin 1997; Browner & Sargent 2011). Amidst the current climate crisis, reproduction -particularly fertility decline- is increasingly understood as a lens for addressing social, economic, and environmental degradation (Dow 2016; Hoover 2018; Wahlberg 2018). The goal is to develop a framework I call Reproductive Extractivism to understand how human reproduction is deeply interrelated with other beings' reproduction and show the analytic possibilities that reproduction offers for probing broader socio-economic processes, such as extractivism. Based on ethnographic fieldwork in Peru, this project will examine the everyday life of reproductive extractivism among peasant communities in Cajamarca and Ayacucho and their "world-making" (Murphy 2017b) practices and responses to environmental degradation. My research will produce new understandings for remedying environmental degradation and its implications for the reproductive lives of peasant and indigenous communities across the world.
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| 26/04/2022 |
£728,243 |
INTERNATIONAL CENTRE OF INSECT PHYSIOLOGY AND ECOLOGY |
Mombasa city is the epicenter of recurrent outbreaks of dengue in Kenya, a disease transmitted primarily by Aedes aegypti that exists as domestic and forest forms (subspecies) in much of sub-Saharan Africa (SSA). The increasing burden occurs against a backdrop of lack of any control measures. Larval breeding habitats known to include diverse artificial and natural habitats could be targeted for control; however, this will be facilitated through improved understanding of the contribution of individual habitats on the vectorial capacity of adult populations defining dengue virus (DENV) transmission risk. This study aims to elucidate the effect of individual breeding habitats on the seasonal dynamics of Ae. aegypti populations including subspecies composition; analyze the influence of specific habitats on emerged adult vector competence for DENV, fitness, microbiota composition, and genetics. Further, potential differences in the DENV interference phenotype of a characterized Wolbachia strain among the subspecies will be tested. A suite of approaches will be employed including genetics, metagenomics, vector competence, microbiology, and microscopy. Results from this study will identify ecological and genetic predictors of local variation in dengue risk to guide targeted vector control and the use of the novel Wolbachia dengue control approach in Kenya and SSA at large.
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| 26/04/2022 |
£368,206 |
UNIVERSITY OF CAMBRIDGE |
Aims:
This interdisciplinary project seeks to understand the human and system factors involved in the safe, effective and timely use of injectable end-of-life symptom control medications for adults dying at home. It will advance an inclusive design research methodology and identify with stakeholders where and how systems for using injectable medications can be improved.
Methods:
Drawing on engineering, patient safety and social science disciplines, I will use innovative systems-driven inclusive design methods to examine the human and system factors involved in the use of injectable end-of-life medications; where and how this complex adaptive system can be improved will be investigated through three sequential stages.
Stage 1. Mixed-methods analysis of reported patient safety incidents occurring in England and Wales using the National Reporting and Learning System (NRLS) database.
Stage 2. Longitudinal patient-centred case studies exploring the views, experiences and interactions of patients prescribed medications, their family caregivers and clinicians.
Stage 3. Stakeholder focus groups with patients, family caregivers and healthcare teams exploring key issues, generating further knowledge of systems for using medications and how these can be improved.
Outputs:
Findings will be disseminated via scientific publications, conferences and targeted online briefings and videos for researcher, clinician and policy maker communities.
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| 26/04/2022 |
£675,592 |
UNIVERSITY OF MANCHESTER |
Rising antimicrobial resistance threatens global health and risks undermining modern healthcare. Phage therapy, using bacteria-specific viruses to treat bacterial infections, is a promising alternative to traditional antimicrobials. However, the development of effective phage therapy is limited by gaps in our fundamental understanding of phage biology. To exert their antimicrobial effect, phages must lyse the bacterial cell, yet, phage lysis is very poorly understood in clinically-relevant systems. I will provide quantitative and predictive understanding of phage lysis of the priority pathogen Pseudomonas aeruginosa by answering the following research questions:
i) How do different phage lysis systems respond to changes in bacterial cell state?
ii) How do combinations of different lysis systems interact?
iii) Can phage-antibiotic synergy be predicted from the phage lysis system and antibiotic mode of action?
I will combine synthetic engineering and single-cell microscopy with biophysical and epidemiological modelling and phage infection experiments to provide multi-scale understanding of bacterial lysis. The results will advance fundamental phage biology and inform the design of effective phage therapy.
Through this fellowship I will develop new empirical and computational skills, obtain expertise in a new pathogen system, gain experience in independent project management and supervision, and develop into an internationally-recognized group leader.
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| 26/04/2022 |
£233,744 |
KING'S COLLEGE LONDON |
Covid-19 has brought to public attention the importance of maps in health research and surveillance today. However, the colonial origins of public health mapping is less well understood although scholars have increasingly acknowledged that colonies were important testing grounds for modern medical science. The proposed project concretely establishes the colonial heritage of modern public health mapping through an in-depth archival study into the cartographic surveillance work of the Public Health Commissioner (PHC) in British India. Public health mapping became routine and systematised under the PHC in the early 20th century and the project addresses for the first time how their India-wide health and disease maps were made, used and circulated in India and beyond. The practices, infrastructures and political considerations which informed the creation, use and circulation of disease and health maps in India depended on the integration of different scales of surveillance and mapping. The provincial public health agencies were responsible for gathering the data which the PHC then converted into India-wide maps. The project then considers the importance of the PHC’s mapping and mapmaking to the international proliferation of public health surveillance in the interwar period, through their working relationship with the League of Nations Health Organisation.
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| 26/04/2022 |
£755,464 |
UNIVERSITY OF OXFORD |
Through electron cryotomography (cryoET) we can visualise cell environments at molecular resolution, revealing the structures and interactions that underpin cellular function. The full potential of cryoET has not yet been realised, in large part because specific molecules are challenging to identify. There is an unmet need for cryoET tags, analogous to fluorescent proteins in light microscopy.
I previously pioneered a tool, SPOTs, to identify proteins in tomograms. SPOTs are DNA nanostructures, easily visualised by cryoET, which bind specific proteins. The existing technique is applicable to the outside of viruses and cells. In this proposal I will design a widely applicable, modular toolkit for labelling inside cells, building substantially on my existing technology through three aims.
I will design tags which undergo a conformational change upon binding their target, providing a visual and fluorescent readout of binding in vitro and in vivo.
I will optimise nanostructure contrast by cryoET and cell delivery efficiency, producing a generalised toolkit that can be adopted by any structural biology lab to address far-reaching research questions.
I will demonstrate this toolkit on two medically important systems: latrophilin signalling which is linked to Attention-Deficit/Hyperactivity Disorder in adults, and polycystin-1 auto-proteolysis which is linked to kidney disease.
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| 26/04/2022 |
£264,822 |
UNIVERSITY OF SHEFFIELD |
UK medical-regulatory discourses frame donor conception in a licensed clinic as the legitimate and safe way to enact donor conception and discourage conceiving with a sperm donor outside of medical institutions. And yet, growing numbers of people are building families this way, through digitally-mediated informal donor conception (DMIDC), facilitated via online platforms and social media groups.
Bringing together digital media studies and the sociology of reproduction, the proposed research will investigate perceptions and practices of DMIDC as way of exploring how the expansion of digital media technologies is shaping, and shaped by, changing reproductive norms and practices. It will do this by analysing ‘official’ evaluations of DMIDC, the reproductive narratives of users and the digital platforms through which DMIDC is enacted. This research will be the first major qualitative study of DMIDC, providing urgently-needed knowledge of what, despite its delegitimised status, is probably now the most common form of UK donor conception. It will develop theoretical understandings of the relationship between digital media and reproductive practice, norms and imaginaries. Furthermore, findings from the project will move debates on DMIDC beyond the current ‘stalemate’ between policies which advise ‘just say no’ and the social reality of a rapidly growing reproductive practice.
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| 26/04/2022 |
£735,854 |
UNIVERSITY OF SHEFFIELD |
The formation of membrane contact sites between organelles is a crucial aspect of cell biology, mediating interorganellar lipid transport. Importantly, the identity of organelles is determined in part by phosphoinositides, a small family of interconvertible phospholipids that act as signposts of membrane identity. I hypothesise that the formation of contact sites is regulated by unique changes to the membrane identity of organelles. To address this concept, peroxisome-lipid droplet membrane contact sites offer a unique opportunity to gain mechanistic insights into phosphoinositide conversion pathways that control their formation. This specific contact is of key physiological relevance for its role in the transfer of very-long-chain-fatty-acids from lipid droplets to peroxisomes, typically in response to oxidative stress and high energy demand. Through a unique combination of cell biological perturbation, discovery approaches, and in vitro reconstitution, I will gain a mechanistic and regulatory understanding of phosphoinositide identity changes during membrane contact site formation. The outcome of my approach will be a framework towards understanding the regulation of contact site formation between membranes with distinct identities. Moreover, it will form the basis for a better understanding of fundamental aspects in cell biology with profound implications to health and disease.
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| 26/04/2022 |
£746,567 |
UNIVERSITY OF CAMBRIDGE |
Peptide presentation on major histocompatibility complex (MHC)-I molecules is central to mounting effective antiviral immune responses. However, our understanding of the antigen processing and presentation (APP) pathway in virus-infected cells is incomplete. In addition to ER aminopeptidases (ERAPs) and tapasin, TAPBPR was recently characterised as a third MHC-I peptide editor. TAPBPR shapes the cellular MHC-I immunopeptidome presented at the cell surface, but its role in viral infections remains unexplored. Additionally, proteomic datasets clearly demonstrate that there are uncharacterised interactions between APP components and viral proteins that may impact immune recognition of infected cells.
My overarching aim is to explore the complex dynamics between viruses and MHC-I APP proteins in immune detection and evasion. I will focus on three aspects:
Do viruses manipulate human TAPBPR?
What other novel mechanisms of MHC-I pathway modulation are employed by viruses?
How does the interplay between viral proteins and APP components impact the MHC-I immunopeptidome displayed to T cells?
This work will represent the first known exploration into the role of human TAPBPR in shaping antiviral T cell responses. Furthermore, it will provide novel avenues for innovation of vaccines and therapeutics manipulating the MHC-I APP pathway.
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| 26/04/2022 |
£784,456 |
THE FRANCIS CRICK INSTITUTE |
Enduring immunological memory is dependent on T cells that reside in frontline tissues. Formation and persistence of these tissue-resident memory T cells (TRM) is controlled by tissue-specific environmental signals, but how communication with local environments shapes TRM biology is unclear, and studying these mechanisms in human TRM remains a significant challenge. The aryl hydrocarbon receptor (AHR) is a key environmental sensor and targetable ligand-activated transcription factor with known involvement in the core TRM transcriptional program. I will investigate how AHR signalling impacts TRM biology in mice and humans at a cellular and molecular level, and develop platforms to make human TRM study significantly easier and more accessible.
First, through in silico deconstruction of mouse and human transcriptomic datasets, I will home in on AHR pathway associations in TRM populations. Next, I will study the impact of AHR on TRM generation, maintenance, function, and plasticity in intestinal and liver tissues following murine enteric infection. Finally, 3D gut culture and organ-on-chip models will be utilised to study molecular interactions in human TRM in vitro. This research will advance our understanding of TRM persistence, and offer the platform to better study human TRM, accelerating knowledge of disease processes and supporting targeted vaccine development.
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| 26/04/2022 |
£755,694 |
UNIVERSITY COLLEGE DUBLIN |
Acute Myeloid Leukemia (AML) has one of the worst prognoses of haematological cancers. It frequently results in post-treatment relapse due to its complex clonal heterogeneity allowing for the expansion of minimal residual disease populations. Therefore, targeting transcriptional pathways common across genetically diverse clones, rather than the dominant clonal genotype, is an avenue that demands exploration. Transcription factor pathways are imminently druggable due to an expanding library of epigenetic inhibitor compounds, however in order to effectively implement this approach, there must first be a molecular understanding of patient-specific transcriptional circuits.
I propose to define the transcriptional circuitry of primary patient AML through super enhancer mapping, using a state-of-the-art technique called CUT & Tag. This strategy avoids artefacts of immortal cell lines and will identify candidate transcription factors (TFs) responsible for leukemic cell fate. Using Hi-ChIP, I will define the mechanisms of action of these TFs, including identification of their leukemic dependency, target genomic sites, and contribution to super enhancer-promoter contacts. Finally, I will ascertain the interactome of these TFs to identify co-regulator proteins which can be targeted chemically. Through this, I will target pan-clonal transcriptional networks to pair patients with appropriate repurposed epigenetic inhibitors for future therapeutic benefit.
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| 26/04/2022 |
£490,946 |
UNIVERSITY OF DURHAM |
Wetlands play critical roles in maintaining the health of the planet, but present a complex range of challenges and benefits for the humans who inhabit them.
This project utilises an integrated bioarchaeological approach to explore human health trade-offs in British wetlands during periods of climatic stability and crisis over the first millennium AD. The project will primarily focus on gathering skeletal evidence of childhood health, as childhood is a period of heightened sensitivity to environmental stressors. Analysis of a range of skeletal and biomolecular indicators will identify disruptions in metabolism, growth, and development, as well as evidence of malarial infection in wetland and non-wetland areas. High-resolution biogeochemical (incremental delta15N, delta13C, and delta34S, CSIA-AA), biomolecular (amelogenin), metabolomic (haemozoin), and histological methods will be used to complement osteological data. These data will provide a long view of the interaction between human health, wetland ecology, and climate change during the stability of the Roman and early medieval warm periods, and the climate crisis of the 6th century. Findings will produce unique insights into the risks and benefits of subsisting in wetland environments, and will elucidate the role of climate in altering their balance.
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| 26/04/2022 |
£1,012,272 |
UNIVERSITY OF MANCHESTER |
This project explores how adipocytes respond to obesity. Why does adipose tissue in people with obesity become unable to store more lipid? I propose that dysfunction of the adipocytes themselves is central, with normal pathways of adipocyte metabolism shutting down as obesity develops. Specifically, I will test the idea that, through clock protein NR1D1, and changing availability of key metabolic intermediate acetyl-CoA, programmes of lipid uptake and storage become down-regulated. Crucially, both NR1D1 and acetyl-CoA affect levels of histone acetylation, a chromatin modification associated with increased transcriptional activity.
I will adopt exciting experimental approaches to define how manipulation of NR1D1 and acetyl-CoA alters adipocyte function. I will use a transgenic mouse model that permits temporal control over adipocyte Nr1d1 expression, and mass spectrometry- and tagmentation-based methods to quantify acetyl-CoA and map acetylated histone distribution. I will study adipocytes from people with obesity or NR1D1 mutation, to show that this has relevance in humans. In sum, I will: 1) define the role of NR1D1 in obesity-related down-regulation of adipocyte function; 2) define the mechanism(s) mediating state-dependent control of adipocyte function; 3) determine the importance of NR1D1 and epigenetic regulation of adipocyte function in human obesity.
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| 26/04/2022 |
£520,033 |
THE FRANCIS CRICK INSTITUTE |
Binding of the Shelterin complex to telomeres protect chromosome ends from recognition by DNA damage repair (DDR) pathways, preventing genomic instability and regulating telomerase recruitment. However, the mechanism of Shelterin activity remains unknown, in particular its role in T-loop formation and telomerase recruitment. I will reconstitute the Shelterin bound telomere in vitro and use single-molecule and structural approaches to answer three key questions: How is the Shelterin complex recruited to telomeres?; How does T-loop structure prevent recognition by the DDR?; How does Shelterin regulated telomere length through recruitment of telomerase? I will use optical-tweezers combined with confocal microscopy to allow observation of Shelterin binding, T-loop formation and telomerase recruitment in real-time at single-molecule resolution. I will develop a novel telomeric DNA forceps technique to directly probe the formation of T-loop structures and telomere extension by telomerase. I will investigate Shelterin induced DNA structural changes through force spectroscopy and atomic force microscopy. I will determine the dynamic structure of the Shelterin complex and T-loop through combined structural single-molecule FRET and molecular dynamic simulations integrated with cryo-EM structural data. Together these novel approaches will provide unprecedented mechanistic understanding of the role of Shelterin in telomere homeostasis and mechanisms of dysregulation in disease.
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| 26/04/2022 |
£342,905 |
MAKERERE UNIVERSITY |
Nonhuman life, environmental and other conditions, like floods, famine, drought, pandemics, and violence, may impact on malaria transmission and infection that progresses to varying levels of severity, treatment and care dynamics. Yet these are inadequately addressed in interventions seeking to eradicate malaria in sub-Saharan Africa. Through document research, stakeholder engagements and ethnography on malaria control in east-central Uganda, I will illuminate human and nonhuman elements, processes and conditions influencing malaria transmission and control. I will critically review social science research on malaria, complemented with in-depth interviews with key people in the malaria control programme, to demonstrate how nonhuman elements and conditions are discounted in studies of human health, risk, infection and wellbeing. I will describe how malaria infection, treatment and healing are connected to the status of nonhuman life forms and conditions of living. I will illustrate how nonhuman elements are often excluded by those focused on human aspects of infection, while humans are often subsidiary to questions of environment and vector. These are all relevant to disease control. I will then work with stakeholders to develop ways to better integrate site-specific conditions and events into future malaria control interventions.
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| 26/04/2022 |
£464,960 |
KING'S COLLEGE LONDON |
Viruses gain access to host cells through the specific recognition of biomolecules at the cell surface. My research focuses on neuropilins, a family of host-encoded surface receptors that recognise multibasic C-terminal motifs in circulating extracellular ligands. I recently demonstrated that the Spike glycoprotein of the pandemic coronavirus SARS-CoV-2 exhibits molecular mimicry to generate a sequence capable of binding to Neuropilin-1, thereby enhancing infection of human cells. Bioinformatic analysis suggests that a broad range of additional viral glycoproteins also generate putative neuropilin-binding motifs, including high-profile pathogens such as MERS-CoV, Influenza A virus, Ebolavirus and HIV-1. I will establish infection screens, utilising pseudotyped lentiviruses and authentic live viruses where appropriate, to directly test the role of neuropilins in facilitating infection of human cells by these pathogens. Through a network of collaborations, I will screen small molecule compounds to identify inhibitors of this infection process. This approach will be supported by biochemical characterisation of the molecular interfaces between viral glycoproteins and neuropilins, and investigation of the cell biological pathways that underpin this infection mechanism. Together, this interdisciplinary approach aims to clarify the role of neuropilins as "pan-viral" therapeutic targets and potentially inform the development of antiviral compounds for the treatment of infectious diseases.
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| 26/04/2022 |
£582,296 |
INSTITUTE OF HEPATOLOGY FOUNDATION FOR LIVER RESEARCH |
Haematopoietic stem cells (HSCs) form during embryogenesis and produce blood cells throughout foetal and adult life through a complex and hierarchical process named haematopoiesis.
The foetal liver (FL) is the primary foetal haematopoietic organ responsible for HSC expansion and differentiation, FL-HSCs then migrate to the bone marrow (BM), the site of adult haematopoiesis.
The BM microenvironment, composed of extracellular matrix (ECM) and stroma cells, directs HSC homeostasis. Despite extensive understanding of the BM-niche, little is known about the factors supporting HSC expansion in the foetal liver. Studies suggest a dynamic interplay between FL-cells controlling hepatogenesis and haematopoiesis, however the role of specific microenvironmental cues supporting these processes remains unknown.
The aim of this project is to understand the complex microenvironment supporting HSC self-renewal during development in the foetal liver. The role of ECM-proteins and how they impact haematopoiesis via matrix molecular and mechanical signalling will be investigated using established tissue engineered models. The FL-niche will be deconstructed and re-built step-by-step to understand the minimal cellular and protein components essential for HSC homeostasis and self-renewal. The study will provide novel data regarding HSCs expansion which will be used to advance HSC-based therapies.
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| 26/04/2022 |
£581,175 |
UNIVERSITY OF OXFORD |
Formaldehyde is a genotoxic metabolite universally produced in our bodies at levels sufficient to cause irreversible DNA damage. This is usually prevented by (1) enzymatic detoxification and (2) DNA repair by the Fanconi Anaemia pathway. Mice lacking this two-tier protection accumulate widespread damage and have reduced lifespan. By studying tissue-specific responses in these mice, I discovered that formaldehyde is especially abundant in the liver and contributes to extensive polyploidisation of hepatocytes. This is also a feature of aged human hepatocytes. The purpose of this research is to discover the mechanisms that regulate DNA damage-induced polyploidisation and define its role in maintaining liver homeostasis. In the first instance I will understand how formaldehyde damages quiescent hepatocytes and forces them to re-enter the cell cycle. I will use hypothesis-driven approaches as well as in vivo CRISPR-Cas9 genetic screens to identify factors central to this process. By characterising aged mice with liver-specific deficiency in formaldehyde protection, I will uncover long-term consequences of polyploidisation and its impact on organ function. In the last part of this project, using different DNA repair-deficient mouse models I will aim to better understand the complex relation between genome stability, polyploidisation and liver cancer.
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| 26/04/2022 |
£785,574 |
BIRKBECK UNIVERSITY OF LONDON |
In the mature brain, the metabolic demands of active brain regions are precisely spatially coupled to oxygen delivery through the haemodynamic response. The development of this spatial coupling is unknown, but it is important to investigate because alterations in neurovascular coupling (NVC) have been implicated in neurodevelopmental conditions such as autism spectrum disorder (ASD). My research will focus on mapping the development of typical and atypical NVC and its relation to spatially localised brain function in the early-maturing sensorimotor domain. I hypothesise that early disruption in NVC affects early sensorimotor specialisation and contributes to later cognitive and behavioural difficulties. To test this, I will build on the multimodal neuroimaging approach I have pioneered that measures brain oxygenation and metabolism using a state-of-the-art optical and electrical neuroimaging device optimised for studying the developing brain. I will map typical NVC across sensorimotor domains using novel multimodal analysis pipelines (Aim 1), examine alterations in coupling in infants with risk for atypical neurodevelopment (Aim 2), establish mechanistic utility by metabolic brain imaging of children with known disorders of metabolic function (Aim 3), and diagnosed autism (Aim 4). This work will illuminate the role of energy supply and demand in typical and atypical brain development.
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| 26/04/2022 |
£530,787 |
MANCHESTER METROPOLITAN UNIVERSITY |
Cerebral palsy is one of the most common neurological childhood disabilities. Children and young people with cerebral palsy have an increased prevalence of mental health problems, such as anxiety or depression, because of reduced peer social engagement and isolation. Middle childhood (age 7-10) is a critical time when children develop peer social skills to prepare them for adolescence and adulthood. However, most interventions address physio-therapeutic needs. More focus on peer socialisation is needed and could have life-altering benefits for children with cerebral palsy. This project proposes to research enhancing peer socialisation through the application of relational play, and how this can be delivered through design-based interventions.
The project will investigate: 1) the mechanisms of peer socialisation, specifically social engagement and social-emotional wellbeing of children with cerebral palsy aged 7-10 years; 2) means of promoting peer socialisation through design-based relational play to empower children in social situations and facilitate their holistic development. The project will use participatory action research to involve children actively in co-designing child-friendly design solutions; test the implementation of selected design interventions; and develop design guidelines and policy for empowering children to initiate, develop and maintain peer social interaction to develop peer social skills and promote social-emotional wellbeing.
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| 26/04/2022 |
£1,079,237 |
UNIVERSITY COLLEGE LONDON |
My research vision ultimately aims to identify targeted treatments for respiratory viral infections, through a detailed understanding of the molecular interactions between the virus and host. Here, I propose to study influenza A virus and SARS-CoV-2 and the role of viral structure and viral-host ribonucleoprotein (RNP) condensation. In particular I will assess the impact on the viral infection cycle and also differences in host responses from normal and smoking-damaged lungs. My hypothesis is that interactions between dynamic viral RNA structures and host RBPs within airway epithelial cells are crucial to viral RNP condensation and the molecular response to infection, and that they are impaired in disease.
I have three key goals:
Establish my functional genomics molecular toolkit in a new patient-derived airway epithelial cell infection model system and obtain global measurements of structure and condensation
Develop a new suite of methods to characterise the dynamics of viral RNA structures and interactions with RBPs at single molecule resolution
Derive an in silico model of RNP condensation and clinical phenotype through iterative integrative computational analysis and machine learning methods and predict high-confidence potential therapeutic targets.
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| 26/04/2022 |
£512,152 |
MAKERERE UNIVERSITY |
Following global declines in malaria burden due to large-scale interventions, highest-burden countries, especially in sub-Saharan Africa, are most affected by stalled progress on further declines. Renewed international strategies for control interventions currently emphasize targeted approaches, supported by enhanced surveillance. To inform these targeted approaches and assess their impacts, small-scale spatial assessments of malaria risk that utilize longitudinal data are vital but need to be thoroughly evaluated to be exploited. Using geostatistical models, I will study the concurrent space-time distribution of incidence and/or risk of malaria at multiple geographical scales to assess the impacts of targeted control interventions across all regions in Uganda, following the initiation of the global high-burden to the high-impact initiative. To do this, I propose using Health Management Information System (HMIS)-based incidence of malaria, estimated at health facility catchment level. Together with environmental covariates, geo-spatial attributes data, and geo-located health facilities, I will: use AccessMod (a WHO supported tool) to estimate health services accessibility and health facility catchments; estimate monthly catchment-level incidence rates using Bayesian conditional autoregressive (CAR) models; investigate attributable impacts of targeted control interventions on incidence using counterfactual analyses; and, regularly share output risk maps with the national malaria control division (NMCD) for policy support.
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| 26/04/2022 |
£408,929 |
UNIVERSITY OF CAMBRIDGE |
Human cytomegalovirus (HCMV) is a persistent, ubiquitous pathogen that causes morbidity and mortality for immunosuppressed and immunonaïve people, particularly in transplant settings. Persistence is underpinned by latency: maintenance of viral genomes without virus production in CD34+ haematopoietic progenitor cells and CD14+ monocytes. HCMV can reactivate as these undifferentiated cells migrate and differentiate in peripheral tissue. This differentiation occurs in transit from bone marrow through the bloodstream to deep tissue which involves changing oxygen tensions, causing hypoxic and mitochondrial stresses on the infected cell, producing reactive oxygen species (ROS). Despite transplanted tissues experiencing similar hypoxia, hypoxia's role in latency and reactivation has not been studied. My preliminary data show that hypoxic, mitochondrial and ROS stresses induce HCMV reactivation in vitro, more so than the paradigmatic mechanisms: cellular differentiation and inflammation. I aim to understand how these stresses cause reactivation at the molecular level, focusing on hypoxia-inducible factor (HIF)1alpha-mediated epigenetic changes in the HCMV genome and changes in infected cell metabolism. I will identify how HCMV modulates cellular responses to hypoxia-induced stresses to support persistence. This work will build a foundation for understanding reactivation under physiological conditions, opening new avenues to suppress HCMV disease in vulnerable patients.
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| 26/04/2022 |
£677,693 |
UNIVERSITY OF EDINBURGH |
Tertiary Lymphoid Structures (TLS) are immune cell aggregates that are found within some tumours. Mature TLS are composed of a functional B cell germinal centre and a T cell zone, and myeloid cells including follicular dendritic cells and macrophages. Recently, TLS have been shown to be biomarkers of prolonged patient survival and enhanced response to immune checkpoint blockade, although the mechanisms remain to be elucidated.
The phenotype and function of TLS-associated macrophages (TLS-TAMs) remain unknown. I will establish the phenotype of TLS-TAMs, in terms of surface markers, chemokine secreted, interaction with other cells and functionality. I will evaluate how TLS-TAMs affect patients’ survival and response to immunotherapies. I will describe how TLS-TAMs are affected by macrophage-targeted cancer therapies. In a pan-cancer approach, this work will be conducted in various cancer types (colorectal, endometrial, ovarian and breast cancers) to evaluate whether TLS-TAMs vary between malignancies or have common features. I will use state-of-the-art spatially-resolved transcriptomics technologies. I will engage in computational method development to facilitate the analysis of this emerging data type.
My project will help understand how TLS affect clinical outcome and allow to identify patients that could benefit from immunotherapy and macrophage depleting therapies to guide clinician’s therapeutic decision-making.
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| 26/04/2022 |
£368,988 |
ABRASCO |
Unhealthy sleep and early-life adversity during childhood and adolescence might trigger long-lasting deleterious effects on people´s mental health. There is evidence to support that sleep affects mental health. Few studies investigate this relationship across the lifecourse using a biosocial perspective. I aim to investigate the association between sleep and mental health throughout development, considering genetic mechanisms and potential interactions between sleep genetics and stress (evaluated as self-report and cortisol concentration). I intent to use data from 4231 participants from the 2004 Pelotas Birth Cohort Study. Self-reported early-life adversity and sleep information was collected since age 12-months old. Mental disorders were evaluated using The Development and Well-Being Assessment (DAWBA) since participants were 6 yrs, when sleep-actigraphy information and saliva samples (for DNA extraction) were also collected. Cortisol will be extracted from hair samples collected at 15-years. The next assessments are due at 18-years. I intent to collect young adult data to address the gap in our knowledge about sleep and mental health across the lifespan. Additional information about causality in sleep-mental health association, critical/sensitive periods shifting these health outcomes during the lifespan, biological mechanisms and sleep-polygenic components and environmental interaction leading to mental health will be provide by this proposal.
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| 26/04/2022 |
£561,844 |
UNIVERSITY OF OXFORD |
Flaviviruses are globally distributed pathogens without currently available effective control measures. Flaviviruses trigger extensive membrane rearrangements of the host’s endoplasmic reticulum, which generate replication organelles (ROs). I will address the longstanding question of how flaviviruses reorganize cellular resources and signaling platforms to avoid immune detection and reproduce within the RO. RO formation depends on host organelles including the endoplasmic reticulum, mitochondria and lipid droplets. These are connected through contact sites, which regulate organelle homeostasis and immune signalling, and are altered during infection. The molecular mechanism of contact site remodelling and its significance in flavivirus infection and associated immune response, however, has been understudied. I will combine biochemical, imaging and genetics-based techniques to map the flavivirus-induced contact site changes (Aim 1); analyse their requirement for virus propagation (Aim 2); and involvement in immune signalling subversion (Aim 3). This will generate a comprehensive mechanistic understanding of the importance of organellar interactions during flavivirus infection and associated innate immune responses. Being universal for (+)RNA virus propagation, insights into RO formation will highlight important differences between viruses and inform of potential therapeutic targets. Ultimately, this project will increase the understanding of flavivirus infection and the biology of the underlying organellar networks that support it.
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| 26/04/2022 |
£472,465 |
UNIVERSITY OF OXFORD |
SARS-CoV-2 has revealed serious inadequacies in how we track infectious disease spread. Despite progress in quantifying individual-level biomarkers at scale, inferring transmission dynamics to inform public health decisions still largely depends on counting cases. Recently, I showed that individual-level viral load measurements from a single cross-sectional sample of RT-qPCR data can accurately estimate an epidemic’s trajectory, overcoming many limitations of case count-based surveillance. Here, I will build a new generation of outbreak analytic tools, leveraging individual-level immunological and pathogen titres to robustly estimate transmission dynamics. First, I will integrate virologic and serologic data from the UK’s SARS-CoV-2 surveillance studies to create a new modelling framework coupling within-host viral and antibody kinetics with population-level dynamics. Using this framework, I will evaluate prioritization of different surveillance strategies across pandemic phases. Second, I will develop new epidemiological inference methods harnessing biological kinetics, validated using UK SARS-CoV-2 data, and evaluated for use in resource-limited settings. Finally, I will integrate viral load data with phylodynamics to improve the rapid characterization of emerging viral variants. Overall, this research will advance how we use individual-based information for infectious disease surveillance, establishing the study of viral load dynamics, or viroepidemiology, as a key tool alongside seroepidemiology and phylodynamics.
|
| 11/04/2022 |
£7,595 |
NATIONAL INSTITUTE OF PSYCHIATRY RAMON DE LA FUENTE MUñIZ |
The Global Forum 2021 meeting highlighted the impact of stigma on people with mental health problems and the challenges with poor social integration. The stigma-discrimination complex, (CED), includes stigma, prejudice, and stereotype which could influence the language and attitudes assumed by the researcher. The investigator should strive to find ways to communicate with people who may have diverse beliefs about the cause of their mental illness. Failure to do so can increase the vulnerability of study participants, thereby compromising informed decision-making.
The "Asociación de Médicos Egresados del Instituto Nacional de Psiquiatría" (AMEINP) and the International Network for Stigma Reduction (RED_ESTIGMA) with the support of some Latin American participants in the Global Forum on Bioethics in Research (GFBR) propose a seminar/workshop in Mexico City to enhance the roles and skills of researchers, members of scientific societies and Research Ethics Committees (CEI, for its acronym in Spanish) to reflect, analyze and understand the ethical duty to evaluate and address the CED of mental health. It seeks to analyze some approaches used for cultural understanding of stigma towards people with mental health problems and review language strategies that researchers can adopt to mitigate or address CED, ensuring its implementation according to ethical standards
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| 11/04/2022 |
£6,962 |
UNIVERSITY OF BOTSWANA |
Research involving people with mental health conditions (PWMHC) has its unique ethical challenges. Conducting research among human participants requires obtaining informed consent. However, PWMHC may have impaired decision-making capacity, which may invalidate consent. Often, surrogates are resorted to for consent which may undermine the autonomy of PWMHC. As a result, this study investigates participants' opinions from Low-and-Middle Income Countries (LMICs) on informed consent for research involving PWMHC. It is expected that the outcome will contribute to academic literature and discussions on this issue.
This study will be in three stages. The first will be a systematic review of empirical studies on informed consent for research involving PWMHC. This will guide the second study, which will utilise qualitative methods to explore the views of patients with psychosis and their caregivers on informed consent for research involving PWMHC. In-depth interviews will be conducted among 15 patients and caregivers dyads who will be purposefully selected from Sbrana Psychiatric Hospital (SPH) in Botswana. The third will involve in-depth interviews with 15 key stakeholders involved in mental health research and policy. Data will be collected using an interview schedule developed and piloted by the researchers and analysed with the NViVo Software using the Framework Method.
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| 11/04/2022 |
£7,455 |
GEORGE INSTITUTE FOR GLOBAL HEALTH (INDIA) |
Research on trans communities including transwomen is extremely limited in India, inspite of the huge social and political injustices that they have suffered over ages. Trans communities are often a closed community and in India many of them become part of 'gharanas'. The gharana system is an institutionalized lifestyle, which defies the heteronormative idea of a family and is a place that makes transgenders feel safe and confident in their expression of identity. However, not everyone belongs to a gharana.
In this project we will collaborate with a transwoman-led non-governmental organization in Kolkata, India. The main objective is to understand the ethical challenges of conducting research on transwomen and to develop a framework for undertaking ethical research with transwomen in India using qualitative research methods. We will interact with transwomen, understand ethical issues in conducting research with transwomen and identify and validate an appropriate ethical framework in consultation with transwomen using qualitative research methodology. We will use a feminist approach and the standpoint theory that postulates that an individual's perspectives are shaped by their social and political experiences. Narrative analysis of the qualitative data will be used to develop the final ethical framework in consultation with transwomen, prior to dissemination.
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| 11/04/2022 |
£6,911 |
NO ORGANISATION |
The aim of this project is to develop a guidance document on how CRPD obligations regarding legal capacity and the process of informed consent of people with mental disabilities should be understood in research scenarios on the basis of a regional ethical discussion with the relevant stakeholders of Latin America (LA). The key goals are:
Discuss the impact of the CRPD committee comment Nº 1 on the processes of informed consent of potential participants with mental disabilities, and more generally on the conduct of research involving people with disabilities in the LA region.
Identify and assess tensions, conflicts, and agreements between article 12 of the CRPD and the CIOMS guidelines in order to find the best ways to understand both and implement them into national research ethics frameworks to ensure the ethical conduct of research involving people with mental disabilities.
Provide an ethics guidance on the conduct of research involving people with disabilities to ensure that it adheres to international ethical standards in LA.
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| 11/04/2022 |
£7,583 |
JOS UNIVERSITY TEACHING HOSPITAL |
The prevalence of children and adolescents (C & A) with mental health conditions is increasing globally. More attention is given to infectious diseases and a paucity of mental health research on C & A exists. This area remains neglected because of lack of effective governance, particularly in LMICs. Effective C & A mental health system is dependent on research governance structures, necessitating the need for an effective governance framework which guides ethical considerations in research and health systems for C & A.
This study aims to assess the extent to which governance frameworks impacts mental health research on C & A, identify governance framework beneficial for C & A in LMICs and generate a consensus that examines indicators which guide ethical practice and good governance.
A systematic review will be used to identify existing governance framework. Thereafter, a mixed method Delphi process comprising minimum 30 experts who meet the following criteria: diversity of expertise, independence, decentralization, and aggregation from LMICs and HICs across the six regions of the World Health Organization will be used to determine a consensus for effective governance for mental health research on C & A.
Outputs generated from this study will be disseminated via seminars/ webinars conferences, publications, and academic and non-academic meetings to facilitate adoption by stakeholders and policymakers.
|
| 18/01/2022 |
£190,773 |
LANCASTER UNIVERSITY |
Despite being a central focus in research, policy, and practice in recent years, health inequalities have widened and are being further exacerbated by the Covid-19 pandemic. The reasons are multiple and complex, but there is increasing concern that the framing of health inequalities may be contributing to implementation challenges. This is important because while the health sector is not alone in grappling with socially-driven inequalities in outcomes, there is a persistent desire to embed a ‘health inequalities’ perspective across all sectors and policies. The aim of this research is to employ theoretical and methodological tools from framing analysis to explore, compare, and critically reflect upon different ways in which inequalities in outcomes are framed across multiple sectors beyond health. These sectors include early years education, youth justice, and housing, and, for each, data will be collected through documentary analysis of academic literature and policy reports; semi-structured interviews with actors working to reduce inequalities; and group 'framing reflection' exercises. The research will produce novel comparative analyses, and interdisciplinary reflections, on contrasting ways of framing inequalities. These findings will illuminate the potential for more cross-sectoral accounts of inequalities that would lead to greater collective understanding and action on the cross-cutting underlying causes.
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| 18/01/2022 |
£277,888 |
UNIVERSITY OF DURHAM |
What is ‘normal’ health?
The way health scientists answered this question changed in the twentieth century, as they relied more heavily on social categories to measure health. These categories, sometimes termed reference-classes, rely on parameters such as age/weight/height/sex/gender/race/class. They still guide how providers distribute care and decide who deviates from ‘normal’ enough to count as disabled. Genetic research provides crucial theoretical scaffolding that legitimates their use. This project will demonstrate how proof of inheritance was established in genetic disability research and how proof of injury/illness was demonstrated in compensation cases. It investigates which categories were used to establish disability causation and interrogates biases inherent to the understanding of ‘biological’ versus ‘social’ determinants of health.
This project therefore moves beyond considering disability as normative, to question the extent to which the categories used to define it are normative. Considering disabled experiences and the use of categories in compensation moderation demonstrates the longer-term consequences of categorisation choices and shows how data has been used to obscure health inequalities related to society and the environment. My innovative interdisciplinary approach will reveal how both disability and eugenics relate to a history of categorizing inequality through obscuring the relationship between the environment and the individual.
|
| 18/01/2022 |
£264,274 |
UNIVERSITY OF STRATHCLYDE |
If mental illness is understood as a deviation from a norm, what prevents people who challenge social norms from being diagnosed with mental illnesses? In the 1960s, as mainstream psychiatric institutions, diagnoses and forms of treatment came under attack from antipsychiatrists across Western Europe and North America, evidence that dissidents were being sent to psychiatric hospitals for expressing views that challenged social norms in the USSR began to emerge.
This project will analyse international campaigns against the political abuse of psychiatry in the USSR, asking what they reveal about psychiatry across the iron curtain at a moment when its legitimacy was being questioned. It will explore politicised debates among psychiatrists about whether similar abuses of psychiatry was taking place elsewhere – in other state socialist contexts, in right-wing dictatorships in Latin America or in Apartheid South Africa – and examine antipsychiatric discussions that compared Soviet psychiatric practices to those in Western liberal democracies.
By probing unstable definitions of four pairs of concepts central to psychiatric and popular discourse on this issue - coercion/freedom, abnormality/normality, madness/sanity, dissent/conformity - this project will demonstrate how the issue of Soviet punitive psychiatry took on divergent, even contradictory, meanings across national borders and political affiliations.
|
| 18/01/2022 |
£292,778 |
UNIVERSITY OF OXFORD |
Parents often describe the enduring impact of their interactions with health care professionals (HCPs) following the diagnosis of a life-limiting fetal condition in pregnancy. These central relationships between parents and the HCPs caring for them in the antenatal period are crucial to how families tackle difficult decisions. Families in this situation are increasingly being offered antenatal palliative care to give them the support they need to plan the future care of their baby.
This research aims to provide a comprehensive analysis of the ethical considerations in providing antenatal palliative care with an eye to informing practice guidance. This will be achieved by using an ethics of care framework to understand the ethical dimensions of patient-caregiver relationships in antenatal palliative care encounters. This project will involve three work packages:
A comprehensive literature review
An empirical ethics study involving observations, audio recordings of antenatal consultations, interviews and focus groups with parents and HCPs
Ethical analysis using an ethics of care framework
This work will inform both clinical guidance and training for HCPs working at the frontiers of palliative care. Involving families and providers at the outset will ensure that the often hidden moral voices of parents and clinicians shape the way forward.
|
| 18/01/2022 |
£247,837 |
UNIVERSITY OF MANCHESTER |
During the current COVID-19 pandemic, the Chinese government celebrated face masks as symbols of modernity and national pride. This project hypothesizes that face mask’s authoritative position in China’s epidemic control today is rooted in Chinese history, specifically the semi-colonial period, when foreign powers and internal political forces were competing for control of China. This project argues that this narrative, of mask-wearing as an integral part of Chinese culture and politics today, is a modern myth. To unpack this myth, this study explores the parallel policies of the British and Japanese Empires, and China’s Nationalist and Communist Parties, in promoting mask-wearing as a form of epidemic control. This project will produce a comprehensive account of the social history of medicine on mask-wearing in the semi-colonial Republican period (1912-1949) in which it asks, ‘How did British and Japanese colonialism, and China’s domestic politics, contribute to masks’ authoritative position in semi-colonial China?’ To answer this central question, the project is structured chronologically around four themes: 1) Masks, race, and epidemics in the 1910s Shanghai International Settlement; 2) The national recommendation of mask-wearing in the 1929; 3) Japanese military promotion of masks in Manchuria (1930s-1940s); and 4) Chinese Communists’ wartime mask-wearing campaigns.
|
| 18/01/2022 |
£197,028 |
UNIVERSITY OF MANCHESTER |
This project offers new approaches to the history of 20th century medico-legal borders and puts migrants’ voices at its centre. Drawing on narratives of mental, emotional, and physical disorders as produced in accounts by arrivals to Britain, Egypt, and Palestine, the project will analyse the varied ways in which migrants understood and negotiated infirmities and border control. I will do this by bringing the conceptual framework of biocredibility together with a pathographical reading of precarious migrants’ historical sources. Focused on a period when imperial authorities accelerated the use of biopower as a tool to manage borders, the research will foreground the transnational circulation of knowledge among refugees, displaced persons, and low-waged labours labeled as ‘medically undesirable’. The empirical research investigates three linked questions: how did the medically undesirable justify their physical and mental illnesses and the suffering they experienced due to this label and to deportation? How does the focus on biocredibility and the reliance on subaltern voices alter or contextualise understandings of colonial borders and public health? How did migrants’ medical knowledge, or lack thereof, affect their relationship with states? The project will make a significant contribution toward understanding the responses to the medicalisation of imperial and colonial borders.
|
| 18/01/2022 |
£176,342 |
UNIVERSITY OF MANCHESTER |
This project focuses on the Soviet Red Cross to examine how Soviet society grappled with successive public health crises after 1953.
Its key goals are:
To understand the place and meaning of medical volunteerism within a socialist welfare state.
To examine how Red Cross volunteers conceptualised their work within the ideologically charged atmosphere of the Cold War.
To assess how practices of medical volunteerism varied across the multi-ethnic USSR.
To develop a model of ‘red humanitarianism’ that brings the USSR into global histories of medical humanitarianism.
The period 1953–1991 saw profound innovation in Soviet medical sciences, including mass production of antibiotics and widespread vaccination. However, severe population depletion, pervasive industrial pollution, and chronic underfunding of healthcare spurred increasing rates of infectious diseases, maternal and infant mortality, and declining life expectancy. In response, millions of Soviet citizens donated time and money to the Red Cross. The organisation tackled healthcare crises that were exacerbated by state policy, whilst remaining dependent on state approval and resources. Combining archival research and oral history, I will explore the meaning, scope, and motivations behind medical volunteerism in a society where compulsory citizen participation was vital to sustaining state healthcare services.
|
| 18/01/2022 |
£331,217 |
GOLDSMITHS, UNIVERSITY OF LONDON |
If we take death as the ultimate harm, the UK has never been a more harmful place for people who use substances. Death rates from both drug- and alcohol-specific reasons are at their highest ever level. Moreover, some areas are experiencing their worst HIV outbreaks among injecting drug users in 30 years, and alcohol-related liver disease is rising steeply. As Covid-19 works to ‘expose and amplify’ existing inequalities, the fear is that these deaths/harms will increase further. However, Covid-regulations have also brought drastic changes to the sector, including long-sought flexibilities in treatment options and regimes. Prominent practitioners refer to these as ‘ripping up the rulebook’ and a ‘natural experiment’ with ‘potential for a lot of learning’. This project studies these experimental practices and what they open-up for improving treatment attractiveness and responsiveness. It maps experiments in service provision through a UK-wide survey and carries out ethnographic inquiry to establish how these practices re-work treatment and the role of service users’ own experimentations in these processes. Extending this experimentality through its methodology, the project brings together key stakeholders in a theatre-informed workshop to quite literally ‘rip up the rulebook’ (clinical/policy guidelines) to provoke further thinking and action on treatment possibilities.
|
| 18/01/2022 |
£266,182 |
UNIVERSITY OF CAPE TOWN |
The calls to decolonize health research in Africa are growing. Two key components of the quest towards decolonization are epistemic justice (equal participation in knowledge production and being respected as a knower) and transformation (by seeing and experiencing others authentically). There is increasing recognition of the importance of epistemic justice and transformation in global health context.
Within infectious disease research (IDR) in the African context, responses to the quest for epistemic justice and transformation place considerable emphasis on inclusion (understood transactionally, meaning the emphasis is on representation). There are limitations to flattening the kind of inclusion suggested in nuanced accounts of epistemic justice and transformation to transactional inclusion. This leaves unexplored whether/how/what kind of inclusion is sufficient to fulfil the vision of decolonization
This project critically explores narratives and practices around inclusion in IDR in Africa and appeals to values in African philosophy to build/articulate a scientific imaginary of the inclusion that we need in light of the broader aim of decolonizing global health research.
To achieve this aim, this mostly conceptual project applies three under-explored theoretical frameworks (constructivism, reflexive positionality and relationalism) to gather evidence of transactional inclusion and develop normative accounts of inclusion that transcend transactional forms.
|
| 02/12/2021 |
£33,988 |
UNIVERSITY COLLEGE LONDON |
8,000+ Venezuelans living with HIV have fled their country and its crumbling health-system in search of life-saving medication. Yet, lived realities of pharmaceutical infrastructures and obstacles of access are scarcely known in host countries where they migrate, resulting in invisiblised migrant-experience and unaddressed HIV/refugee-related stigma.
How the project will look:
In collaboration with the Centre-for-Excellence-in-Chronic-Diseases(CRONICAS) at the Cayetano-Heredia-University(UPCH), Lima Museum-of-Memory,-Tolerance- & -Social-Inclusion(LUM), UCL-Culture, ONIGO-design-studios, and migrants living with HIV, we will place digitally-literate Peruvian & UK publics directly into migrants ‘shoes’ so that they can experience authentic pharmaceutical obstacles, develop deeper understandings of migrant experience, and engage meaningfully with the research. This will be achieved through developing a virtual ‘pharmacy escape-room’ (VER), designed collaboratively with HIV-positive Venezuelans, to tell real-world stories and involve the public in migrant worlds with the decisions/obstacles they face on a ‘lived’, experiential level. Post-initiative, collaborative discussions will be held between migrants and VER ‘players’, encouraging the public to greater value such people-centred health research, empower those with HIV to communicate their health-struggles, and address the HIV empathy gap through collaboratively brainstorming stigma reduction strategies.
What we will achieve for:
Research - This activity will enrich the research by feeding back collaboratively produced data surrounding HIV/migrant stigma reduction into the main project.
Collaborators- Migrants will be empowered through communicating lived experiences and pharmaceutical obstacles to the public and reflecting on changing perceptions in post-activity collaborative roundtables.
Public Participants – HIV empathy gap will be collaboratively addressed, incorporating pre- and post-gameplay public perspectives on stigma reduction and community integration.
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| 02/12/2021 |
£42,665 |
KING'S COLLEGE LONDON |
The INDiGO trial will test the efficacy of micronutrient interventions on developmental outcomes in young infants. If our trial shows positive benefits the next step will be studies of effectiveness with a view to integrating targeted nutrition interventions in early infancy, beyond exclusive breastfeeding. As part of this vision, we recognise that other aspects of nurturing care, such as responsive caregiving, are also important determinants of neurodevelopmental outcomes, such as school readiness and mental health. Currently, most health messages delivered at antenatal and postnatal care clinics in The Gambia focus on more immediate health issues, with the aim of reducing morbidity and mortality in the short term. To ensure the outcomes of the INDiGO trial are fully impactful, we will work with the local community in The Gambia to determine how to most appropriately promote and enable nurturing care practices within routine health care.
In phase one, we will use qualitative research approaches, to obtain a better understanding around caregiver, community and stakeholder perceptions on nurturing care. This will include (i) what is perceived as adequate and optimal care, (ii) understanding of the five aspects of nurturing care, and (iii) the barriers to and facilitators of nurturing care practices. In the second phase, with continued involvement from community members and stakeholders, we will co-produce and pilot a communication tool for implementation across antenatal care (ANC) clinics in The Gambia, aimed at promoting the concept of nurturing care in infancy and early childhood having life-long and intergenerational benefits.
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| 02/12/2021 |
£49,350 |
AMSTERDAM INSTITUTE FOR GLOBAL HEALTH AND DEVELOPMENT |
Antimicrobial resistance (AMR) disproportionately impacts low- and middle-income countries (LMIC) and overcoming AMR requires public understanding and engagement (1,2). The ROTA-biotic project evaluates the impact of vaccines on antibiotic usage in Zambia and Ghana. Caregivers in Zambia and other LMICs are often insufficiently informed about the hazards of inappropriate antibiotic use and AMR (2). This public engagement proposal aims to increase knowledge and awareness of AMR among caregivers of children under-5 using school-going children. To achieve this goal, we propose a youth-led intervention in Zambia where high-school children educate primary caregivers of under-5 children about AMR using narratives and performing arts. Our work will demonstrate implementation and outcomes of a process by which children will:
Be engaged in the co-creation of a knowledge-based intervention with social scientists, local actors and artists, teachers of basic science, and community-based safe motherhood action groups (SMAGs)
Be included in a research process, specifically recruitment, data collection and interpretation of findings, and
Lead the implementation of intervention activities created by them and informed by caregivers and other stakeholders
This will result in the production of visual materials and performing arts set/s aimed at educating caregivers on the concept of AMR and their role in controlling resistance in their children. Our work will facilitate broader dissemination of impactful AMR storylines within ROTA-biotic sites, schools, and ministries of health and education in both Zambia and Ghana.
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| 02/12/2021 |
£99,798 |
KING'S COLLEGE LONDON |
This project will culminate in a series of co-produced immersive performances for the public which explore the idea of neurodiversity and the experiences of neurodivergent individuals. Musical compositions, which sonically and verbally depict neurodivergent experiences, will raise up neurodivergent voices and engage neurotypical audiences to reflect on what it means to be neurodivergent. Audiences will be encouraged to contemplate how we conceptualise individual differences in how our brains function, and to challenge negative stereotypes surrounding neurodevelopmental conditions (e.g., autism, ADHD).
The project will commence with a series of online interviews[1] with people who identify as neurodivergent to explore the concept of neurodiversity: how neurodivergent people experience the world differently, what may underpin these differences, and how does the neurodiversity approach differ from the traditional medical model. The project team will attend a co-production workshop to reach a consensus on themes that emerged in the interviews that should be showcased in the final performances. From this, musical interludes will be created based on the agreed themes. In parallel to the creation of interludes, a Neurodiversity Framework document will be created to summarise the neurodiversity approach, key themes from focus groups and lessons learnt from the project. This will serve as a guide to others interested in co-production projects with neurodivergent communities. A short film of the project will be disseminated through social media and public film festivals nationwide to ensure far-reaching impact.
[1] We will also offer alternative methods of engagement (e.g., written, voice notes) to ensure the project is inclusive
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| 02/12/2021 |
£83,519 |
UNIVERSITY COLLEGE LONDON |
To date there is little accessible and relatable information about the neuroscience of OCD for those affected, especially for those who could benefit from this information the most: young people and their parents at early stages of the illness. This project, designed in collaborative working group sessions with lived experts and in partnership with OCD Action and the International OCD Foundation, will overcome the prevailing disconnect between neuroscience research and the OCD community through a co-productive and explorative practice.
By the end of this project we will have:
Built two engaging digital toolkits – one for young people (YP) with OCD, and one for their parents – that will bridge the gap between neuroscience and the personal experiences of those affected by OCD.
Tailored our toolkits to the needs of our target audience and shaped future research proposals in collaboration with patients/carers/charities through a series of ‘hypothesis exchange’ workshops.
Established a strong relationship between key community gatekeepers/lived experts and the research team.
Embedded resources developed into existing support networks in the UK and internationally through partnerships with OCD Action (UK’s largest OCD charity) and International OCD Foundation (largest international OCD organisation).
Our vision is that these toolkits will help establish an understanding that OCD is a brain illness that can be treated. By creating engaging, interactive toolkits for YP with OCD and parents, we will challenge misconceptions of OCD and provide vital resources identified (by both our working group and partner charities) as a gap in OCD support.
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| 02/12/2021 |
£43,097 |
QUEEN MARY UNIVERSITY OF LONDON |
Research enrichment will have enhanced collaboration and co-creation processes with young autistic adults through a series of activities aimed to engage particular constituent groups.
A visual essay film narrated by autistic contributors conjuring the imagined experience of autistic children in clinical films of 1950s, will have reached film festival audiences. It will have engaged psychologists through a feature on the BMJ medical humanities site. The podcast, featuring a conversation between a neurodivergent team and a guest film professional discussing a film, will have connected an autistic perspective with cultural influencers. Instagram and QR code projects showcasing the method of film practice co-creation will have shared with industry professionals the work of autistic creatives, proposing a progressive and inclusive example of how films, and art can be made.
The shared co-creation methodology exists as a model that can be taken up by autism-focused charities and cultural organisations. The podcasts have profiled the professional work of early career autistic cultural commentators and the visual essay has enabled important debate to take place with psychologists and clinicians. Research discoveries will have reached an extensive general arts and film audience; our special events and workshops have offered a nuanced understanding of neurodivergence, benefiting constituencies who have limited narratives of autism, and research enhancement activities will have reached a large number of the neurodiverse community, including carers.
The visual essay, podcasts, publication, and co-creation methodology will have impacted the field of Film Studies, enabling neurodiverse perspectives to act as a prism for re-thinking film pedagogy.
|
| 30/11/2021 |
£1,813,555 |
UNIVERSITY OF BRISTOL |
Cell competition is a fundamental quality-control process that leads to elimination of less fit cells from tissues. The first competition type discovered was Minute cell competition, where cells heterozygous-mutant in ribosome protein genes (RPG) - known as Minute in Drosophila - are eliminated by wild-type cells. Minute cell competition may be frequent in diseases characterized by aneuploidy, like cancer, where deletions of large genomic regions often lead to RPG loss.
The work proposed will advance our knowledge of the mechanisms of Minute cell competition and unveil its possible role as a tumour vulnerability. I will:
a) Elucidate the mechanisms of Minute cell competition in mammals. We will establish mammalian Minute cell competition assays to study it mechanistically and elucidate if oxidative and proteotoxic stress, which cause Minute competition in flies, lead to cell competition in mammals.
b) Identify how Nrf2, master-regulator of the oxidative stress response, causes the Minute loser status. Recently we identified many novel Nrf2 target genes that cause competition, including importantly metabolic enzymes. Focusing on metabolism, we will identify small-molecule modulators of cell competition that could be used therapeutically.
c) Use human cancer bioinformatics and Drosophila genetics to elucidate how RPG-mutant human cancers overcome their loser status.
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| 30/11/2021 |
£3,491,551 |
UNIVERSITY COLLEGE LONDON |
This proposal aims to understand how the neural circuits of the cerebellum implement computations that drive learning. The cerebellum has long been proposed to evaluate predictions about the consequences of actions using error signals delivered by the climbing fiber, a form of supervised learning. Our recent discovery that the cerebellum also exhibits signals associated with reward has transformed our view of cerebellar function and suggests that the cerebellum may also implement reinforcement learning. We will identify the sources of cerebellar reward and error signals and examine how they work together during learning in cerebellar and downstream circuits using an unprecedented combination of tools: circuit-wide and brain-wide recordings of activity using Neuropixels probes, anatomical tracing of input and target structures, and all-optical interrogation using 2-photon imaging and 2-photon optogenetics to provide causal links between activity in functionally defined cerebellar microzones and behaviour. These experiments will reveal how the cerebellar cortex interacts with other brain areas during learning; they will provide crucial constraints for constructing models of cerebellar cortex; and they will reveal clear targets for manipulation of an important neural circuit that may ultimately have translational relevance, particularly for treating the disorders of movement and cognition that may have cerebellar origins.
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| 30/11/2021 |
£1,863,430 |
UNIVERSITY OF YORK |
The research will focus on understanding how dsDNA viruses fill their capsids with DNA. The main emphasis is on using structural approaches, mostly Cryo-EM, although we will also use complementary biophysical techniques including activity/binding assays, to define composition and stoichiometry of protein-nucleic acid complexes, in addition to the affinity of the interaction.
Key goals:
To understand the mechanism of DNA translocation by dsDNA viruses that fill their capsid with DNA using a terminase protein. This research will be based on in vitro packaging systems that we have established for bacteriophages HK97 and P23-45; and will also utilise crAssphages isolated from the human gut.
To understand the structure-function relationship in FtsK-like DNA packaging motors present in another large class of dsDNA viruses comprising bacterial tectiviruses, corticoviruses and eukaryotic poxviruses. This research will be performed using corticovirus RC12 and tectivirus PhiKo.
|
| 30/11/2021 |
£3,500,000 |
UNIVERSITY OF EXETER |
This proposal builds on novel insights from our recent genetic discovery that a primate-specific KRAB Zinc Finger Protein (KZFP), ZNF808, is required for human pancreatic development. Our preliminary studies show that ZNF808 silences primate-specific MER11 transposons and that these need to be controlled for normal pancreas development, underscoring that this process differs between humans and rodents.
This project brings together an international and interdisciplinary group of experts to uncover the role and implications of human-specific regulation in pancreatic beta-cell development. We will:
1. Dissect the interplay between ZNF808 and other primate-specific KZFPs, MER11 elements, and transcription factors in pancreas development. This will use stem cell-derived models of beta-cell differentiation coupled with genome editing, functional genomics and computational approaches;
2. Sequence and analyse the genome of patients with diabetes to identify novel genes essential for beta-cell development and causal mutations in regulatory elements, focusing on transcription factor binding sites within primate-specific MER11 elements;
3. Assess the impact of disrupted human beta-cell development by examining the phenotype, post-natal growth and metabolism of patients with mutations disrupting beta-cell development and fetal insulin secretion.
These investigations will provide essential new knowledge to propel scientific efforts aimed at cell-based therapies for people with diabetes.
|
| 30/11/2021 |
£1,092,568 |
UNIVERSITY COLLEGE LONDON |
This project has two main components, each exploring how the genome mediates our phenotypic responses to environmental pressures. The first component will develop new statistical methodology to pinpoint genetic sequence variants that have facilitated humans' ability to adapt over long-term time-scales to their environments, and hence are vital for influencing health. Specifically, this work will leverage large-scale cohorts (e.g. UK Biobank) containing people of mixed ancestry, whom typically are ignored in such analyses, to provide a substantial increase in the power to infer and characterise adaptation signatures. For the second project component, we will leverage available epigenetic data from hundreds of studies to identify loci that show high methylation variability across multiple tissues, ethnicities and ages, and for which methylation marks likely are established in the early embryo and stable throughout the life course. Cross-referencing such loci with published epigenome-wide association studies (EWAS) can indicate causal pathways whereby specific exposures modify methylation, which in turn influences health outcomes (e.g. disease susceptibility) throughout the life course. By combining both project components, we will test the hypothesis that these regions of variable methylation are conserved in human populations as a means to enable efficient adaptation to rapidly changing environments.
|
| 30/11/2021 |
£1,453,634 |
UNIVERSITY OF WARWICK |
Motorised intracellular transport allows cells to organise their contents, establish and maintain polarity and deliver building blocks to specific subcellular regions. It is achieved by kinesins and dynein that walk in a processive, unidirectional manner along microtubules. These transport motors also regulate the stability and arrangement of microtubule tracks. By sliding microtubules relative to each other, motors polarity-sort microtubules, generate pushing forces to induce morphogenesis events and advective flows for bulk cytoplasm transport. How motors switch between cargo transport and microtubule organising functions remains to be understood. We will dissect the mechanisms that activate the major transporters KIF1C and dynein for microtubule bundling and sliding in human cells. Because microtubule organisation requires motors to work in teams, we will aim to understand how these motors cooperate to generate large, collective forces and prevent a fruitless tug-of-war between opposite polarity motors. Finally, we will elucidate the prevalence and mechanisms of generating extensile forces in parallel microtubule arrays as these are the predominant arrangements in polarised cells, but only antiparallel sliding has been understood thus far. Success in this project will provide major insights into the mechanisms that establish and maintain cell polarity and why mutations in these motors cause disease.
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| 30/11/2021 |
£3,309,491 |
UNIVERSITY COLLEGE LONDON |
My ambition is to generate a neurological model that incorporates the many different ways that the brain can support language functions. Recovery from aphasia will then be formulated in terms of: (A) the availability of brain structures that could learn to support a lost function; and (B) factors that determine whether of not patients engage these structures.
In three work-packages, I will study very large samples of patients recovering from aphasia in the first weeks and months post-stroke.
(1) Task-based fMRI will identify the neural systems supporting each of 13 language tasks in patients who have damage to different parts of the normal language system.
(2) Anatomical MRI, with biophysical modelling, will investigate changes in tissue microstructure (e.g. iron levels, free water and neuronal density) and ask whether these changes occur in peri-lesional tissue and/or the neural systems observed with fMRI.
(3) The multiple non-lesion factors affecting early recovery (e.g. co-occurring cognitive impairments, clinical interventions, physical and mental health) will be investigated, controlling for lesion-site.
The neural systems identified in Work-package 1 will be incorporated into neurological models of language. Work-packages 2 and 3 will identify the factors that influence whether or not these systems are engaged during recovery.
|
| 30/11/2021 |
£1,353,295 |
UNIVERSITY OF LEEDS |
We discovered a molecular mechanism that regulates virus assembly in different families of positive-sense, single-stranded RNA viruses and the para-retrovirus Hepatitis B Virus. These viruses encompass multiple dispersed sequences/secondary motifs termed Packaging Signals (PSs) in their genomes (gRNAs) that have distinct affinities for their cognate coat protein (CP). This hierarchy of CP affinities defines a preferred assembly pathway, simplifying assembly in complex molecular environments and ensuring genetic robustness to mutation. In this research programme we will investigate a further major gRNA-encoded principle of viral infectivity. Virions are transport vehicles between host cells, that cannot afford to become too stable, or they would lose the ability to deliver their cargoes. It appears that PS-gRNA contacts rearrange in the fully assembled virion, preparing it for gRNA release in response to defined cues from the host cell. We will explore the role(s) of this "molecular frustration" in clinically-important viral lifecycles using a unique interdisciplinary combination of tools we have created. As PSs motifs are evolutionarily conserved across viral families, their interactions with CP lend themselves as targets for broad-spectrum anti-viral therapy, including an emerging Virus X. Insights into cargo encapsidation and release can also be exploited in vaccination and gene therapy.
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| 30/11/2021 |
£578,742 |
UNIVERSITY OF YORK |
We discovered a molecular mechanism that regulates virus assembly in different families of positive-sense, single-stranded RNA viruses and the para-retrovirus Hepatitis B Virus. These viruses encompass multiple dispersed sequences/secondary motifs termed Packaging Signals (PSs) in their genomes (gRNAs) that have distinct affinities for their cognate coat protein (CP). This hierarchy of CP affinities defines a preferred assembly pathway, simplifying assembly in complex molecular environments and ensuring genetic robustness to mutation. In this research programme we will investigate a further major gRNA-encoded principle of viral infectivity. Virions are transport vehicles between host cells, that cannot afford to become too stable, or they would lose the ability to deliver their cargoes. It appears that PS-gRNA contacts rearrange in the fully assembled virion, preparing it for gRNA release in response to defined cues from the host cell. We will explore the role(s) of this "molecular frustration" in clinically-important viral lifecycles using a unique interdisciplinary combination of tools we have created. As PSs motifs are evolutionarily conserved across viral families, their interactions with CP lend themselves as targets for broad-spectrum anti-viral therapy, including an emerging Virus X. Insights into cargo encapsidation and release can also be exploited in vaccination and gene therapy.
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| 30/11/2021 |
£1,655,328 |
UNIVERSITY OF GLASGOW |
To ensure accurate genome transmission, eukaryotes employ regulated DNA replication programmes where DNA synthesis initiates in S-phase at multiple defined origins. Despite considerable understanding, many questions remain: what dictates origin location; how (in)flexible is a cell’s DNA replication programme; and when do cells employ origin-independent DNA replication? This application seeks to examine the DNA replication programme of two eukaryotic parasites, Trypanosoma brucei and Leishmania major, where DNA replication flexibility appears central to their biology:
1. T. brucei chromosomes are compartmentalised into a stable, highly transcribed core and unstable, transcriptionally silent subtelomeres, with dramatically differing levels of mapped origins. This application will ask how and why replication compartmentalisation occurs.
2. T. brucei survival relies on recombination of subtelomeric genes encoding Variant Surface Glycoproteins into telomere-adjacent transcription units, one of which is replicated uniquely early in S-phase. This application will ask how such targeted DNA replication occurs and if it drives recombination.
3. L. major appears to have evolved genome-wide DNA replication programme re-wiring: just one origin is activated in each chromosome during S-phase; and subtelomeric DNA replication occurs outside S-phase. This application will ask if L. major has de-emphasized conventional origin-derived replication, allowing more flexible DNA replication to promote genome plasticity.
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| 30/11/2021 |
£3,624,260 |
UNIVERSITY COLLEGE LONDON |
Sensory perception, cognition and motor function all rely on neural processing that is distributed across brain regions. Much of this processing is carried out by the neocortex and cerebellar cortex, which anatomical studies show are highly interconnected, forming multiple closed loops. But the neocortex and cerebellum have traditionally been studied separately. To understand how they work together as a system to form associations, learn motor tasks, predict the sensory consequences of movement and make decisions, it is critical to study how information is represented and communicated between these structures – at the neural population level. We will record neural population dynamics in the neocortex and cerebellar cortex, simultaneously, during reward-based behavioural tasks. We will use widefield whole brain imaging, high resolution dual region 3D two-photon imaging and optogenetic approaches. These will enable us to record and play back specific patterns of neuronal activity thereby testing hypotheses on cortico-cerebellar communication and cerebellar function. This will be complemented with multiscale models that link cellular mechanisms to population level properties. Elucidating fundamental principles of communication, distributed processing and learning will reveal how neural populations in the neocortical and cerebellar circuits work together to learn sensorimotor associations and perform skilled motor tasks.
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| 30/11/2021 |
£2,109,150 |
UNIVERSITY OF EDINBURGH |
Oligodendrocyte precursor cells (OPCs) have an established role in generating myelinating oligodendrocytes. However, many undifferentiated OPCs reside throughout the CNS lifelong suggesting additional, yet unclear roles of this cell population in regulating CNS form and function. Recently, my group has revealed that OPCs can sculpt neuronal connections, indicating that this cell type indeed has fundamental roles besides myelin generation. However, we do not know how OPCs exert these functions, nor do we know how resident OPCs integrate into neuronal networks, how they communicate with surrounding neurons, and how this communication shapes neural circuit assembly. Here, I propose a multiscale approach using zebrafish as model organism in which we use gene expression analysis, gene targetting and manipulation of neuronal activity, combined with structural in vivo imaging, physiological and behavioural analyses. Using these assays, we will determine how individual OPCs are integrated in a defined neural network and how they contribute to activity-dependent refinement of neuronal connectivity. Furthermore, we will elucidate the genetic code by which individual OPCs mediate connectivity between neurons and test how dysfunctional OPCs affect circuit assembly and animal behaviour. Together, this will reveal novel roles of OPCs for circuit formation, function and dysfunction.
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| 30/11/2021 |
£3,500,000 |
INSTITUT DE RECHERCHE EN SCIENCES DE LA SANTé DIRECTION RéGIONALE DE L'OUEST |
Vector control is by far the most effective intervention for reducing malaria infection. It has contributed 78% of the total reduction of the disease burden from 2000-2015. Progress however has slowed since 2015 due to insecticide resistance, and there are calls for investments in new interventions. Gene drive is one of the most promising vector control approaches on the horizon. It requires the release of small numbers of modified mosquitoes with the aim of suppressing their populations or blocking the transmission of pathogens. Implementation of this strategy however requires that i) critical knowledge gaps in the ecology of gene drive be addressed, ii) an exhaustive landscaping of risks assessment and management plans be developed, and iii) technical capacity be built in Africa to take ownership of the technology. This project will, for the first time, connect and mobilize African scientists and their international partners to produce and gather key scientific information that will equip the public and policymakers with the requisite knowledge to take decision on whether or not to accept the technology. Four leading regional research institutes across Africa aided by two international world-class UK-based universities will join forces to run this interdisciplinary program.
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| 30/11/2021 |
£2,094,546 |
IMPERIAL COLLEGE LONDON |
The prevalence of neurodegenerative disorders is increasing at an alarming rate, but our limited understanding of disease mechanisms has impeded the development of new treatments. The association between mitochondrial DNA (mtDNA) mutations, ageing and disease has been known for some time, but a causal link is mostly supported by extreme mouse-mutants or rare human genetic diseases. Our preliminary analysis has uncovered an unexpected, and enormous, diversity of hidden (or ‘cryptic’) mtDNA mutations at the single-cell level in aged humans. We have established new mathematical and experimental methods enabling us to show the functional consequences of these cryptic mutations, and have preliminary evidence they have aging-like effects on gene-expression which can be controlled by caloric-restriction. Here we will map the accumulation of cryptic-mtDNA-mutations in the human brain throughout the life-course, and then model this process in mice. We will determine whether three interventions can decelerate cryptic-mutation accumulation, and thereby slow progression in mouse models of Parkinson’s disease. Parkinson’s disease has been closely linked to age-related mtDNA mutations in humans. We anticipate this will show a direct link between the accumulation of cryptic-mtDNA-mutations in single-cells and age-related pathology at the single-cell level, and show that this is amenable to therapeutic manipulation.
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| 30/11/2021 |
£1,380,654 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
The recent pandemic has highlighted the importance and great potential of electronic health record data for addressing urgent public health questions in a timely manner, while demonstrating key gaps in existing methodology for this setting.
The overall aim of this proposal is to develop statistical methodology to remove barriers that have hampered important public health issues in COVID-19 being fully addressed; and to apply the methods to answer the immediate and arising public health questions in COVID-19 and more broadly.
Key goals are to:
develop a suite of methodological tools to enable computationally-efficient self-recalibrating risk prediction in EHR databases;
develop a framework for assessing the worth of different treatments within EHR databases, accounting for potential high-dimensional confounding and implementing approaches to estimate individual treatment effects within this;
create analytic approaches to address causal questions requiring data from two separate sources in the absence of full individual linkage.
Data held within the OpenSAFELY platform and the UK Clinical Practice Research Database will be used to motivate the statistical methodological work. Optimal methodological approaches will be applied to address important questions arising in COVID-19 and more broadly, to key questions in chronic disease.
|
| 30/11/2021 |
£2,081,649 |
KING'S COLLEGE LONDON |
During division, eukaryotic cells perform a dramatic reorganisation of their cytoskeleton and their internal membranes. Whilst we know much about how the genome is separated, our understanding of how the cell reorganises, partitions and separates its organelles remains poorly understood. During division, the nuclear envelope (NE) is dismantled and regresses into the endoplasmic reticulum (ER), a major organelle occupying over a third of the cellular volume. This hybrid organelle is distributed as a continuous membrane system between daughter cells as cells leave division, but how this membrane is actually separated is unknown. This hybrid membrane also envelops the separating chromatin discs and a machinery called ESCRT-III assembles transiently at the reforming NE to seal gaps in this membrane.
We will use quantitative proteomics and structural mass spectrometry to identify control mechanisms allowing spatiotemporally controlled assembly of ESCRT-III at the reforming NE. We will use whole-cell volumetric EM correlated with live-cell imaging measurements of ER-connectivity to understand how the ER is physically separated during mitotic exit. We will use these approaches to examine how ER-separation and NE-reformation are coordinated and integrated with the inheritance of other major organelles, giving us new insight into the cellular reorganisation occurring as cells complete division.
|
| 30/11/2021 |
£2,151,007 |
UNIVERSITY OF MANCHESTER |
Immunological control at the gingiva, a key oral barrier, is poorly understood. This is an oversight as loss of gingiva immune homeostasis results in the development of periodontitis, the most prevalent chronic inflammatory condition of humans. Crucially, periodontitis is known to exacerbate many extra-oral diseases, including Alzheimer’s Disease, gastrointestinal cancer, COPD and rheumatoid arthritis. Thus, delineating immune mechanisms underpinning gingiva health would ensure development of better periodontitis therapies with implications for the treatment of other diseases.
This program will redefine our understanding of how effective gingival immunity is enforced. We recently revealed an unappreciated mechanism by which gingiva innate cells develop, identifying haematopoietic stem and progenitor cells (HSPC) resident in healthy gingiva that locally generate neutrophils and monocytes. Providing insights into the gingival haematopoietic niche we will outline how gingiva-resident HSPC support barrier integrity and impact periodontitis pathology, detailing functional consequences for neutrophils and monocytes of generation within gingival tissue. Moreover, we will ascertain whether gingiva-generated innate cells mediate inflammatory consequences in extra-oral tissues, providing unprecedented mechanistic insight into how periodontitis potentiates distal pathologies. Combined, this program will develop new concepts in mucosal immunology, substantially advancing the field of oral immunology, and identify novel strategies for therapeutic manipulation in periodontitis.
|
| 30/11/2021 |
£2,560,675 |
UNIVERSITY COLLEGE LONDON |
The existence of place, directional, boundary and grid cells in the rat hippocampal formation provides strong evidence that it functions as a cognitive map containing map-like representations of familiar environments which enable the animal to identify its current location together with desirable and undesirable locations, and to move towards or away from these. Using our newly developed honeycomb maze, we have shown that the CA1 place cells support flexible navigation by pointing the direction to the goal and, in addition, evaluating the suitability of all non-goalward directions as possible options if the goalward choice is not available. We plan to explore the properties of this representation, its environmental and path integation inputs and the way in which it underpins flexible navigation.
We have also shown that the CA1 place cells are sensitive to the size of the environment. Their firing rates are modulated by a range of environmental sizes with some cells preferring small environments, others intermediate sized ones, and yet others firing only to the largest environment. We will study exactly which aspect of environmental size and shape these cells are monitoring and how they are doing so.
|
| 30/11/2021 |
£2,593,547 |
UNIVERSITY OF CAMBRIDGE |
The overarching goal is to determine the functional heterogeneity within prefrontal cortex contributing to individual variation in the aetiology and treatment of key symptoms of major depressive disorder (MDD) including sadness, anhedonia (social and non-social), negatively biased decision making and lack of control/helplessness. Insights gained should facilitate refinement of individual diagnosis and treatment strategies. Key prefrontal regions in which altered activity is linked to MDD and its treatment will be targeted in a non-human primate, common marmosets. Specifically, acute chemogenetic activation/inactivation of these regions will determine (i) the relationship of the lateral orbitofrontal cortex to reward loss and disappointment/sadness, (ii) the contribution of the dorsolateral prefrontal cortex to conflict in decision making and negative bias, (iii) the involvement of the pregenual cingulate cortex in the ability to control environmental events. Behaviour and cardiovascular activity will be measured across multiple computerized cognitive tests and PET/functional MRI will assess distributed effects on circuit activity. With MDD onset associated with adolescence, acute regional interventions during adolescence will identify windows of perturbational vulnerability, whilst multi-parametric MRI will provide neurocircuit developmental insights. Foundational work on marmoset social development will establish novel toolsets for applying our approach in the social domain; highly relevant to MDD onset.
|
| 30/11/2021 |
£2,073,725 |
UNIVERSITY OF OXFORD |
I propose multi-modal, cross-species experiments to first determine the neurophysiological mechanisms underpinning motor plasticity, and then to develop approaches that drive plasticity to enhance behaviour. I will focus on the role of neural dynamics, particularly on phase-amplitude coupling of theta- and gamma-activity (theta-gamma PAC), in two key nodes of the motor network: the primary motor cortex (M1) and thalamus, to address these key aims:
Decoding the neurochemical and circuit underpinnings of M1 theta-gamma PAC and how it modulates network connectivity during motor plasticity
Driving motor network connectivity to optimise motor plasticity
Determining clinical relevance: the role of GABAergic signalling and theta-gamma PAC in stroke recovery
I will capitalise on the advantages of cross-species investigations to determine the causality and cell-type specificity of neural dynamics underpinning plasticity. I will drive plasticity using novel human neurophysiological tools to stimulate, and record from, deep brain structures to enhance behaviour. Finally, I will translate the physiologically defined stimulation approach developed in the fellowship to enhance behaviour in chronic stroke survivors. Taken together, this work will provide an essential understanding of the physiological changes underpinning motor skill acquisition, as well as resulting in putative therapeutic interventions to enhance stroke recovery: a substantial, under-met, clinical need.
|
| 30/11/2021 |
£3,426,793 |
UNIVERSITY OF CAMBRIDGE |
The unfolded protein response by which cells adapt their endoplasmic reticulum (ER) to changing levels of ER-stress, globally promotes fitness in eukaryotes. However, the outcome of specific pathological processes associated with ER stress may be improved by modulating the activity of specific strands of the UPR. Here we shall focus on three promising yet understudied aspects of the response, in hope of uncovering details that will enable us to exploit failures of homeostasis in the UPR. All three involve enzymes that we hope to attack with modern tools of Cryo-EM, CRISPR-based gene editing, somatic cell genetics, small-molecule (metabol)omics and structure-based tool-compound discovery.
The key ER chaperone BiP is regulated post-translationally by FICD-mediated AMPylation/deAMPylation. Understanding this bi-functional enzyme will provide a handle to manipulate conditions in the ER.
Stress-mediated attenuation of protein synthesis hinges on phosphorylated eIF2 attenuating the nucleotide exchange factor eIF2B via a recently discovered allosteric mechanism. We will search for endogenous metabolites and chemical ligands that exploit this path to allosterically regulate eIF2B bi-directionally.
The eIF2-directed holophosphatase that terminates signalling, has recently become accessible to structural studies; these we aim to deepen in hope of devising strategies to target this recalcitrant strand of the stress response pathway.
|
| 30/11/2021 |
£2,381,916 |
UNIVERSITY OF MANCHESTER |
Cell state transitions, whereby cells move from one state to another (i.e. from progenitor to differentiated cell), sometimes reversibly, are of key importance to most areas of biology, including development, regeneration and cancer. Our understanding of this inherently dynamic process is limited by the molecular approaches that are commonly used, such as "omic" approaches which are sophisticated and powerful, but essentially static, relying on "snapshot" data. My research vision is to pinpoint the mechanisms by which cell state transitions take place in real time by applying live molecular imaging, quantitative data and dynamical mathematical approaches.
We will study ultradian gene expression oscillations of key transcription factors (TFs) because recent data suggests that they represent a prevalent yet under-appreciated mode of regulation and are important in enabling cell state transitions. We will focus on how TF oscillations are decoded, the area that we know least about. We will study mammalian and zebrafish neurogenesis, ideal systems for capturing the impact of oscillations in a developmental context.
The proposal has three aims:
Aim 1. To visualise and characterise oscillatory dynamics during cell-state transitions.
Aim 2. To understand the function and decoding of oscillatory gene expression.
Aim 3. To uncover new oscillatory gene expression.
|
| 30/11/2021 |
£1,126,103 |
ST GEORGE'S, UNIVERSITY OF LONDON |
Early targeted intervention reduces risk of diabetic complications. We will compare the effectiveness of artificial intelligence (AI) based retinal image analysis, genotyping and linked health record data from people with diabetes mellitus to predict diabetes related complications - incident diabetic eye disease (particularly progression and sight-threatening retinopathy) and systemic (nephropathy, neuropathy, cardiovascular disease). We will apply novel end-to-end AI/machine learning approaches to retinal feature analysis and validated automated AI-enabled retinal vasculometry measurement to one of the largest and most ethnically diverse NHS Diabetic Eye Screening Programmes from North-East London (105,000 patients seen annually, 90,000 with 5 years follow-up, 40,000 with 10 years). We will develop new prognostic models, using retinal image analysis, genetics and health record data (alone and in combination) to predict diabetic complications (particularly retinopathy progression); model performance will be compared with published risk scores/algorithms. Models will be externally validated using the US Early Treatment Diabetic Retinopathy Study, cohort with gold standard retinopathy grading and high complication rates (20% mortality at 5 years). Findings will provide an early warning system of complications, which could be exploited within existing healthcare pathways to trigger early intervention.
|
| 30/11/2021 |
£1,829,135 |
UNIVERSITY OF OXFORD |
Vacuolar H+-ATPases (v-ATPases) are ATP-driven proton pumps that acidify intracellular compartments. Acidification is important for a plethora of cellular processes, ranging from neurotransmitter uptake to lysosomal degradation. The timing of acidification is essential for pathways where lowering of the luminal pH is vital, e.g. virus/protein activation, cargo-receptor separation. Despite decades of research, key open questions persist: How is v-ATPase regulated during a process that replenishes synaptic vesicles (SVs) and sustains neurotransmission? Is lysosomal pH dynamically regulated - if yes, how? What are the consequences of poorly regulated acidification for cellular homeostasis and health?
We will tackle these questions through Rabconnectin-3a, a conserved brain-enriched protein whose mutations cause mental retardation, neuropathy and/or hearing loss. Little is known about Rabconnectin-3a due to its large size, lack of tools and early embryonic lethality. We cloned Dmxl2 gene encoding Rabconnectin-3a, generated mouse models and a specific antibody, and detected Rabconnectin-3a on all organelles that acidify. I propose to examine a role of Rabconnectin-3a in the regulation of acidification, and to characterize its functions at the synapse and in two disorders. A multi-disciplinary approach will be employed, from studies of individual organelles to a characterization of neuronal networks by a combination of genetics and electrophysiology.
|
| 30/11/2021 |
£3,500,000 |
UNIVERSITY OF EDINBURGH |
Antifungal resistance is increasingly prevalent, raising fungal-borne disease frequencies in humans and crops important for human wellbeing. Conventional wisdom that resistance results solely from genetic mutations has been overturned by our landmark discovery that epigenetic gene repression can cause resistance via heterochromatin-island ‘epimutations’ that arise in fission yeast exposed to external insults. Transient ectopic methyl-H3K9-heterochromatin is normally rapidly erased by the counteracting Epe1-H3K9-demethylase. However, external insults/antifungals inactivate Epe1 via MAP Kinase-induced, proteasome-mediated cleavage, allowing heterochromatin-island formation. Epimutation-mediated repression of mitochondrial protein levels likely confers resistance through mitochondrial dysfunction. We propose that innate or imposed metabolic stress predisposes some cells in populations to form epimutations, and that heterochromatin islands increase mutation frequencies in underlying resistance genes. We will dedicate our expertise in chromatin-mediated epigenetic regulation to understanding how antifungals alter fungal epigenetic landscapes to promote resistance. We will determine how antifungals influence resistant epimutant emergence in human (Cryptococcus neoformans) and wheat (Zymoseptoria tritici) fungal pathogens. Using fission yeast as our workhorse alongside pathogenic fungi we will explore mechanistic conservation and divergence, and real-world impact. Evidence that heterochromatin-dependent epimutations provide a general pathway for initial antifungal evasion would dramatically alter understanding of resistance mechanisms in human and crop fungal pathogens, and beyond.
|
| 30/11/2021 |
£1,580,874 |
UNIVERSITY OF SHEFFIELD |
This proposal aims to generate a multi-scale understanding of the remodelling events (fusion and perforation) that change the topology of an epithelial sheet during organogenesis. Failure of these processes underlies common congenital anomalies, such as ocular coloboma, spina bifida and cleft palate.
We will study the developing zebrafish inner ear, which undergoes three rapid epithelial fusion and perforation events, each involving just a few cells. This model system is amenable to genetic, transgenic and pharmacological manipulation, and offers superb opportunities for live imaging.
Key goals are to:
Use live imaging to map patterns of mitosis and apoptosis across the developing ear
Identify genetic requirements for cytoskeletal, adhesion and cell shape changes during inversion of epithelial curvature
Image and manipulate cell behaviour during epithelial fusion and perforation, including live imaging of cytoskeletal changes
Test the role of selected signalling pathways (aGPCR, Wnt/Fzd1, Netrin) in the fusion/perforation event
Test the role of apoptosis in remodelling during and after epithelial fusion/perforation
The findings will improve our understanding of vertebrate otic organogenesis, with more general relevance to identify conserved modules of cell behaviour during epithelial morphogenesis. The project establishes new collaborations with experts on epithelial morphogenesis and cell signalling in other developing organ systems.
|
| 30/11/2021 |
£2,080,541 |
UNIVERSITY OF OXFORD |
The symptoms of malaria occur when Plasmodium parasites replicate within human blood cells. The largest parasite protein family displayed on Plasmodium falciparum-infected erythrocytes contains the RIFINs and STEVORs. Recently, applicants on this award discovered that RIFINs can suppress human immune cell function by mimicking the human ligand of inhibitory immune receptor LILRB1. We have also discovered RIFINs which bind four other human inhibitory immune receptors. We now aim to determine:
"How do RIFINs and STEVORs modulate human immunity during malaria?"
This requires a collaborative effort, bringing together the latest tools in transgenic parasite biology, structural biology, biophysics of cell interfaces and high-throughput technology.
Using these tools, we will determine how RIFINs which bind to five different inhibitory immune receptors affect survival of infected erythrocytes in the context of killing by four types of human immune cell, and will show how RIFIN-targeting antibodies modulate these effects. We will conduct high-throughput experiments to determine which RIFINs and STEVORs provide a survival advantage in the context of immune cell-mediated killing and will determine the ligand binding properties of all RIFINs and STEVORs from one parasite genome. These studies will show how RIFINs and STEVORs manipulate human immune cell function during malaria.
|
| 30/11/2021 |
£1,555,142 |
KING'S COLLEGE LONDON |
The complement membrane attack complex (MAC) is a human immune pore that directly kills Gram-negative bacteria. The bacterial envelope of these pathogens is composed of two lipid bilayers separated by a peptidoglycan layer. MAC pores must be locally assembled on the outer membrane by the C5 convertase to rupture both membranes and directly lyse cells. While structures of MAC show how the pore forms in a single lipid bilayer, the dimensions of the complex are incompatible with the depth of the bacterial cell envelope. Here we propose that the key for MAC’s bactericidal activity hinges on the local structure of the envelope and the clustering of pores. We will exploit a platform of novel artificial cell mimics to identify the fundamental determinants of bacterial killing. By integrating structural information from cryo electron microscopy with dynamic information from single molecule imaging we will address two central questions in innate immunity: 1) where is MAC located in the context of the cell envelope and 2) how does the C5 convertase control local clustering of MAC. In doing so, our results will provide a foundation for understanding why some bacteria are resistant to killing by MAC.
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| 30/11/2021 |
£1,844,554 |
UNIVERSITY OF SHEFFIELD |
The processing of sensory information is a fundamental feature of human biology, yet we have limited understanding of how it occurs in vivo. The auditory system provides an ideal model to investigate sensory processing, as it incorporates arrays of cells with a precise organisation preserved from the periphery to the brain.
High-fidelity sound perception relies on cochlear hair cells and their nerve fibres to accurately encode acoustic information over broad frequency and intensity ranges. Our current knowledge of this complex process derives largely from ex vivo experiments, since in vivo recordings with subcellular resolution from the intact mammalian cochlea have long been considered unfeasible. This has created a substantial barrier towards our understanding of auditory function, since ex vivo work cannot replicate the sophisticated anatomy, innervation and physiology of the cochlea.
My laboratory has developed surgical and microscopy approaches that, combined with in vivo gene delivery and genetically modified mice, allow us to study the function of mammalian sensory hair cells and their synapses in vivo. We will use this pioneering approach to identify the mechanisms regulating cochlear function, how they change throughout life and, more broadly, to study how the ear and the brain communicate with each other.
|
| 30/11/2021 |
£1,659,685 |
UNIVERSITY OF EXETER |
We aim to resolve the chemical identity of molecular patterns that trigger antifungal immunity, and to exploit this information to understand immune evasion during disease progression and inform the future development of improved antifungal diagnostics. Our collaborative team will address this critical challenge through our complementary expertise in state-of-the-art high throughput approaches involving carbohydrate chemistry, antifungal immunobiology, genomics and precision reverse genetics.
Our immune defences provide protection against the constant threat of infection by opportunistic fungal pathogens, and pathogen recognition is a vital first step in these defences. We previously defined the relative contributions of major pathogen-associated molecular patterns (PAMPs) in the cell wall of Candida albicans that are recognised by pattern recognition receptors (PRRs) to illicit immune responses. We also discovered that this major fungal pathogen exploits host signals to activate PAMP masking strategies and evade immune recognition. Critical questions emerge from these studies. (1) What are the chemical identities of the actual PRR-ligands within PAMPs? (2) How does the fungus modulate PRR-ligand exposure as it adapts to host niches? (3) How does this modulation impact fungal virulence and anti-fungal immune responses? Answering these questions, which underlie fungal recognition phenomena, will provide invaluable opportunities for diagnostic and therapeutic developments.
|
| 30/11/2021 |
£2,450,016 |
UNIVERSITY OF YORK |
Leishmania donovani infection is characterised by widespread parasite dissemination within and between multiple tissues, a process intimately linked to the parasite’s intracellular lifestyle in myeloid cells. Yet despite dissemination underpinning the pathogenesis of visceral leishmaniasis (VL) and post kala azar dermal leishmaniasis (PKDL), little is known about this critical aspect of parasitism. To address this knowledge gap, we propose a program of research involving: i) comparative in situ analysis of infected human and rodent tissue at single cell resolution (including spatial proteomics / transcriptomics and mass spectroscopy imaging); ii) the application of sequence tag-based analysis of microbial populations to probe parasite within-host population dynamics, and iii) iterative rounds of modelling and experimentation to test hypotheses related to lateral parasite spread in the skin. By applying these orthogonal approaches at key inflection points in the natural history of disease, we will identify key changes in myeloid cell phenotype and function associated with dissemination, discover novel bottlenecks impacting parasite establishment and replication temporally and across different tissues, and gain new insights into the key transition from VL to PKDL. This research will increase our fundamental knowledge of L. donovani-host interactions and provide new targets for host-directed therapy aimed at minimising parasite dissemination.
|
| 30/11/2021 |
£1,858,706 |
IMPERIAL COLLEGE LONDON |
Gut mucosal surfaces are vulnerable to infection and diarrhoeal diseases remain a major public health concern worldwide. Many bacterial pathogens employ a T3SS to inject effectors that enable colonisation and evasion of immune responses. Thus far, most studies have concentrated on studying one effector at a time. However, in the majority of cases, single effector mutants do not present a disease phenotype in animal models. Using the mouse-adapted pathogen Citrobacter rodentium as a model, we have shown that the reason for the lack of phenotypes is due to the fact that, rather than operating individually, the effectors can form distinct intracellular subnetworks that can sustain significant perturbations while maintaining virulence. Moreover, we coined the term context-dependent essentiality to define how an effector/cytokine is essential for infection in a specific subnetwork but not another subnetwork. Our overarching aim is to explore the effector network paradigm and to address the following goals: (i) Explore context-dependent effector and cytokine essentialities; (ii) Investigate whether age and the host genetic background play a role in maintaining the expansive effector network; (iii) Build computational models to study and predict infection outcomes; iv) Study signal transduction from injection of effectors into intestinal epithelial cells to immune responses.
|
| 30/11/2021 |
£2,366,520 |
UNIVERSITY OF CAMBRIDGE |
Orientia tsutsugamushi (Ot) is an obligate intracellular Rickettsiales bacterium that causes the mite-borne human disease scrub typhus, a leading cause of severe febrile illness in Asia and an emerging public health challenge in other parts of the world. Scrub typhus is the most significant rickettsial disease in severity and prevalence. Its fundamental biology is not well understood, limiting advances in the development of urgently needed vaccines, diagnostics, and treatments. My lab has spent the past eight years working in the USA and Thailand to develop Ot into a robust and experimentally tractable system. We are now poised to gain a deep understanding of the cellular microbiology of this organism. We recently identified Ot subpopulations with distinct physical properties. This project will characterize the mechanism whereby these Ot forms enter cells and escape detection by the endolysosomal pathway. We will also investigate how Ot exploits the host cellular machinery to grow and develop; budding-off mechanisms preceding bacterial dissemination also will be explored. Our knowledge of Ot heterogeneity will provide essential insights for development of improved diagnostic tools. Our physical presence in Thailand and our local partners who can rapidly apply laboratory findings to the clinic will benefit at-risk populations the most.
|
| 30/11/2021 |
£570,748 |
KEMRI-WELLCOME TRUST RESEARCH PROGRAMME |
The lack of reliable, timely data on deaths (who, when, what) and births in SSA continues to pose a considerable challenge to estimating intervention needs. Many events across Africa remain invisible to national and international health metrics and health system planners. Informed health policy requires reliable descriptions of births and the age, sex and causes of death for the entire population. New context-specific evidence is required to understand the challenges that plague CRVS systems in Africa. I will use a network of surveillance sites in Kenya to answer four related questions: a) What and where are the gaps and inefficiencies in the current civil registration processes? b) What is the true proportion of unregistered births and deaths in Kenya? c) do individuals have the same probability of being registered by CRVS when they are born or when they die? and d) Why are some births or deaths not registered and are these events systematically different, and what are the potential opportunities and strategies to strengthen registration of all children. This body of work will inform the design of an intervention package aimed at improved monitoring of changes in mortality and natality and demonstrate how to achieve comprehensive CRVS in Kenya
|
| 30/11/2021 |
£1,178,520 |
KEMRI-WELLCOME TRUST RESEARCH PROGRAMME |
The lack of reliable, timely data on deaths (who, when, what) and births in SSA continues to pose a considerable challenge to estimating intervention needs. Many events across Africa remain invisible to national and international health metrics and health system planners. Informed health policy requires reliable descriptions of births and the age, sex and causes of death for the entire population. New context-specific evidence is required to understand the challenges that plague CRVS systems in Africa. I will use a network of surveillance sites in Kenya to answer four related questions: a) What and where are the gaps and inefficiencies in the current civil registration processes? b) What is the true proportion of unregistered births and deaths in Kenya? c) do individuals have the same probability of being registered by CRVS when they are born or when they die? and d) Why are some births or deaths not registered and are these events systematically different, and what are the potential opportunities and strategies to strengthen registration of all children. This body of work will inform the design of an intervention package aimed at improved monitoring of changes in mortality and natality and demonstrate how to achieve comprehensive CRVS in Kenya
|
| 30/11/2021 |
£1,828,847 |
CARDIFF UNIVERSITY |
Age-related arterial stiffening is a leading cause of neurological problems. The excessive cardiac pulsatile energy reaching the brain’s capillary bed damages the blood brain barrier. Loss of arterial elasticity with age is a natural process normally linked to primary hypertension and cardiovascular disease. However, mounting evidence suggests a strong causal link between reduced arterial elasticity in the body and brain disorders such as small vessel disease, stroke, and many forms of dementia.
We lack technology to image pulsatile flow in the cerebrovascular tree at multiple scales, from large arteries to capillaries. This has hampered our ability to understand the mechanisms by which arterial stiffness progresses in the brain and its contribution to blood brain barrier breakdown and consequent neural degeneration.
I will address this in three themes. The first will develop innovative MR imaging techniques, a Cerebrovascular Stiffness Toolbox, that can link vessel stiffness at all scales to capillary level damage. The second will characterise healthy and compromised buffering during ageing and hypertension. The third will compare acute interventions that change vascular stiffness in mechanistically differing ways (ACE inhibitor vs. calcium channel blocker anti-hypertensives and organic vs. inorganic dietary nitrate) to determine which might best prevent brain arterial stiffening.
|
| 30/11/2021 |
£1,880,390 |
UNIVERSITY OF EDINBURGH |
The correct regulation of the inflammatory response is critical to maintaining human health. Immune cells operate within a complex environment and are exposed to several different and often competing signals. They respond to damage signals produced at sites of tissue injury, ‘find me’ cues from apoptotic corpses, bacteria at sites of infection as well as attractive signals emanating from pre-malignant cancer cells. How exposure to one of these signals affects an immune cell’s ability to respond to subsequent cues is a largely understudied area of inflammatory cell biology but it is critical if we are to come up with novel therapeutic ways to manipulate inflammatory cell behaviour in the clinic. In this research proposal we will leverage the powerful genetics and live imaging potential of the fruitfly Drosophila to address this process of innate immune priming/memory. We will investigate how innate immune cells sense and respond to the earliest damage signals that trigger inflammation and uncover how exposure to these signals alters subsequent inflammatory behaviour. We will identify novel molecular controllers of the recognition, uptake and processing of apoptotic corpses as well as understand the inflammatory consequences of apoptotic cell uptake both in wounds and within the emerging tumour microenvironment.
|
| 30/11/2021 |
£3,902,813 |
KING'S COLLEGE LONDON |
Chronic pain is a frequent and disabling facet of many immune-mediated diseases, including inflammatory arthritis. A particularly puzzling phenomenon is that during disease-modifying treatments, pain can become uncoupled from inflammation. This results in minimal disease activity but persistent pain for the individuals affected.
Pain in the absence of overt inflammation is frequently ascribed to dysfunction of spinal cord and cortical pain circuits. Conversely, pain during inflammation is seen as a natural consequence of immune cells driving peripheral neuron hyperactivity. This perspective, however, neglects the potential of tissue-resident stromal cells, like fibroblasts, to drive pain in the absence of inflammation.
Our overarching hypothesis is that fibroblasts are key drivers of persistent pain in inflammatory disease. Using rheumatoid arthritis as a model, we will unite expertise across traditionally distinct disciplines to:
Demonstrate that human sub-lining synovial fibroblasts are a prominent source of pro-algesic mediators and can induce neurite outgrowth.
Demonstrate that sub-lining fibroblasts drive neuronal hyper-excitability and pain behaviours.
Find novel analgesic targets by blocking fibroblast-derived pro-algesic mediators or fibroblast sub-populations.
Our research will provide much-needed interdisciplinary insights into the basic principles of how peripheral nerves and fibroblasts interact in painful disease and accelerate the urgent search for more effective analgesics.
|
| 30/11/2021 |
£1,601,492 |
UNIVERSITY OF OXFORD |
Adaptive immunity provides essential protection from infectious diseases. This system depends on the ability of lymphocytes to reach distinct compartments within secondary lymphoid organs (SLOs), where specialized cells mediate controlled activation, and where homeostatic survival and peripheral tolerance-promoting cues are presented. Whilst much progress has been made towards defining the mechanisms that regulate these events in lymph-nodes, relatively little is known about how they are orchestrated in the largest SLO in our body, the spleen. Progress in this area lagged largely due to challenges in developing the necessary imaging technology to explore dynamic behaviour of cells within live intact spleens. Our group pioneered cutting-edge imaging approaches that allow us to perform this analysis with high resolution for the first time. Here, we will use a combination of advanced imaging approaches to define the microanatomical structures and molecular mechanisms that facilitate T cell 1) access into splenic T-zones, 2) acquisition of initial activation signals, and 3) egress before/after differentiation into effector cells. These studies will not only resolve fundamental open questions in the field, but also provide a solid foundation for future works aiming to understand how the spleen orchestrates immune responses and how it can be modulated for therapeutic interventions.
|
| 30/11/2021 |
£1,676,751 |
NEWCASTLE UNIVERSITY |
Staphylococcus aureus is a major antibiotic-resistant bacterial pathogen that colonises the nares of a large proportion of the human population. In common with several other bacterial pathogens, S. aureus encodes a Type VII protein secretion system (T7SS). While previous studies have implied a role for the T7SS in infection persistence, our work has shown that the S. aureus T7SS secretes large protein toxins whose primary targets are bacteria. We propose that S. aureus uses its T7SS to compete with components of the nasal microbiota during colonisation. Furthermore, in preliminary work we have identified a completely novel T7 substrate protein that may represent a new family of antibacterial toxins. Here we aim to characterise this novel substrate family, and address the role of the T7SS and its secreted toxins in colonisation. We will determine which bacterial species in nasal microbiomes are sensitive to T7SS-dependent antagonism by S. aureus. The antibacterial toxins we have identified must cross the envelope of competitor bacteria to access their cellular targets. We will define the pathway used by a large nuclease toxin to reach the bacterial cytoplasm. Collectively our work will significantly advance understanding of the role of the T7SS in bacterial antagonism.
|
| 24/11/2021 |
£1,268,533 |
IMPERIAL COLLEGE LONDON |
This project will identify the cis-regulatory networks that operate in non-alcoholic fatty liver disease (NAFLD) and characterise their role in hepatocyte lipidomic traits.
I will carry out single-cell multi-omics in a cohort of liver biopsies representing different stages of NAFLD progression to identify the active genes and corresponding cis-regulatory elements with unprecedented resolution. I will:
identify the hepatic cell populations that are mostly altered in different degrees of NAFLD and their corresponding marker genes;
identify the transcription factors that drive the transcriptional/phenotypical changes detected with NAFLD progression;
pinpoint the hepatic cell populations whose genetic disruption contributes the most to the heritability of NAFLD and/or NAFLD-associated traits.
To gain mechanistic insights into the contribution of specific genetic loci to NAFLD risk, I will:
carry out variant level in silico and experimental analyses to prioritise variants likely to be causal;
use the single-cell multi-omic maps to assign noncoding NAFLD risk variants to target genes in specific hepatic cell populations ('NAFLD genes');
perform an unbiased loss-of-function genetic screen to identify 'NAFLD genes' that affect intracellular lipid morphological features in human hepatocytes;
use gain/loss-of-function models (regulatory variant and gene levels) in human hepatocytes to validate findings and further characterise hits from the genetic screen.
|
| 24/11/2021 |
£654,442 |
UNIVERSITY OF MANCHESTER |
Children and young people’s (CYP’s) mental health is an urgent priority. Dramatic, socio-economic changes following the COVID-19 pandemic has already disproportionately affected families, and with economic uncertainty, further shocks are expected. This fellowship shall use epidemiology, biostatistics, causal inference and machine learning applied to high-quality psychiatric surveys to investigate how changes to the family ‘ecosystem’ affects CYP mental health.
The first goal is to describe typical family ecosystems and assess CYP mental health in each. The second goal will be to conduct first network analysis of mental health symptoms within families using graphical networks. The third goal will be to estimate the effect of acute changes from the pandemic (e.g. school closures) on CYP mental health. Finally, longer term changes to the family ecosystem will be determined, then analysed to assess their effect on CYP. For the latter two, I shall use causal mediation analysis to determine modifiable determinants of mental health and interaction analyses to determine which children are vulnerable, and what modifiable factors could create resilience. A website disseminating findings and provided a children’s mental health dashboard shall be co-created with a CYP advisory group.
|
| 24/11/2021 |
£1,201,313 |
UNIVERSITY OF BIRMINGHAM |
The human gut microbiota is a dense and interdependent community and has a mutualistic relationship with the human host. These microorganisms have significant but poorly-understood impacts on health, development, and disease. The major carbon source for these microbes are glycans and polysaccharides and a proportion of these are derived from the host, such as those from mucins and immunoglobulins. This research will focus on how the infant gut microbiota uses the N-glycans in breastmilk as a nutrient source. These N-glycans are an abundant nutrient source for the infant gut microbiota, but remarkably understudied in this context. The anticipated output of this research would be to highlight healthcare improvements, such as pre- and probiotics, that can be made for those infants that do not have access to breastmilk. This is significant as the UK has one of the lowest rate of breastfeeding in Europe, with only 34 % of mothers continuing to 6 months and 0.5 % to 12 months. This output will be achieved by producing a detailed molecular understanding of the enzymes used by Bifidobacterium spp. to access this nutrient source. This study will also characterise how these nutrients are cross-fed between different species and strains.
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| 24/11/2021 |
£1,241,381 |
UNIVERSITY OF OXFORD |
Antibiotic tolerant bacteria transiently enter a non-growing ‘persister’ state in which they can survive exposure to bactericidal antibiotics despite not being resistant. After treatment finishes, persisters can resume growth leading to infection recurrence such as often seen in urinary tract infections (UTIs). Furthermore, typical once-daily antibiotic dosing can lead to rapid evolution of tolerance-conferring mutations. Despite their importance, we understand little about the physiology of persister cells or how they evolve in clinical settings. Here, I will take an interdisciplinary approach, using state-of-the-art single-cell fluorescence microscopy, high-throughput phenotyping, evolution experiments, and genomic analysis to link together our understanding of how genetic mechanisms triggering tolerance in E. coli lead to distinct cell physiological states and how physiology in turn affects antibiotic susceptibility. Importantly, I will test persister susceptibility to novel potential treatments, including bacteriocins and bacteriophages. To test these molecular-level concepts in a clinical scenario, I will analyse the genomes of a unique set of uropathogenic E. coli strains collected from patients who experienced treatment failure to determine how tolerance evolves during treatment of UTIs. Together, this data will be used to identify novel strategies to minimize the evolution of antibiotic tolerance during treatment of UTIs and bacterial infections more broadly.
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| 24/11/2021 |
£1,282,199 |
UNIVERSITY OF OXFORD |
The basal ganglia are implicated in a wide range of behaviors and are particularly important for many types of learning. The diversity of basal ganglia function is tied to cortical diversity; indeed, the entire cortex outputs to the basal ganglia, which is routed in a loop via the thalamus back to the cortex. These three components of the cortex, basal ganglia, and thalamus likely form an archetypal circuit which carries out similar computations in the perceptual, cognitive, and motor domains. The way in which activity propagates across these structures, and how this propagation changes to support learning, are largely unknown. I propose to investigate the interdependence within this circuit by building on my prior work on communication between the cortex and striatum. In those experiments, I developed methodology towards defining the functional relationship between structures, and identified specific learning-induced changes. Here, I will trace those changes across structures throughout learning, I will determine how these changes affect the little-studied output arm of the basal ganglia, and I will causally determine which connections within this circuit drive specific components of both activity and learned behavior. These experiments will contribute toward a holistic understanding of a major neural circuit.
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| 24/11/2021 |
£986,766 |
UNIVERSITY OF BIRMINGHAM |
This fellowship focusses on the growth hormone secretagogue receptor-1a (GHSR1a), a G protein-coupled receptor (GPCR) that binds the orexigenic hormone ghrelin, and is an attractive pharmacological target to regulate appetite. I hypothesise that efforts to target GHSR1a have poor outcomes as GHSR1a signalling is complex, involving GPCR heterodimerisation, interacting proteins and dynamic spatiotemporal signalling. I postulate these mechanisms exist to facilitate GHSR1a’s role as a ‘hub’ at arcuate neurons, where physiological signals are integrated to regulate appetite. Understanding these mechanisms could define new therapeutic targets for obesity and undernutrition.
My fellowship will explore GHSR1a signalling in detail. Aim 1 and 2 will address: how GHSR1a interacts with other GPCRs at membranes; how this modulates signalling; if heterodimers form in hypothalamic brain tissue; and whether this affects ghrelin-mediated physiological functions. Aim 3, will identify proteins that interact with GHSR1a and how they affect GHSR1a signalling. Aim 4 will determine how interacting proteins affect GHSR1a trafficking, and whether GHSR1a can continue to signal from intracellular sites once internalised. State-of-the-art kinetic signalling assays (cAMP Glosensor, calflux, NanoBiT-BRET, HTRF); advanced microscopy (TIRF microscopy with single-particle tracking, HILO, single-molecule pull-down); quantitative proteomics (peroxidase-catalysed proximity labelling); and animal models will be utilised to achieve these aims.
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| 24/11/2021 |
£1,260,735 |
UNIVERSITY OF OXFORD |
More than 100 chromatin proteins have been identified as causative genes in human genetic disease. Most of these genes are broadly expressed and have fundamental roles in transcriptional regulation, yet their disruption causes tissue-specific effects. We do not understand the molecular basis of this tissue-specificity, as it has been challenging to identify the specific cell types affected and to study the consequences of these mutations in the proper tissue context.
I will focus on Cornelia de Lange Syndrome (CdLS), a genetic disorder of cohesin function. Cohesin is a ring-shaped protein complex that encircles DNA and stabilises the 3D folding of chromatin. Mutations in cohesin complex members are thought to disrupt chromatin folding and impair cells’ ability to properly regulate gene expression. This project will determine which genes are particularly cohesin-sensitive and lead to the tissue-specific pathologies of CdLS. I will identify dysregulated genes by applying single-cell and spatial transcriptomics to CdLS mouse models. I will find common chromatin folding features of these genes using genome architecture mapping and look for similar patterns of disruption in banked CdLS patient samples. This project will lay the foundations for a broad research programme exploring chromatin disruption in other developmental diseases.
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| 24/11/2021 |
£537,211 |
UNIVERSITY OF CAMBRIDGE |
Monoclonal antibodies have revolutionised medicine, yet the majority of the proteome remains off limits owing to its intracellular localisation. We identified a receptor for antibody inside cells with E3 ubiquitin ligase activity called TRIM21, which represents a powerful tool by which antibodies can degrade intracellular targets. During the SHDF, we found that delivery of antibodies to a mouse model of pathological tau, a protein that becomes aggregated inside neurons in several neurodegenerative diseases, resulted in protection against aggregated tau in a TRIM21-dependent manner. In this extension, we aim to investigate how different epitopes of tau result in differing mechanisms of protection. Specifically, we will test whether TRIM21-dependent mechanisms and blocking of entry of tau to the cytosol can be achieved by binding alternative epitopes. We will use the results to compare immunotherapies that rely and different mechanisms in vivo. Secondly, we aim to determine the ability of antibodies to gain access to the cytosol of neurons in a quantitative manner. We will examine the properties of cells and antibodies that enable this transfer and whether TRIM21-mediated protein knockdown can be elicited and further improved. Together the results will extend immunotherapy to the intracellular environment for future therapy against neurodegenerative diseases.
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| 24/11/2021 |
£559,842 |
UNIVERSITY OF DUNDEE |
Intestinal intraepithelial T lymphocytes (IEL) reside at the forefront of mucosal immunity, located as they are between nutrient-absorptive intestinal epithelial cells, close to the anaerobic microbes in the intestinal lumen. This specialized environment dictates the fuels and oxygen available to IEL and metabolites that influence their function. I aim to understand how mitochondria and cellular metabolism regulate cellular bioenergetics, macromolecule biosynthesis, redox balance, and metabolite waste management in IEL, thus driving appropriate responses to intestinal metabolic perturbations, including diet and microbial challenges. In this project, I will investigate how metabolic adaptation of IEL to the nutrient-limiting, hypoxic intestinal environment enables their homeostasis and response to infection. We will use cutting-edge techniques including:- stable isotope tracing of glucose utilisation in vivo and mitochondrial metabolomics to elucidate sources of energy fuelling IEL responses; high-resolution respirometry to obtain detailed insights into mitochondrial regulation; genetic models and super-resolution microscopy to study mitochondrial dynamics; and signalling studies to understand how IEL are metabolically activated. This work will provide fundamental insights into the unique metabolic wiring of IEL and illuminate links between diet, intestinal metabolism and intestinal immune responses, findings that can be leveraged therapeutically to tune IEL activity in infectious, autoimmune and/or metabolic diseases.
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| 24/11/2021 |
£813,463 |
IMPERIAL COLLEGE LONDON |
I propose a new and significant departure from our current studies of mTORC1 signalling. The majority of the complexes involved in integrating signals affecting cell-growth have now been understood at a basic molecular level; our understanding of how all of the signalling components fit together at the lysosome, however, remains compromised and incomplete. In particular the TSC and GATOR2 complexes have been implied to modify membranes and to have homology to COPII membrane trafficking components respectively. My intention is to bind our purified TSC and GATOR complexes to lysosomal vesicles to interogate them biochemically, and tailor our on-grid purification techniques to purify and enrich lysosomal signalling complexes for cryo-EM tomography. I expect to learn key details of the mechanisms underpinning signal integration at the lysosome in the mTORC1 signaling pathway, and more generally of the (dys)regulation of cell-growth.
Goals:
- To understand the effects of lysosomal membrane binding on TSC and GATOR protein complex signalling; does lysosomal recruitment affect signal integration and GAP function in each case?
- To understand the effects of binding of the TSC and GATOR complexes on the lysosomal membrane; does membrane remodelling take place in either case, and what is its likely function if so?
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| 24/11/2021 |
£1,100,243 |
UNIVERSITY OF OXFORD |
The primate brain’s reward and decision systems are shaped by biological needs to fine-tune nutrient balance under ecological constraints. Here, we investigate how neurons in these brain systems evaluate specific macronutrients (fat, sugar, protein) and sensory food qualities (taste, flavour, texture) to implement human-typical value-based food choice. We record single-neuron activity from amygdala, orbitofrontal cortex, and anterior cingulate cortex while macaques perform an ecologically inspired food-choice task to obtain nutrient rewards and track visual-nutrient associations. We determine how neurons encode valuation and decision processes for specific nutrients to regulate nutrient balance. Building on our recent work, we apply the Geometric Framework for Nutrition to link monkeys’ nutrient choices and neuronal signals to ecological reference points and foraging strategies. In a parallel neuroimaging study, we translate the same nutrient-choice task and rewards to human functional brain networks. Using transcranial focused ultrasound stimulation in macaques, we test which brain areas contribute critically to nutrient-balancing food choices. Computational modelling determines how neurons interact mechanistically to generate identified neural and behavioural patterns. By challenging neurons with an ecologically relevant food-choice problem for nutrient rewards, we aim to discover functional principles governing the primate brain’s reward systems and identify vulnerabilities for their dysfunction in diseases.
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| 24/11/2021 |
£653,924 |
UNIVERSITY OF YORK |
The bio-activity of cell surface membrane proteins, which perform diverse and critical functions, is governed by membrane trafficking decisions. Internalised surface proteins rely on different endosomal recycling pathways that return them to the surface. My lab has used yeast as a discovery system to identify critical machinery that regulates the trafficking of surface proteins, and we have started to mechanistically dissect their function. We hypothesise critical regulators of yeast recycling, which have obvious human orthologues, function through novel modes of action (Aim 1). As our yeast papers have generated testable hypotheses in mammalian cells, we have optimised assays to measure endocytosis and recycling in cultured human cells, which will be used to understand how surface protein recycling is coordinated through specific lipid regulators (Aim 2). This aim will also be the basis for an exciting complementary research direction in collaboration with Chris Stefan, LMCB, UCL. Finally, we plan to understand how surface proteins are regulated at the surface membrane itself, as we recently revealed this regulation integrates with endocytosis/recycling (Aim 3). In combination, this research programme is aimed at discovering and defining fundamental trafficking mechanisms that control surface protein bio-activity across eukaryotic systems.
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| 24/11/2021 |
£668,564 |
UNIVERSITY OF SHEFFIELD |
Epithelial-to-mesenchymal transitions (EMTs) and mesenchymal-to-epithelial transitions (METs) allow cells to shift reversibly between adherent, static states and more detached, migratory states. Crucial for the formation of many tissues and organs, they are also key drivers of cancer metastasis. METs are often described as the reverse of EMT, driven by the downregulation of EMT-inducing factors. Accordingly, in the Drosophila midgut, we have shown that the EMT transcription factor Serpent needs to be downregulated for MET to successfully proceed, suggesting that there are common mechanisms underlying both processes. However, we recently showed that downregulation of Serpent is not sufficient for MET, and that specific extrinsic cues are also required. These cues appear to drive MET through pathways that are distinct from those affecting EMT. I propose to identify the common and distinct molecular mechanisms underlying EMT/MET. I will do this by interrogating our recently generated single-cell datasets, which chart gene expression changes in midgut cells as they transition from epithelial to mesenchymal states and back again, with our analytical and experimental toolkits. Given the role of EMTs and METs in cancer metastasis, this will likely lead to the identification of therapeutic targets for blocking one process without inadvertently promoting the other.
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| 24/11/2021 |
£848,519 |
UNIVERSITY OF CAMBRIDGE |
All human tissues contain specialised macrophages, that have specific functional properties key to function of the organ where they reside. The human placenta has specialised fetal macrophages termed Hofbauer cells (HBC) located within human placental villi from 18 days post conception to term. They are extra-embryonic immune cells because they are present before any vascular connection to the embryo. Importantly, they are the only placental immune cell throughout gestation. Although, the early appearance of these cells is indicative of an origin from primitive haematopoietic stem cells, this remains to be formally investigated.
During my current fellowship, using state-of-the art technologies, I have demonstrated that first trimester HBC have unique phenotypic and functional properties, in comparison with adult macrophages. I will now: i) characterise the putative HBC progenitors identified in pilot studies, ii) determine the ontogeny of two HBC subsets that I found at term, HLA-DRpos and HLA-DRneg HBC iii) analyse how HBC respond to a common pathogen capable of vertical transmission, Listeria monocytogenes.
These experiments will determine the origin, differentiation, phenotype and function of HBC throughout gestation. The findings will provided a much-needed experimental framework to further study their role in normal and pathological pregnancies.
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| 24/11/2021 |
£535,361 |
UNIVERSITY OF GLASGOW |
New malaria control measures are urgently needed and their development requires a better understanding of the complex life cycle of the disease agent - a protozoan parasite from Plasmodium genus. The biggest bottleneck of this cycle takes place during the initial stages of obligatory mosquito transmission when Plasmodium gametocytes fertilise and create motile ookinete forms, able to penetrate the insect midgut. This transition requires major modification of the parasite's transcriptome but the molecular mechanisms regulating this process are still very poorly understood. Their investigation is further complicated by the fact that Plasmodium zygote contains two parental genomes and both mono- and bi-allelic expression has been observed during the ookinete development.
During my fellowship, I have been investigating the parasite's transcriptome during the ookinete formation and the role of key transcription factors and chromatin accessibility in this process. Now I propose to analyse the sex-specific allele expression at this stage, using both rodent and human malaria models, and the combination of genetic crosses, single-cell sequencing and conditional mutagenesis. This will add an additional dimension to the datasets I have already produced and consolidate my research programme by generating a comprehensive model of the gene expression changes at the ookinete stage
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| 24/11/2021 |
£774,372 |
IMPERIAL COLLEGE LONDON |
Apicomplexan pathogens such as Toxoplasma gondii are obligate intracellular parasites. These parasites are dependent upon the secretion of a highly conserved group of apical organelles for host cell invasion. In T. gondii a lipid post-translational modification (PTM) called palmitoylation is known to regulate apical organelle secretion. Perturbation of palmitoylation disrupts apical organelle secretion, impacting motility and invasion, highlighting its critical regulatory role in this fundamentally important process. While individual palmitoylated protein species have been studied, the wider molecular basis for the regulation of apical organelle secretion by this cysteine-targeted PTM is not known.
This PTM been identified throughout the T. gondii proteome, but it remains to be determined: (1) which specific palmitoylated cysteines on proteins regulate apical organelle secretion? (2) how does this PTM influence the molecular function of these proteins? Studying PTMs one-by-one is challenging. Addressing our questions and overcoming this challenge, we will take advantage of a new CRISPR-based proteome engineering method we have pioneered. This will be complemented with focused cell and biochemical analyses to define how palmitoylation regulates the fundamental process of apical organelle secretion. This will be the first functional analysis of how palmitoylation regulates a specific cellular process in T. gondii.
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| 24/11/2021 |
£671,399 |
UNIVERSITY OF CAMBRIDGE |
Mitochondrial mutations are associated with a spectrum of incurable diseases and ageing. They often arise as unique variants among thousands of wild-type genomes. Their subsequent prevalence, which shapes disease progression and mitochondrial DNA (mtDNA) evolution, depends on how they compete with the pre-existing genomes for transmission. The nuclear genome, which encodes most mitochondrial proteins and functions, can modulate aspects of mtDNA competition. How it works, however, remains unclear as few tools exist to experimentally dissect the nuclear inputs. We have established powerful in vivo and cell-culture based heteroplasmic systems in Drosophila to identify and study the nuclear inputs. Through a genome-wide in vivo screen using deficiencies, we identified multiple nuclear regions containing genes that influenced mtDNA competition (Chiang et al., 2019). We have also identified multiple nuclear genes and compounds that influence mtDNA transmission through the RNAi and compound screening of immortalised cell lines. To fully benefit from these new discovery platforms, we will complete the RNAi and compound screens and characterise some already identified candidates in detail. This will put us in a unique position to reveal molecular rules governing mtDNA transmission and uncover targets for interventions that reduce the propagation of pathogenic mitochondrial mutations.
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| 18/11/2021 |
£120,000 |
BOTSWANA HARVARD AIDS INSTITUTE PARTNERSHIP |
Perinatal transmission is a major route of hepatitis B virus (HBV) transmission in countries with high prevalence rates. 80-90% of HBV infections acquired in the first year of life result in a chronic infection. HBV e antigen positivity and/or HBV viral loads, increases risk of perinatal transmission. HBV vaccination has reduced HBV incidence in infants in some parts of the world. However, the African region has the highest HBV incidence of 2.34% in children under 5 years of age. The World Health Organization plans to eliminate HBV by 2030, by decreasing the HBV prevalence to less than 0.1% in children who are 5 years of age. This project aims to investigate viral transmission dynamics and intra-host evolution of HBV in mother-infant pairs in Botswana. We will screen for HBV infections in 450 mother-infant pairs from a previous study conducted in 2016–2021. We will further determine HBV diversity in the HBV positive mother-infant pairs using next generation sequencing and novel bioinformatics pipelines. This study will enhance understanding of HBV evolution and inform development of vaccines which are effective against vaccine escape mutations and including routine HBV screening as part of antenatal care. Understanding HBV evolution gives insights in virus-host interactions.
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| 18/11/2021 |
£310,290 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
Chronic hepatitis B (CHB) infection affects 257 million individuals and accounts for 900,000 deaths annually. The World Health Organisation has set targets to eliminate hepatitis B virus (HBV) by 2030. However, there are significant gaps in our understanding of the mechanisms underlying HBV disease evolution in Africans. As a result, current guidelines have poor performance to correctly identify Africans in need of CHB treatment, and available antiviral treatment does not clear CHB infection or eliminate risk of cancer.
Recent advancements in metabolomics provide a unique opportunity to identify metabolites and mechanisms involved in HBV persistence and spontaneous hepatitis B surface antigen (HBsAg) loss (functional cure).
In this project, I will use serial plasma/serum samples collected between 2011-2020 during annual follow-up of a well characterised cohort of African adults with CHB infection in The Gambia to identify metabolic fingerprints of HBV-disease progression and HBsAg loss. I will then directly measure the in vitro influence of candidate metabolites on HBV replication and clearance (macrophage response) using a liver-on-chip microphysiological system. Finally I will propose cellular pathways of HBV-disease progression and potential targets for cure.
Study findings will support the development of adapted HBV guidelines for Africans and drive further research towards cure.
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| 18/11/2021 |
£849,898 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
Despite the implementation of pneumococcal conjugate vaccines (PCVs) in infant immunisation programmes across Africa, residual carriage of pneumococcal vaccine serotypes (VTs) amongst under-fives in the household poses substantial risk to infants too young to be vaccine protected.
Using a vaccine probe approach, I will determine if under-fives are the primary source of VT transmission to PCV-age-ineligible infants living within the same household in Malawi. I will enrol 784 mother-infant pairs and their PCV-immunised household contacts 12-59 months old (HHC) into a two-arm randomised controlled trial. The HCC will receive either a single booster of the 13-valent PCV (PCV13) in the intervention arm or a comparator vaccine in the control arm. With regular sampling of households, I will determine the extent to which the PCV13 booster for HHCs indirectly protects (cocoons) PCV-age-ineligible infants from VT carriage. Transmission within the household will be examined by sampling pneumococcal carriage and shedding using bacteriologic and cutting-edge genomic sequencing methods.
Combining epidemiological and genomic investigations, I will determine the proportion of VT carriage among PCV-age-ineligible infants attributed to under-fives living within the same household. I will also generate evidence to inform policymaking considerations of the benefits of a targeted PCV booster dose in low-resource settings.
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| 18/11/2021 |
£56,000 |
WELLCOME SANGER INSTITUTE |
Despite the implementation of pneumococcal conjugate vaccines (PCVs) in infant immunisation programmes across Africa, residual carriage of pneumococcal vaccine serotypes (VTs) amongst under-fives in the household poses substantial risk to infants too young to be vaccine protected.
Using a vaccine probe approach, I will determine if under-fives are the primary source of VT transmission to PCV-age-ineligible infants living within the same household in Malawi. I will enrol 784 mother-infant pairs and their PCV-immunised household contacts 12-59 months old (HHC) into a two-arm randomised controlled trial. The HCC will receive either a single booster of the 13-valent PCV (PCV13) in the intervention arm or a comparator vaccine in the control arm. With regular sampling of households, I will determine the extent to which the PCV13 booster for HHCs indirectly protects (cocoons) PCV-age-ineligible infants from VT carriage. Transmission within the household will be examined by sampling pneumococcal carriage and shedding using bacteriologic and cutting-edge genomic sequencing methods.
Combining epidemiological and genomic investigations, I will determine the proportion of VT carriage among PCV-age-ineligible infants attributed to under-fives living within the same household. I will also generate evidence to inform policymaking considerations of the benefits of a targeted PCV booster dose in low-resource settings.
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| 18/11/2021 |
£300,867 |
KEMRI-WELLCOME TRUST RESEARCH PROGRAMME |
Despite high prevalence of iron deficiency and anaemia in Africa, there are longstanding concerns regarding whether treatment of iron deficiency by giving iron supplements increases the risk of infections, hospitalisation, and deaths. Previous studies have not conclusively addressed this dilemma due to study design limitations such as confounding bias, reverse causality and a requirement of large sample sizes and long follow-up times to investigate rare outcomes in clinical trials. During my post-doctoral studies, I conducted a GWAS and identified novel genetic variants that are unique to African populations that can be used to proxy iron status and anaemia. This now affords me the unique and exciting opportunity to test how these variants influence severe infections and mortality using a Mendelian randomisation approach that overcomes many of the limitations of previous study designs. I propose to identify likely causal genetic variants through fine-mapping, comprehensive functional annotation, and integration of my findings with transcriptomic and epigenomic data. I will then determine whether the prioritised causal variants influence risk of severe malaria, bacteraemia, tuberculosis, and mortality using already available data/samples from large case-control studies in Africa. This novel approach has not previously been applied to iron status and infections/deaths in Africa.
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| 18/11/2021 |
£123,536 |
KEMRI-WELLCOME TRUST RESEARCH PROGRAMME |
Severe anaemia and bacteraemia are strongly associated in African children, although the precise mechanisms underlying this association remain unknown. I found that this association is observed with specific organisms (e.g. Escherichia.coli, non-typhoidal Salmonella) but not others (e.g. Staphylococcus aureus). Given the multiple putative aetiologies of severe anaemia and increase in antimicrobial resistance, developing a full understanding of the mechanisms that predispose to these bacterial infections will enable the development of better interventions. I propose to test the hypothesis that disruption of iron metabolism and/or immune pathways contributes to increased risk of bacterial infections among severely anaemic children. I will utilise clinical and laboratory data and samples collected over the last 21 years to examine the associations between severe anaemia, immune responses, bacterial iron acquisition and genetic signatures of bacteria during severe anaemia. I will also evaluate the effects of anaemia on bacterial vaccine responses using data and samples from vaccine trials conducted in Kilifi. Findings from this project will elucidate key iron and immune pathways that can be targeted to develop interventions for severe anaemia and prevention of bacteraemia.
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| 18/11/2021 |
£133,014 |
SOUTH AFRICAN MEDICAL RESEARCH COUNCIL |
Forced migrants’ health is a global concern, especially because forced migration is expected to increase substantially driven by war and human caused climate change [1]. In South Africa, there are approximately 2.1 million forced migrants (refugees). This population experiences poor health, driven by exposure to violence, and xenophobia, which further limits access to health care. High rates of intimate partner violence (IPV) have been found among these population [2]. However, little is known about how gender inequalities, xenophobia, and experiences of forced migration, intertwine to shape IPV among forced migrants. This innovative study uses a mixed methods approach and co-development process with young (18-30) forced migrants to understand and then address IPV in forced migrant communities in Durban, South Africa. I will first, using qualitative and quantitative data describe these issues, then co-develop with Youth Peer Research Associates (YPRAs), who are forced migrants themselves, an intervention to address IPV. Finally, I will assess the intervention’s feasibility and acceptability with young (18-30) forced migrants. I will also, together with YPRAs, engage extensively with forced migrant communities, advocacy groups, and government, ensuring research translates to policy change. Study results will inform the co-design of a pilot RCT with this population.
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| 18/11/2021 |
£269,339 |
UNIVERSITY OF CAPE TOWN |
Despite the recognition of anaemia as a global health priority of particular relevance to low- and middle-income countries, little is known about its impact on the developing brain. The aim of this neuroimaging research is to investigate the impact of antenatal maternal anaemia on brain structure and neurodevelopment in children from two high-risk South African birth cohorts. Both a traditional, high-field MRI and the newly introduced Hyperfine low-field MRI will be used to answer this research question, and to explore whether the findings can be replicated across systems. The high-field MRI will be used to determine whether the association between antenatal maternal anaemia and lower corpus callosum and basal ganglia volumes in 2-3 year-olds from a preliminary birth cohort study persists in the same children at age 6. This relationship will also be investigated in 2-3 year-old children from a second birth cohort to confirm whether findings can be replicated, and to assess the role of iron-deficiency. The low-field MRI system’s ability to detect brain alterations associated with antenatal maternal anaemia will be assessed by comparing replicated neuroimaging finds across MRI systems in the second birth cohort. Structural brain changes will be correlated with neurodevelopmental outcomes in both birth cohorts.
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| 18/11/2021 |
£296,299 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
Drivers of population differences in vaccine-specific immune responses and vaccine efficacy are not completely understood. This project will address the hypothesis that pre-vaccination immunological and metabolic profiles are key determinants of vaccine response, and parasite exposure a key driver of these profiles.
Three interrelated Ugandan trials have been designed to investigate the impact of helminth and malaria exposure and treatment on immune responses to a panel of live (BCG, Yellow Fever, oral Typhoid), virus-like particle (HPV) and toxoid (Tetanus/Diphtheria) vaccines among adolescents. The current project will exploit the unique opportunity provided by samples from these trials, to investigate
1. pre-vaccination immunological parameters underpinning high and low vaccine responses, using multiplex Luminex® immunoassays and high-dimensional multi-parameter (≥30) spectral flow cytometry
2. cellular and circulating metabolic profiles and their association with magnitude of vaccine response, using flow cytometry and plasma metabolome measurement by high-throughput mass spectrometry
3. relationships between parasite exposure, immunological and metabolic profile, and vaccine responses, using regression, causal mediation and multi-omics approaches
The rich collection of distinct datasets generated will provide a unique opportunity to employ integrative computational analyses for a comprehensive view of biological predictors of vaccine response.
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| 18/11/2021 |
£140,959 |
INSTITUT DE RECHERCHE EN SCIENCES DE LA SANTé DIRECTION RéGIONALE DE L'OUEST |
Genetic control approaches through application of CRISPR/Cas9-based gene drives represent a promising strategy to control vector borne diseases such as malaria. While the technology is still being optimized, there is urgent need to address several knowledge gaps crucial for safe and effective field implementation. One of the most important need is to elucidate ecological processes that will influence spread and persistence of transgenes in wild mosquito populations; such as mosquito migration and aestivation. This research project aims to understand these phenomena with the objective of developing a reliable field data-based predictive model of transgene diffusion in the field.
Short and long-range migration, aestivation and spatial population dynamics of An. gambiae (s.l.) will be explored in a group of village clusters in Burkina Faso, to understand their relative contribution to the sustainability and spread of malaria mosquitoes across different ecological settings. Activities will include sequential mark-release-recapture experiments to quantify and characterize dispersal and survival using long-term marking approaches and entomological surveillance to measure spatial population dynamics and highlight the role of aestivation. All these data will be used to inform and build accurate modelling tools for vector control.
Keywords: Genetic control, Gene drive, Mosquito migration, Mosquito aestivation, Mark-Release-Recapture, predictive model.
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| 18/11/2021 |
£674,526 |
UNIVERSITY OF CAPE TOWN |
TBM is associated with high rates of mortality and morbidity in children. A delay in diagnosis and brain injury (manifest by infarcts) are important drivers of poor outcome. TBM is a challenge to diagnose due to its non-specific presentation and brain injury is often permanent at hospital admission. Highly sensitive blood-based biomarkers of brain injury could aid in earlier clinical suspicion of meningitis, prompter treatment, and improved patient outcome. Although promising in cerebrospinal fluid, biomarker kits have lacked sensitivity in blood. In this study we will test a new blood-based kit with 1000-fold greater sensitivity for biomarkers ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP), which predicts injury severity and outcome in patients with traumatic brain injury. Further, we will examine advanced brain imaging (magnetic resonance and diffusion tensor imaging) over the first 6 months of treatment to identify structural and microstructural biomarkers of outcome. Previous research suggests that neuroexcitotoxicity and cytokine profiles associated with diffuse cellular inflammation may be mechanisms driving TBM brain injury. Therefore, we will also examine the association of metabolomic and genetic markers of neuroexcitotoxicity and differential inflammatory profiles with outcome to identify novel potential treatment targets to mitigate brain injury and improve outcome.
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| 16/11/2021 |
£820,936 |
UNIVERSITY COLLEGE LONDON |
Hemianopia is common following acquired brain injury, and is estimated to affect over 230,000 people living in the UK. Despite its high prevalence and well-described impact on society, it is a neglected clinical problem with no treatments to recover vision. My research shows that patients with hemianopia can show residual vision in their blind field, a phenomenon called 'blindsight'. Patterns of blindsight and one's capacity for visual retraining appear to vary according to the presence of preserved 'secondary' visual pathways. Where pathways remain intact, they represent an important potential target for rehabilitation. I will use cutting-edge neuroimaging techniques in patients and healthy controls to build a normative connectivity atlas of the central visual pathways. I will quantify the relationship between secondary visual pathway integrity and function in patients and controls, to learn how to optimally drive their response. I will use results to develop a novel visual-training protocol targeting the ventral visual stream, and test whether the integrity of ventral and dorsal visual pathways can predict improvement with visual training protocols targeting those two domains in patients with hemianopia. Understanding the secondary visual pathways will expand neural targets and enhance precision through a customised approach to treat hemianopia.
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| 16/11/2021 |
£685,229 |
UNIVERSITY OF MANCHESTER |
The fovea is the small depression at the neurosensory retina that underlies high-resolution central vision. It is particularly vulnerable to disease and disruption of its normal architecture causes visual disability. Notably, foveal morphology varies significantly across individuals and this is thought to be linked to variations in foveal development. The molecular causes and functional consequences of this anatomical diversity are incompletely understood. Addressing this knowledge gap is this proposal’s main objective.
My central hypothesis is that variation in foveal morphology is caused by variation in the pigmentation of the retinal pigment epithelium (RPE), the monolayer supporting retinal neurons. To test this, I will analyse retinal scans available through the UK Biobank and perform a genome-wide association study of image-derived foveal phenotypes. Preliminary analyses have highlighted a number of variants including a common missense change in tyrosinase, the rate-limiting enzyme of melanogenesis. I will use high-resolution imaging to study how foveal morphology is altered in people carrying this tyrosinase variant. I will also generate iPSC from these individuals and use CRISPR-Cas9 editing to study/rescue melanin defects in iPSC-RPE.
This work will elucidate the molecular factors that underlie variability in foveal morphology and will advance understanding of both fundamental and clinically-relevant neurobiology.
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| 16/11/2021 |
£932,288 |
UNIVERSITY OF EDINBURGH |
Neutrophil driven tissue injury is a common feature of inflammatory lung disease. I have shown that tissue neutrophils are biosynthetically active and utilise extracellular proteins to fuel de novo protein synthesis. The neutrophil proteome is highly dynamic, with protein turnover regulating key process and defining effector functions at sites of injury. The mechanisms which determine the repertoire of neutrophil protein synthesis are unknown. The requirement for ATP and amino acids suggests a role for the nutrient-sensing kinases, AMPK and mTORC1 and the related proteolytic organelle, the lysosome. mTORC1 and AMPK respond to environmental signals in a cell-specific manner to permit or restrain growth. Neutrophils are non-proliferative but synthetically active cells and, as such, are subject to unique growth pressures. The role of the mTORC1/AMPK/lysosome axis in responding to these pressures and the factors downstream of them which drive protein synthesis in the neutrophil are unknown. I hypothesise that delineating these pathways will identify novel therapeutic targets in neutrophilic inflammation.
My key aims are therefore to:
1. Determine the factors which regulate neutrophil protein synthesis
2. Investigate the relationship between protein synthesis and inflammation in the neutrophil
3. Target protein synthesis in tissue neutrophils to alter outcomes in inflammatory lung disease
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| 16/11/2021 |
£644,817 |
UNIVERSITY COLLEGE LONDON |
I previously showed that in Alzheimer's disease (AD) amyloid beta constricts brain capillaries via signalling to pericytes.
I now wish to investigate:
(1) Parkinson's disease (PD) / Lewy Body Dementia (DLB), where alpha-synuclein evokes ROS production and hypothesise that endothelin will be released (as observed in AD) and evoke pericyte-mediated capillary constriction to decrease cerebral blood flow.
(2) The role of APOE receptor LRP-1 in regulating increased tau phosphorylation in AD. LRP-1 is a master regulator of tau uptake/spread and highly expressed on pericytes. In AD model mice, pericyte deficiency leads to tau pathology and early neuronal loss. Thus, pericyte LRP-1 may play an important role in clearing/processing tau in the setting of amyloid pathology. I will examine whether AD-like tau pathology develops in an APP knock-in AD/pericyte-LRP-1 deficient mouse model.
(3) The effect of Covid-19 on live human pericytes and capillaries.
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| 16/11/2021 |
£843,855 |
KING'S COLLEGE LONDON |
Cognitive symptoms of schizophrenia account for a significant proportion of the disease’s morbidity but have no effective pharmacological treatments. Cognition involves coordinated patterns of activity in functional brain networks, which in turn depend on interactions between excitatory glutamatergic pyramidal cells and inhibitory GABAergic interneurons. Perturbation of the excitatory and inhibitory (E/I) balance may underlie disruption of the functional networks in schizophrenia, and therefore result in cognitive impairments. Normalisation of this putative E/I imbalance represents a promising therapeutic target for novel treatments of schizophrenia, particularly those intended to improve cognition. A major obstacle to investigating these hypotheses is the lack of methods to derive mesoscale measures of E/I imbalance from observable macroscale measures of functional networks in patients.
I will develop a novel cross-species biomarker of E/I balance, derived from computational modelling of functional MRI and EEG. I will validate the approach using a mouse model in which the true microcircuit nature of E/I dysfunction is known. I will then use this method to characterise E/I balance in individuals with schizophrenia and determine possible connections with cognitive impairments. Finally, I will use the approach to elucidate whether memantine, a potential treatment for cognitive deficits in schizophrenia, acts by restoring E/I balance.
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| 16/11/2021 |
£1,130,275 |
UNIVERSITY OF OXFORD |
Oesophageal adenocarcinoma (OAC), a disease of unmet need, demonstrates high rates of chromosomal instability (CIN).
CIN constitutively activates the cGAS-STING pathway, producing extracellular 2’3’cGAMP which should stimulate host immune cells. Recently, we identified upregulation of ENPP1 as a key mechanism of immunosuppression in CIN-high cancers, hydrolysing 2’3’cGAMP and increasing adenosine in the tumour microenvironment (TME).
My data support that:
- Fibroblast-ENPP1 expression is a mechanism of immune exclusion, upregulated by extracellular vesicles (EVs) from CIN-high cells
- ENPP1 correlates with a protumourigenic extracellular matrix (ECM) promoting immunosuppression.
This fellowship will identify novel targets mediating immunosuppression in CIN-high OAC.
AIMS
(1) How do constitutively cGAS-STING-active CIN-high tumours signal to stromal cells, resulting in ENPP1 upregulation?
EVs from CIN-high and CIN-low cells will be profiled (proteome, miRNA, genome).
(2) What influence does CIN-associated fibroblast ENPP1 expression exert on the ECM?
Organoid-fibroblast co-cultures will delineate how fibroblast-ENPP1 influences tissue stiffness, using biomechanical characterisation.
(3) Is T-cell exclusion from the TME ENPP1-dependent and fibroblast-specific, and what are the underlying mechanisms?
OAC samples will be characterised (using flow cytometry and digital spatial profiling) identifying fibroblast-ENPP1-regulated immune populations. Tri-culture models (matched organoid-fibroblast-immune cells) will analyse T-cell reactivity and cytotoxicity regulated by fibroblast-ENPP1 and novel targets.
|
| 16/11/2021 |
£666,043 |
KING'S COLLEGE LONDON |
Cerebellar anomalies represent the most consistent defect in many prevalent neuropsychiatric disorders such as autism. Imbalance in excitatory: inhibitory (E:I) neurons has been implicated in the pathogenesis of these disorders in the cerebral cortex yet the precise role of E:I imbalance in cerebellar associated disease has been largely overlooked. We recently identified a novel human genetic disorder associated with cerebellar hypoplasia and autistic features caused by mutation in PRDM13 and subsequently discovered a novel function for Prdm13 in cerebellar GABAergic interneuron fate specification. Little is currently known about what regulates GABAergic interneuron specification or how these neurons function to influence behaviour. I will identify central regulators of inhibitory cell specification in the cerebellum, and the underlying molecular mechanisms and consequences of altered specification on circuit function. I will combine mouse genetics, single cell transcriptomics and state-of-the-art in vivo functional imaging and electrophysiology to address the following goals:
(1) Characterise molecular mechanisms driving specification and diversification of cerebellar inhibitory interneurons.
(2) Identify how Prdm13 regulates inhibitory fate specification.
(3) Determine consequences of Prdm13 disruption on the functional properties of cerebellar interneurons.
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| 16/11/2021 |
£472,823 |
UNIVERSITY OF CAMBRIDGE |
My overarching research goal is to understand the mechanisms by which body weight and hypothalamic-pituitary-gonadal axis function are coupled, and how this becomes disrupted in obesity.
We have identified three girls with severe obesity harbouring duplications at chromosome Xp11.22-p11.23. Duplications at this locus are associated with obesity and precocious puberty in other patients. The minimal critical region encompasses PCSK1N, a gene that encodes ProSAAS, a propeptide highly expressed in the hypothalamus and neuroendocrine tissues.
Very little is known about the function of ProSAAS in humans. In cells, ProSAAS-derived peptides inhibit prohormone convertase 1/3 (PC1/3), an enzyme that cleaves and activates hormones and neuropeptides including those regulating food intake. In the hypothalamus, Pro-opiomelanocortin (POMC) is cleaved into alpha melanocyte stimulating hormone (alphaMSH) which activates melanocortin-4 receptor (MC4R) to suppress food intake. Our team has previously shown that genetic loss of function of PC1/3, POMC or MC4R causes obesity in humans.
In this fellowship, I will test the hypothesis that excess ProSAAS causes obesity in patients with Xp11.22-p11.23 duplication. Combining mass spectrometric peptide analysis, advanced microscopy and metabolic phenotyping in patients, I will evaluate ProSAAS’s role in regulating the intracellular processing, trafficking, secretion and function of key neuropeptides involved in energy homeostasis.
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| 16/11/2021 |
£1,218,129 |
UNIVERSITY COLLEGE LONDON |
The immune system is central to almost every aspect of human health and disease, with tissues accepted as the determinative site of immune cell function. Biopsies have provided valuable insight but remain static snapshots that miss the critical temporal dynamics of immune responses. The ultimate aspiration would be to observe real-time, unperturbed, immune cell behaviour deep within the tissues of patients. The eye can realise this goal, as the transparent ocular tissues are inherently suited for repeated in vivo imaging across time.
I discovered offset-aperture adaptive optics scanning laser ophthalmoscopy (AOSLO) allowed label-free, non-invasive imaging of individual immune cells within the mouse retina. This project will apply the approach to man for the first time, pioneered in patients with retinal inflammation (Uveitis). Achieving this would transform patient care through improved diagnosis and monitoring, alongside unprecedented opportunities to study fundamental human immunobiology.
To interpret the offset-aperture characteristics of recorded immune cell subsets, I will establish the first mouse AOSLO platform in the UK. These intravital recordings will be directly correlated to ex vivo immunohistochemistry using a highly multiplexed technique I recently developed (3D-IBEX). This technique will be further employed to construct the first 3D human retina atlas of health and disease.
|
| 09/11/2021 |
£300,000 |
IMPERIAL COLLEGE LONDON |
Emergence of SARS-CoV-2 variants has underscored the importance of genomic surveillance in enabling timely identification of new viral threats, and the role of transmission modelling in characterising the public-health risk they pose. These analyses have largely been considered independently of each other during the pandemic however, despite evidence that genomic and epidemiological data can provide complementary insights into virus dynamics. I will develop a Bayesian transmission-modelling framework reconciling both data-sources and use this framework to systematically compare the epidemiological properties (e.g. transmissibility, disease-severity and immune-evasion potential) of key variants (including but not limited to Alpha, Beta, Gamma and Delta), across settings including Brazil, Colombia, India, Panama, South Africa and the UK. I will explore how the dynamics of variant establishment and spread are shaped by intrinsic variant properties and their modification by epidemiological context (e.g. control measures or levels of population-immunity), and examine whether there is evidence for different contexts influencing the establishment of variants with particular properties. This work will improve our understanding of the types of SARS-CoV-2 variants likely to establish and spread in the future; inform decisions aimed at mitigating their potential public-health impact; and provide insight into the ways epidemiological pressures influence viral evolution.
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| 09/11/2021 |
£300,000 |
UNIVERSITY OF OXFORD |
Despite significant increases in our understanding of brain functioning over the last decades, the translation of this knowledge into novel therapeutic approaches had lagged behind. Here, I propose a network dynamics approach to alter brain circuits and cognition in a cross-species, closed-loop manner, employing both rodent as well as human experiments.
First, I will perform exploratory experiments to probe frontal cortex neural dynamics during flexible decision making, concomitantly in rodents using high-density local field potential (LFP) recordings and in human subjects using magnetoencephalography/electroencephalography (MEG/EEG). I will employ a singular analysis pipeline with a particular interest in interactions between theta and gamma oscillations. Following this, I will perform open-loop non-invasive transcranial alternating current manipulations of neural circuits and cognition restricted to a rodent model to explore and optimize stimulation parameters. Finally, I will perform phase-dependent, ultra-fast closed-loop stimulation in both rodent and human subjects to dynamically modulate network oscillations and cognitive functioning in a non-invasive manner.
Successful completion of this ambitious project could have important translational implications for a wide range of disorders of the brain, from neurology to psychiatry.
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| 09/11/2021 |
£300,000 |
UNIVERSITY COLLEGE LONDON |
Quick and effective decision-making in a rich sensory world requires animals to use prior knowledge and internal goals to prioritise relevant sensory evidence to guide their actions. Spatial attention is the cognitive ability to constrain the processing of sensory evidence to particular spatial locations while ignoring presumed irrelevant sensory evidence from other locations. The mechanisms by which spatial attention is realized in neural circuits are poorly understood.
I will use a combination of Neuropixels recordings, circuit tools, and computational analyses and modelling in a novel attentional change detection task wherein mice continuously track attended content without responding. This will allow neural investigation of attentional mechanisms and attended sensory content in the absence of motor confounds.
Firstly, I aim to determine how neural representations of sensory evidence are modulated by spatial attention in brain areas representing task-relevant sensory evidence. Secondly, I aim to understand how interactions between brain areas causally shape attended task-relevant sensory representations and dynamics.
The outcome of this work is a better understanding of how attentional processes mechanistically influence task-relevant sensory processing at a single-cell, neural population, and circuits levels. This will help us develop a model of how internal cognitive processes integrate with the external sensory world.
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| 09/11/2021 |
£300,000 |
UNIVERSITY OF OXFORD |
Arthritogenic alphaviruses are re-emerging mosquito-borne viruses that cause severe arthritis. Chikungunya virus (CHIKV), the most prominent arthritogenic alphavirus, has caused explosive outbreaks affecting millions of people world-wide. Currently, there are currently no available vaccines or specific drugs against the virus. Global spread of Aedes mosquito vectors underscores the potential emergence and threat of arthritogenic alphaviruses.
The humoral response to CHIKV infection is key in controlling infection. However, currently there are few studies that have characterised human CHIKV mAbs from vaccinated volunteers, so our understanding of the underlying cellular and molecular mechanisms induced by CHIKV vaccines is limited. The first-in-human trial of ChAdOx1 Chik in Oxford elicited outstanding immunogenicity. It induced neutralising antibodies against 4 distinctive CHIKV lineages and 100% seroconversion by PRNT50. The same vaccine also conferred some cross-protective efficacy against MAYV in mice.
I will characterise the nature of the immune responses arising from CHIKV vaccines by achieving following aims:(1)Isolate human mAbs from volunteers in the ChAdOx1 Chik trial; (2)Functionally characterise a panel of neutralising mAb (3)Characterise the structural basis for how CHIKV-specific mAbs and broadly reactive mAbs target alphaviruses. This project will provide valuable insights into human antibody response to vaccination and identify candidate mAbs for therapeutic intervention.
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| 09/11/2021 |
£300,000 |
UNIVERSITY OF BRISTOL |
Daily partitioning of feeding is crucial for well-being and survival, but neuronal mechanisms underlying this process remain poorly understood. The dysregulation of circadian rhythmicity seen in the modern 24/7 society leads to obesity, cardio-vascular problems, metabolic syndrome and some kinds of cancer, constituting a major public health burden. Recently, we found that a brainstem satiety centre – the dorsal vagal complex (DVC) harvests exceptionally robust timekeeping properties, which are additionally sensitive to diet. This projects aims at understanding the neurochemical identity of the DVC clock, its possible ways of entrainment and role in physiology and obesity. These goals will be achieved with the use of a unique combination of tools, including cutting-edge molecular techniques (single-cell RNAseq and RNAscope) and real time monitoring of bioluminescence reporters. Additionally, we will combine optogenetic tools to stimulate vagal afferents, with multi-channel electrophysiology ex vivo and behavioural monitoring of food and water intake. Moreover, the output of the brainstem clock will be measured with the working brainstem-gut model. Results of this project have a potential to elucidate neural mechanisms of daily rhythms in satiety, but also possess clear translational clinical values for a restoration of circadian rhythmicity in obese patients by timed vagus nerve stimulations.
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| 09/11/2021 |
£300,000 |
UNIVERSITY OF BRISTOL |
Social transitions during emerging adulthood (starting further education/training/employment, leaving the family home, cohabitation, marriage, parenthood), have been shown to influence health and related behaviours in subsequent years. However, there is a lack of evidence on adult social transition patterns among today’s young people, or the likely complex mechanistic pathways to later health outcomes.
Using rich clinical, questionnaire, genetic, and linked administrative health data from three contemporary European cohorts, and advanced longitudinal epidemiological methods, this project will address the following objectives:
Determine the most common adult social transition patterns in terms of timing, quantity, and unique combinations.
Identify causal determinants of adult social transition patterns.
Determine the causal relationship between different adult social transition patterns and adult health outcomes.
Estimate the contribution of psycho-social factors as moderators/mediators of the relationship between different adult social transition patterns and health outcomes.
Estimate bi-directional associations between different adult social transitions, and psychological and socio-economic (psycho-social) factors.
Where possible, I will explore these objectives separately for different important subgroups, e.g. by sex, to establish who might need targeting/supporting differently. The research project's overall aim is to provide evidence that can better inform support of young people and prevent downstream adverse health outcomes.
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| 09/11/2021 |
£300,000 |
UNIVERSITY COLLEGE LONDON |
How are signals conveying sensory information and internal physiology combined to produce adaptive behaviour? The strategic location, connectivity and diverse neuronal composition of the habenular nuclei suggest that they may act as a hub where multimodal information converges to facilitate selection of appropriate actions. These nuclei also display conspicuous left-right asymmetries in terms of neurochemistry, neuronal activity and connectivity. I propose to investigate the role of the habenulae and their neuronal asymmetries in selection of behavioural responses, and how these responses are modulated dependent on internal states. Specifically, I will implement a behavioural assay based on phototaxis in larval zebrafish and compare responses between wildtype fish and genetic mutants with disrupted habenular asymmetry, following different sensory contexts (luminance history) and internal states (feeding states). By bridging physiology and spatial transcriptomics, I will then aim to identify the habenular neuronal sub-types and their functional features that impact the encoding of relevant behavioural parameters, as well as their state-dependent modulation. Through this project, I will gain a better understanding of the neural and molecular basis of adaptive behaviour, as well as advance the research field in fundamental aspects of habenular physiology and functional roles of circuit asymmetries.
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| 09/11/2021 |
£300,000 |
UNIVERSITY OF OXFORD |
Over 60% of Parkinson’s disease (PD) patients will experience visual hallucinations (VH) as their disease progresses. The mechanisms underpinning VH are not well understood, hindering development of treatments. VH in PD likely relate to the inability to resolve ambiguous visual information; a process shaped by inhibitory neurotransmitter GABA in the healthy brain. Here, I will investigate the role of pathological GABAergic inhibition in visual processing that may result in VH.
My proposal has two aims. First, to identify the subtype of GABAergic signalling (tonic vs. phasic) that predominantly affects ambiguous visual processing, thus introducing new pharmacological targets for reducing misperceptions. Second, to identify connections between brain regions that relate to pathological GABAergic signalling during VH in PD. Using non-invasive non-invasive ultrasound neuromodulation, I will target these connections to reduce VH in PD.
My work will use complementary methods in healthy adults and PD patients with VH, overcoming limitations that testing either population would incur. I will provide a mechanistic understanding of VH, proposing putative targets for therapeutic interventions to alleviate VH symptoms in PD patients.
Key words: Parkinson’s disease, visual hallucinations, GABA
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| 09/11/2021 |
£300,000 |
UNIVERSITY OF OXFORD |
Anorexia nervosa (AN) is a serious psychiatric condition characterised by restricted food intake that leads to life-threatening weight loss. AN patients suffer with disruptions in the metabolic and neurocognitive processes that guide eating behaviour. However, it remains unclear how these processes interact to drive a core AN feature: maladaptive choice behaviour, where patients prefer low-calorie foods despite starvation. This fellowship will examine how interactions between metabolic markers and neural mechanisms involved in value-based choice shape eating behaviour in AN. To achieve this, I will combine computational modelling, high-field (7-Tesla) neuroimaging and metabolic profiling to comprehensively characterise, for the first time, how AN patients estimate reward value and use it during decision-making, by addressing three primary aims:
Develop behaviour assays to examine value-guided decision-making in AN for food and non-food reward and apply computational modelling techniques to generate estimates of reward value.
Optimise 7-Tesla functional neuroimaging of dopaminergic midbrain activation during decision-making.
Apply these tools in a high-field, case-control neuroimaging study of AN to investigate group differences in the neuro-computational mechanisms of value estimation, examine how these are modulated by gut hormones, and test whether they predict real-world eating behaviour and symptom trajectories.
Keywords: Anorexia, decision-making, 7-Tesla MRI, midbrain nuclei
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| 09/11/2021 |
£300,000 |
UNIVERSITY OF OXFORD |
Post-translational modifications (PTMs) greatly diversify the properties and functions of proteins. ADP-ribosylation (ADPr) catalysed by the family of PARP enzymes is a therapeutically-relevant reversible nucleotide-sugar PTM with roles in pathogen infections, immune signalling, and the DNA damage response.
Recently, advances in proteomic techniques enabled the identification of non-canonical cysteine (Cys) ADPr modification sites in human cells. PARP7 has been proposed as a Cys-ADPr-transferase while PARP8 is auto-modified exclusively on Cys, strongly suggesting inherent Cys-ADPr activity. Human Cys-ADPr hydrolases are currently unknown. Multiple known Cys-ADPr substrates and phenotypes from mouse PARP7 knockout suggest roles in cancer and important physiological roles in the regulation of the immune system and development. Despite recent findings, very little is known about the molecular mechanisms of Cys-ADPr signalling and its roles in human cell signalling.
I will perform systems-wide profiling of Cys-ADPr sites in human cells using a novel enrichment technology and mass spectrometry-based proteomics. Using CRISPR-Cas9 genome editing as well as biochemical approaches, I will develop a toolkit to study this PTM site-specifically to ultimately characterise its roles in cellular signalling. This will inform future drug discovery efforts that exploit site-specific targeting of cysteine PTM sites.
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| 09/11/2021 |
£300,000 |
UNIVERSITY COLLEGE LONDON |
Mental health problems have a significant impact on society. Health-related behaviours such as sleep, exercise, dietary habits, alcohol use and smoking are modifiable and may be important risk-increasing or protective behaviours associated with depression, anxiety and psychosis. The biological and causal mechanisms underlying these associations are, however, poorly understood. Additionally, both children’s and their parent’s health-related behaviours are associated with childhood mental health symptoms, suggesting that intergenerational mechanisms may be important.
During this fellowship, I will use advanced genetically informed designs to investigate whether shared biological pathways and causal relationships may explain associations between health-related behaviours and mental health. I will identify genes involved in these associations and investigate their biological implications. Causal relationships will be investigated using new methods that mitigate bias due to unmeasured confounders, and whilst accounting for intergenerational transmission of risk. I will investigate whether genetic or environmental mechanisms can account for intergenerational associations.
Findings will advance aetiological models and inform causal inference. Confirming causality will be essential knowledge to help prioritise targets for intervention. Findings can inform whether interventions will be most promising when aimed at parents, in the case of environmentally mediated routes of transmission, or individuals, in cases of genetic transmission risk.
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| 09/11/2021 |
£300,000 |
UNIVERSITY OF OXFORD |
Sleep is a vital physiological process. However, we still lack a molecular interpretation of sleep pressure and a detailed map of the neural circuits underlying sleep regulation in the mammalian brain. Drosophila research informs us that oxidative stress build up, and sensing by beta-subunits of voltage gated potassium channels could reflect an evolutionarily conserved principle which underlies accumulating sleep need, a process termed sleep homeostasis. I recently demonstrated that mammalian cortex plays a role in vigilance state control and sleep homeostasis. My project merges these two lines of research and tests if pyramidal neurons in the cortex sense sleep need via redox-sensitive KVbeta subunits and subsequently initiate sleep through projections to the centromedial thalamus and lateral hypothalamus. I will perform in vivo electrophysiological sleep recordings in Kcnab1-3 mutant mice and chemogenetically stimulate cortical pyramidal neurons to assess whether sensing of oxidative biproducts of neuronal activity underlies sleep homeostasis. I will further perform optogenetic stimulation of pyramidal neuron terminals in centromedial thalamus and lateral hypothalamus and use retrograde tracing to map out the pathways through which cortex interacts with subcortical sleep-control areas. This project could reveal key principles of sleep physiology and advance sleep science and sleep medicine alike.
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| 09/11/2021 |
£300,000 |
UNIVERSITY OF CAMBRIDGE |
During early embryonic development, pluripotent cells differentiate, change shapes, and rearrange spatially to form the blueprint of the adult body. Classically, the orchestration of cell fate commitment in the developing embryo has been attributed to the activity of biochemical signalling pathways. More recently, biophysical factors have emerged as important players in this process.
The aim of my research project is to explore how cell fate is influenced by cell surface mechanics in gastruloids, a multicellular model system mimicking a gastrulating embryo. I will first trace changes in cell shape and mechanics concomitant with cell differentiation towards mesendoderm and neurectoderm in the multicellular context of the gastruloid. To achieve this, I will implement advanced microscopy techniques and state-of-the-art methods for in situ mechanical characterisation. In the final stages of the projects, I will perturb cell mechanics during gastruloid growth using (opto)genetic tools, and monitor the impact of these perturbations on cell fate and spatial patterning.
My project will generate a single-cell-level understanding of the interplay between cell surface mechanics, cell shape, and cell fate in developing gastruloids, and thus contribute to answering the long-standing question in developmental biology of how physical determinants coalesce with biochemical signalling to drive embryogenesis.
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| 09/11/2021 |
£300,000 |
UNIVERSITY COLLEGE LONDON |
My research aims to develop a new generation of sensitive, low-cost, nanoparticle-based diagnostic platform technologies by exploiting the quantum properties of nitrogen-vacancy centres in fluorescent nanodiamonds. My previous proof-of-concept work showed that selectively manipulating their fluorescence with microwaves gave a fundamental detection limit of just 0.5 particles/µL in lateral flow assays, a 105-fold improvement over commonly used gold nanoparticles. Their brightness and electromagnetic field manipulation enable biosensing modalities that are not possible with existing technologies. In this fellowship I will:
Develop proximity-based assays using nanodiamonds with magnetic nanoparticles, addressing the limitations of FRET-based approaches. Preliminary feasibility modelling suggests possible separation distances up to 930 nm, allowing a range of diagnostic assays using larger biomolecules. This could also allow the separation of specific and nonspecific signals using optically detected magnetic resonance.
Combine CRISPR-based diagnostics with nanodiamonds, removing the amplification step currently required to reach clinical sensitivities. I will develop a tri-functional probe with a low-cost nanodiamond lateral flow readout, giving a projected 7,500-fold improvement over gold nanoparticles.
Investigate time-gated fluorescence imaging – exploiting nanodiamonds' relatively long fluorescence lifetimes – in combination with previously demonstrated microwave modulation, to further reduce background in lateral flow, improving nanodiamond detection limits towards the single-particle regime.
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| 09/11/2021 |
£300,000 |
UNIVERSITY OF CAMBRIDGE |
My main objective is to address outstanding questions of how inductive cues direct cell-fate specification in the early mouse embryo, focussing on the second fate decision, where FGF4 signalling mediates asynchronous segregation of the inner cell mass into epiblast and primitive endoderm (PrE). Current understanding of this developmental step is limited to cell-intrinsic properties, like intracellular signalling and transcription factor networks, whereas the mechanisms of ligand delivery remain unknown. I hypothesize that local variations in the FGF4 morphogen gradient are driving the asynchronous allocation of epiblast and PrE. Here I propose to determine (1) how FGF4 is communicated from cell-to-cell and (2) how this signal is differentially integrated to produce cell-fate decisions. To accomplish this challenging task, I will employ the tools of live-cell single-molecule localisation microscopy (SMLM) to image the FGF4 morphogen gradient and transcriptional outputs, in vitro and in vivo. This work will result in the creation of machine learning platforms for the analysis of SMLM data and a quantitative spatiotemporal model for the formation of the FGF4 morphogen gradient. This interdisciplinary project will allow me to directly measure previously inaccessible parameters about the FGF4 morphogen gradient that have long been sought.
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| 09/11/2021 |
£300,000 |
UNIVERSITY OF YORK |
Horizontal gene transfer (HGT) enables microbes to rapidly acquire novel genes such as those conferring antibiotic resistance. Virus-like particles called gene transfer agents (GTAs) mediate high-frequency HGT but remain largely unstudied.
Understanding how GTAs recognise their hosts will allow us to assess their impact on environmental HGT and will inform biomedical applications such as gene delivery to the microbiome. To achieve this, I aim to characterise molecular mechanisms of receptor recognition by GTA proteins. Putative receptor-binding proteins will be produced, and their carbohydrate ligands identified by glycan arrays and mass spectrometry. The importance of individual protein regions will be assessed by structural analysis of protein-ligand complexes and domain exchange between two related GTA producer species.
Knowledge of how GTA particles package bacterial genes during assembly is important for understanding GTA evolution and for informing strategies to interfere with GTA-mediated HGT. I aim to describe DNA packaging in genetically distinct GTAs. Cells in an intermediate state of GTA production will be produced by chemical induction and reporter-based cell sorting. Wild-type and DNA packaging gene knock-out strains will be analysed by mass spectrometry and whole cells by cryo-electron tomography to achieve a holistic overview of the DNA packaging process in situ.
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| 09/11/2021 |
£300,000 |
UNIVERSITY COLLEGE LONDON |
Macropinocytosis is an evolutionarily conserved yet ill-studied endocytic process. It is characterised by the formation of Rac1-actin-dependent membrane ruffles and shares the same core machinery with the process of cell migration. Macropinocytosis can be utilised by professional antigen-presenting cells like macrophages to sample their surrounding environments for signs of infection or by cancer cells to fuel their proliferation. Despite its important roles in many pathophysiological conditions, factors that regulate macropinocytosis remain largely unclear.
Traditionally, it is believed that growth factors play a central role in triggering macropinocytosis. However, recent in vitro evidence suggests physical cues such as hydraulic pressure and membrane tension also significantly impact this process. Nevertheless, an in vivo model that intercalates physical factors in the regulation of macropinocytosis is still lacking.
This proposal looks at the highly macropinocytic macrophages and aims to combine the advantage of the mechanically tunable Xenopus embryos with the high-resolution imaging capability of zebrafish embryos and larvae to address three key questions:
Can tissue mechanical properties affect the migration and macropinocytosis of macrophages?
Establishing a Xenopus ex vivo primitive myeloid-derived macrophage model for macropinocytosis study.
Can substrate stiffness affect bacterial clearance by macrophages during wounding and inflammation?
Keywords: Macropinocytosis, mechanosensing, macrophages, Xenopus, zebrafish.
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| 09/11/2021 |
£300,000 |
UNIVERSITY OF CAMBRIDGE |
Infectious disease remains a global health burden. Blood and immune cells play a central role in underlying pathology, however long-term consequences of infection on these cells in otherwise healthy people are unknown. This project aims to understand whether infection modifies cellular programmes, leaving scars on the haematopoietic system, even after recovery, that compromise health in later life. Using a murine influenza model, non-infected, infected and recovered groups (where subjects are administered antiviral treatment post-infection and are analysed after a period of time) will be investigated. By combining a DNA barcoding tool with single cell Multiome analysis of bone marrow cells from these groups, a high dimensional comparison of the transcriptome and epigenome of sister cells will be generated. These data will address fundamental questions including whether cell fate potential is and remains perturbed by infection. Next, following bioinformatic stratification of the data and employing in vitro functional experiments to screen candidate genes using CRISPR-Cas9, molecular targets to be manipulated in vivo will be identified. These experiments will address whether it is possible to mitigate effects of infectious perturbations on the haematopoietic system. Overall, this work will begin to elucidate mechanisms driving the response to infection and highlight potential therapeutic interventions.
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| 09/11/2021 |
£300,000 |
UNIVERSITY COLLEGE LONDON |
Obsessive-compulsive disorder (OCD) is a common and debilitating mental health condition with limited treatment success. The first-line psychotherapeutic treatment, Exposure and Response Prevention (ERP), is only effective for ~50% of patients. My goal is to understand this failure and to improve OCD treatment success.
ERP aims to suppress compulsions using precepts from learning theory, but computational mechanisms underlying its success/failure have never been studied. Using a novel task that mimics ERP and applying computational modelling, I will quantitatively characterise clinical predictors of ERP failure in OCD patients undergoing therapy. This will allow me to understand why ERP fails, and how we can improve it to prevent failure.
In a second workstream, I will examine the other major symptom of OCD, obsessions, that psychotherapy currently does not adequately target. Little is understood about how obsessions arise or become distressing in OCD. Using cutting-edge MEG machine-learning decoding techniques, I will examine how mental representations and thought processes are distorted in OCD, which could quantify why obsessions are so distressing and how we can target this core process in future treatments.
Using a computational psychotherapy approach, this research promises to revolutionise how we understand, improve, and construct effective, individualised treatments for OCD.
|
| 09/11/2021 |
£300,000 |
UNIVERSITY COLLEGE LONDON |
Diabetic neuropathy is the most common complication of diabetes, yet the underlying aetiology of this disorder remains poorly understood. A growing body of evidence suggests that diabetic neuropathy involves nerve injury downstream of reduced local blood flow due to capillary dysfunction. Pericytes are key regulators of capillary blood flow in other tissues, and are central to the pathophysiology of other diabetic disorders including diabetic retinopathy. Pericyte loss has been reported in patients with diabetic neuropathy, but the consequences are unexplored. We hypothesise that pericyte pathology drives reduced blood flow in diabetic neuropathy, thereby contributing to nerve injury. To test this hypothesis we will:
1) Characterise the progression and distribution of lower limb pericyte, capillary and neuronal dysfunction
2) Elucidate changes in pericyte function and how pericytes contribute to vascular dysfunction
3) Resolve whether pericyte and sensory neuron dysfunction in diabetes occur secondary to hyperglycaemia or ischaemia
4) Translate observed results to the Db/Db type 2 diabetes model and human tissue
To this end, this project will use a combination of ex vivo and in vivo functional study to evaluate the time-course, mechanisms and implications of pericyte dysfunction/loss during diabetes, and how this contributes to diabetic neuropathy.
|
| 09/11/2021 |
£300,000 |
UNIVERSITY OF OXFORD |
T cells use small and dynamic microvilli to efficiently scan cells for abnormalities. Recognition induces synapse formation; a large polarised interface that drives effector functions e.g. cytotoxic granule release. The importance of the actin cytoskeleton in microvilli and synapse formation is well established. However, it remains unclear how actin remodeling is spatiotemporally coordinated to drive these structures and whether they are impacted by metabolic state. This proposal aims to (1) identify the drivers of microvilli formation and dynamics, (2) explain how the cytoskeleton is coordinated from microvillar scanning to synapse formation, and (3) explore the link between cytoskeletal remodeling and metabolism. Aims 1 and 2 will focus on Rho GTPases; the ‘master regulators’ of the actin cytoskeleton. I will use biosensors, optogenetic manipulators, light-sheet microscopy, and computer vision analyses to quantify and manipulate GTPase signaling networks in relation to microvilli and synapse formation in 4D. Aim 3 will use biosensors, pharmacological manipulation, and metabolic readouts to examine the impact of metabolic state on microvillar scanning and synapse formation. All aims will use tuneable reconstituted systems to capture and manipulate these key behaviours. Complete understanding of cytoskeletal remodeling may uncover novel ways to control T-cell function for therapeutic benefit.
|
| 30/09/2021 |
£20,000 |
UNIVERSITY OF AUCKLAND |
This proposal repurposes funding that Wellcome had intended for use to support LMIC delegate travel to the INGSA biennial conference. It would now enable acceleration of our Online Outreach and Training Strategy. Our current funding envelope pre-dates the pandemic, and did not anticipated the extent of online delivery now required. We have tried hard to transform programming with existing resources, but gaps remain. Will now focus on delivery of accessible, inclusive and interactive capacity-building online. We have content that can be turned into pedagogically-robust modules and made available via a reputable learning platform. Deliverables include:
"INGSA Shorts" series of 2-3 minute videos which condense learning/wisdom from the 2021 conference (estimated cost: $12,000 NZD)
Minimum three MOOC-style courses, framed around the conference's themes: Science Advice in Crisis (i.e. lessons learned from the pandemic); Science advice for complex/long-term issues (i.e. foresight/resilience; Evidence/democracy. Content drawn from 2021 conference and other Wellcome/IDRC funded programming including past LMIC workshops, the Covid-19 comparisons, Knowledge Associates projects. This approach leverages the full complement of INGSA programming (estimated cost: $28,000 NZD)
We will work with new INGSA Board and LMIC partners to co-design, contextualise and field-test material, ensuring that content and format is robust and appropriate to context.
|
| 30/09/2021 |
£49,243,757 |
BOSTON UNIVERSITY |
The overall objective of this proposal is to build and accelerate the early development of a globally relevant, scientifically diverse portfolio of antibacterial projects (treatments, preventatives and diagnostics) with scientific/drug development and portfolio management rigor ensuring the most efficient and effective use of funding to deliver clinically valuable projects that, upon graduation from CARB-X, increase the likelihood of securing follow-on funding from private or public funders for advanced-development activities.
The strategy, scope and budget to guide investment priorities will be set by the JOC but is expected to continue to include the most important bacterial pathogens highlighted on the CDC Threat/WHO Priority Pathogen Lists and include projects from early- to clinical-stages of development and will be refined from time-to-time based on strategic review update processes.
The antibacterial preclinical pipeline is in the hands of less than 400 small enterprises. With 5 years of unprecedented success, CARB-X is uniquely poised to identify the most promising programs, provide what these teams lack (funding and gaps in their expertise), and to manage the resulting portfolio to protect us all from drug-resistant infections. We look forward to working with you in the years to come to bring products to patients.
|
| 30/09/2021 |
£89,870 |
UNIVERSITY OF THE WEST OF ENGLAND |
Our goal is to collaborate with the SL+ teams to galvanise innovation in research and practice in ISL, and to enable multiple stakeholders to locate themselves within, access and contribute to the ISL landscape.
We are proposing a three-phase programme of work (each is explained in more detail later):
Explore and map phase: we will develop a ‘landscape view’ of the field. The SL+ projects will be key ‘landmarks’ in this map, and we will contextualise their work in a broader context, and to identify where gaps and opportunities remain.
Connect and develop phase: we will run a series of virtual workshops and events to share and test the emerging findings from the SL+ programme with key stakeholder groups. This phase will focus on three areas: the relevance of the research for current policy and practice; how it can be mobilised; and gaps and opportunities for further research
Mobilise and sustain phase: we will act on the findings of the first two phases to finalise and share useful tools and resources, and we will support network(s) to access and use these. We will support the programme teams and other stakeholders to take forward new research, building on prior learning
|
| 30/09/2021 |
£20,000 |
WORLD OBESITY FEDERATION |
Leveraging our existing projects and partnerships with young people, World Obesity has a unique opportunity to help the HCN expand its audiences, as we mobilise youth organisations from food, health and climate spaces to help disseminate the messages produced and take forward the HCN’s work in 2022. By focusing on youth rather than driving a specific issue ourselves, we open the door to mobilise and create momentum across a wide range of areas relevant to HCN. In the lead up to COP26, World Obesity will work with youth leaders to produce advocacy videos for social media based on the HCN core messages. The short videos will be montaged into a digital youth HCN manifesto, which will be launched at The UN Climate Change Conference of Youth (COY). Following COP26, we will continue to develop the youth arm of HCN, convening a workshop for young people already engaged, as well as other youth leaders who emerged at COP26. The virtual convening will aim to reflect on COP26, refine the HCN’s existing messages and co-create new strategies to progress the HCN’s work in 2022. In Q1 2022 we will also produce three podcast episodes, hosted on our youth facing platform Healthy Voices.
|
| 30/09/2021 |
£49,999 |
UNIVERSITY OF LEEDS |
This award will fund preparatory work for a project exploring "genetic imaginaries" and their cultural and biomedical genealogies in African literatures and creative cultures. The main aim of this preparatory work is to provide proof of concept for an innovative literary medical humanities methodology: creative writing workshops designed to explore, examine, and observe the creative processes involved in conceptualising and (re)imagining the genetic as it relates to embodied conditions and differences, genetic "categories," lived experience, and public health. Through this award, I will prepare for and run two pilot workshops in Cameroon and Nigeria to establish protocols and good practice for creative writing workshops as part of an interdisciplinary medical humanities methodology. I will also develop my theoretical and practical understanding of co-production through research and mentorship, undertake field trips to make connections with medical humanities researchers and publishers, and extend my conceptual thinking on genetics. I have arrived at these plans following careful reflection in response to the constructive feedback of the Wellcome interview panel for my prior application to the Wellcome Research Fellowship in Humanities and Social Sciences Award scheme. Through these activities, I hope to lay the groundwork for an application to the Wellcome Career Development Award.
|
| 30/09/2021 |
£19,667 |
PUBLIC HEALTH ASSOCIATION OF SOUTH AFRICA |
We aim to primarily disseminate HCN’s messages on Energy Systems That Protect Climate and Health to government and civil society so as to promote health- centred climate policy and advocacy in South Africa.
Expected outcomes:
A database of audiences for a targeted dissemination campaign;
a social media campaign about the key HCN messages;
press releases with AMREF and the SA Medical Association;
monthly webinars about climate and health at COP26;
regular engagement with HCN global partners in the run up to COP26;
a published journal paper about the campaign;
an online resource for public health educators and professionals about protecting public health from climate change, and educating for sustainable healthcare, which incorporate key HCN policy messages.
These will support HCN’s intended short-term outcomes by enhancing collaboration between health and non-health advocacy organisations in SA; disseminating key messages of HCN briefs to key target audiences; and strengthening the capacity of PHASA as a champion for health- centred climate policy and advocacy in SA, especially with respect to energy policy.
|
| 30/09/2021 |
£99,600 |
UNIVERSITY OF CAMBRIDGE |
The proposed economic analysis aims to estimate the extent to which a carbon price on energy could transform road transport, increasing active travel including the use of public transport, bringing benefits to both the climate and health. This extends an analysis underway (Phase 1) assessing the impacts of carbon pricing on the land-use sector on agricultural production, food prices, diets, and health outcomes.
The work will comprise modelling the consequences of carbon pricing at two levels: (i) keeping global temperature rise below 2oC above pre-industrial levels; (ii) achieving a rise of less than 1.5oC. The analysis will also consider potential differential effects of carbon pricing across socio-economic groups and between high, medium and low-income countries, as a basis for identifying policy interventions to equitably mitigate harmful outcomes.
This analysis will contribute to the goal of The Lancet-Chatham House Commission which is to identify actions that can impact positively across the shared drivers of threats to human and planetary health. Importantly it will provide novel evidence for the ways in which co-benefits and co-costs of interventions might form a significant part of the political and economic cases for intervening at national and international levels and optimising policy design.
|
| 30/09/2021 |
£262,700 |
UNIVERSITY OF SHEFFIELD |
Not available |
| 30/09/2021 |
£76,300 |
UNIVERSITY OF LEIDEN |
Not available |
| 30/09/2021 |
£20,000 |
RESEARCH AND TRAINING CENTER FOR COMMUNITY DEVELOPMENT |
NCDs-VN (hosted by RTCCD), together with other national partner NGOs, is poised to establish a CSOs-One Health and Climate Change Partnership (CSO-OHCCP) to increase government action and coordination on health and climate change. The CSO-OHCCP will use the HCN policy briefs and recommendations as a basis for engagement with Vietnamese government ministries to influence key policies relating to health and climate change, and will work closely with national government delegates attending COP26 to encourage incorporation of HCN policy priorities into national negotiating positions. This will be achieved through the translation of materials, organisation of meetings and events for both civil society and government, policy submissions to government, and accompanying communications campaigns, as well as direct participation in the Vietnamese COP26 delegation. Through this work, civil society organisations working across health and environmental issues in Vietnam will become united and better coordinated and will continue to advocate on health and climate change in months and years to come. RTCCD/ NCDs-VN will be responsible for overall management and delivery of the project, and makes this proposal for activities with a budget of 20,000 GBP.
|
| 30/09/2021 |
£20,000 |
BRAZILIAN INSTITUTE FOR CONSUMERS DEFENCE |
Considering the current discussions on the urgency for food systems transformation and climate change mitigation, in view of the UN global events Food Systems Summit and COP26 and their outcomes, Idec proposes to articulate partners and deepen discussions at national and regional levels, influencing the political agenda. The proposal's objectives are: 1) To translate and disseminate the four Health and Climate Network (HCN) briefings in order to expand dialogue with strategic partners in Latin America involved in COP26; 2) To promote discussions to deepen connections on current food systems and their outcomes on the people's and planetary health in Brazil and Latin America.
Proposed activities are: a) To translate to Portuguese and Spanish and disseminate the four briefings in Idec's own media and explore other media and share them among strategic partners in Latin America; b) To present the HCN Briefing 1 on Food Systems in strategic meetings, to discuss its recommendations in Brazil; c) To fund investigative journalism from a well-recognized journalism agency to further deepen the discussions raised in Briefing 1, producing in-depth materials about food systems and climate agenda; d) To develop podcast episodes on topics related to Briefing 1 targeting key stakeholders on the climate agenda.
|
| 30/09/2021 |
£20,000 |
SLOCAT PARTNERSHIP ON SUSTAINABLE, LOW CARBON TRANSPORT |
Tackling transport emissions has positive impacts. The benefits of transforming mobility paradigms spans across the notion of planetary health that includes human health and the health of our planet. Whether it is curbing emissions, reducing deaths in road crashes, enabling healthy lifestyles, supporting mental health with reclaimed streets or better integrating spatial and transport planning; the transport-air pollution-health-climate nexus is a multiplier.
Aim: Strengthening the nexus to advance two complementary objectives by March 2022:
Capitalise on the interdependence between the enablers and disruptors of transport systems transformation and health to influence climate action policy and investment frameworks.
Facilitate medium-, long-term strategic collaborations beyond the transport community.
Intended Outcomes
Mutually-reinforcing benefits of transport, health & well-being and climate action better understood.
Economies of scale and costs of inaction soundly established and clearly communicated.
Structured collaboration between a diverse group of experts, thought leaders and policy-makers.
Transport policies and investments defined with an integrated look at health implications and vice-versa.
Target Audience
Policy makers, sectors associations, knowledge and academia, governments, multilateral organisations, NGOs, philanthropy and industry
Global, national and local level actors engaged in the international processes on climate change and sustainability (e.g. COP26 and the Second UN Conference on Sustainable Transport).
|
| 30/09/2021 |
£19,956 |
PUBLIC HEALTH FOUNDATION OF INDIA |
The proposed work aims to convene stakeholders-health professionals, academia, civil society organisations, think tanks and policy makers to disseminate the recommendations from the policy brief on climate resilient health systems developed by the Health and Climate Network(HCN). The Public Health Foundation of India(PHFI) and its sister organisation- Centre for Chronic Disease Control(CCDC) are strategically poised to deliver the stated objectives given the extensive networks and collaborations already existing as a platform for transformative work with the health systems in India. PHFI's Centre for Environmental Health , recognised as a Centre of Excellence by the Government of India's Ministry of Health and Family Welfare within its National Program for Climate Change and Health, is engaged in providing technical inputs for development of an implementation framework for green and climate resilient health systems which will be customised for use across every state in India. CCDC's Health and Environment Leadership Platform(HELP), established collaboratively with Health Care Without Harm works with private hospitals to commit to decarbonisation as part of the Race to Zero initiative of UNFCCC for COP 26 and beyond. The team will leverage recommendations from the specific brief and related briefs on energy, transport and nutrition to enhance uptake and implementation.
|
| 30/09/2021 |
£300,000 |
ROYAL SOCIETY |
To ensure continuity of a resource valued by both the scientific and education communities, in 2021, the Royal Society Education Committee supported a request for the Society to apply to the Wellcome Trust for legacy funding that will enable it to take over the Science Education Tracker (SET). The Society proposes that it leads the next phase of this research study, while exploring options for future funding and sustainability. SET is a detailed online survey of young people in England aged 11-18, which explores views and attitudes towards science education and STEM careers. The Royal Society has contributed to both previous SET Tracker studies and has secured approval internally for a similar scale of additional funding, were this application successful. As a trusted organisation, independent of government, and with a long-term commitment to science education, the Society will ensure the legacy of SET and maintain the principles and purpose as part of the Wellcome Trust's legacy. The Royal Society will provide governance and oversight of initiative, working with Engineering UK as delivery partners, notably through its research team to oversee procurement and project management. Engineering UK will provide in-kind support to the project equivalent to the Society's own funding.
|
| 30/09/2021 |
£348,227 |
C40 CITIES |
This research will contribute to a more complete narrative for why a rapid and sustainable energy transition is needed. Critically, this work will question the calls for a medium-term reliance on natural gas as a transition fuel. There are legitimate cases for gas as a transitory fuel, but large-scale investment over the next few decades will prevent the world from reaching the 1.5oC climate target, will increase air pollution and negative health impacts, and will increase the risk of stranded assets.
This work will explore optimal urban transition pathways for gas (given that cities are key markets for natural gas), balancing the benefits of gas as a transition fuel with the need for a rapid transition to clean energy. Acknowledging the complexity of such a transition in the various different global contexts of C40 cities, we will develop a number of optimal transition pathways, creating decarbonisation narratives that reflect climate, health and development needs.
Project aim: to model the optimal pathways for a sustainable and equitable transition away from natural gas (based on modelling climate, air quality, health and economic impacts), and utilise the research results to enable cities to make the case for change at COP27.
|
| 30/09/2021 |
£238,000 |
MUSEUMS ASSOCIATION |
The Mindsets Engagement and Fund programme is designed to contribute to the development of science centres, alongside museums, as relevant organisations that represent, support and work with their communities. Science centres will join a mixed cohort that participates in an engagement programme exploring how to apply the "Mindsets" for the science centres and museums of the future and will request funding individually or within partnerships formed within the cohort to run two-year projects up to a value of £150k. External and internal evaluation will run alongside the programme to measure its impact and explore changemaking in the science centre and museum sectors. This application is for part funding for a wider programme in a collaborative partnership with UKRI and the Liminal Space creative agency. A narrative description of the wider programme with associated logic model, budget and timeline is enclosed in attachments to this application.
|
| 30/09/2021 |
£515,058 |
SERVAREGMP |
The proposed project will establish a manufacturing process to produce ZAC-3, intended to be an effective, low-cost IgG1 MAb against cholera, at very low cost and in a thermostable formulation that mitigates or eliminates the need for cold chains. This project concludes with the use of the developed biomanufacturing process to generate sufficient ZAC-3 for use in pre-clinical efficacy and toxicology studies. |
| 30/09/2021 |
£435,000 |
UKRI-MRC |
Not available |
| 30/09/2021 |
£248,605 |
UNIVERSITY COLLEGE LONDON |
The climate crisis affects us all, but not equally. Those who have contributed least to climate change, suffer the most from its health consequences. Racial injustice exists independent of the climate crisis, however climate change provides a new channel through which these discriminations can manifest. In this grant we will explore the intersection between climate, health and racial justice, engaging with the ‘most affected people and areas’ (MAPA).
To realise climate and health justice, MAPA must be central to discussions on reimagining solutions. We will centre our conversations on health inequalities identified by MAPA, prioritising those who are already suffering the worst physical and mental health impacts. We will listen first, via stakeholder meetings in Brazil, the Philippines and Uganda, and then conduct art-based engagement with young people in these sites. The work will be underpinned by evidence collated for an academic review paper and we will develop an educational module that can be used longer term. We will also encourage co-learning across the three sites, where young people can help to empower each other. Our work will target the Conference of the Parties 27 (COP27) meeting, where we will hold an event and also run webinar and podcast series.
|
| 30/09/2021 |
£149,775 |
UNIVERSITY OF HERTFORDSHIRE |
The Primary Science Quality Mark, based at the University of Hertfordshire is seeking a discretionary grant of £149,775.00 from Wellcome to enable it to increase its ability over the next two years to improve leadership in primary science in UK schools most affected by the Covid-19 pandemic. This will address gaps in provision and increase children’s access to exciting, inspiring and relevant science education that leaves them well-prepared to progress further in science, and well-informed about science in their everyday lives.
|
| 30/09/2021 |
£586,671 |
WORLD ECONOMIC FORUM |
Not available |
| 30/09/2021 |
£203,010 |
UNIVERSITY OF OXFORD |
Reporting and sharing cumulative antimicrobial susceptibility testing data on a regular basis is crucial to inform antimicrobial resistance (AMR) action plans at local, national, and global levels. We recently developed and tested in seven hospitals in seven countries a pilot application, "AutoMated tool for Antimicrobial resistance Surveillance System (AMASS)", that allow clinical microbiology laboratories to analyze their routinely collected microbiology and hospital data files (in CSV or Excel format) onsite and generate AMR surveillance reports (in PDF) for immediate use and anonymous summary data (in Excel) for depositing in a data repository website.
Here, we propose to (1) enhance AMASS so that it can generate additional outputs; including crude excess mortality due to AMR infections, crude excess mortality associated with AMR infections, proof-of-principle outbreak detection, and Weighted-Incidence Syndromic Combination Antibiogram (WISCA), (2) improve AMASS codes so that it complies with best-practices in software development and FAIR (Findable, Accessible, Interoperable, Reusable) Data Principles, and (3) pilot implementation and evaluate AMASS in 20 participating hospitals in low and middle-income countries (LMICs).
The project will collaborate with Oxford Tropical network, ACORN and WHONET to ensure that the project will be beneficial, compatible and easy-to-uptake by a wide range of hospitals in LMICs.
|
| 30/09/2021 |
£40,727 |
CBM UK |
The Africa Centre for Disease Control (CDC) is part of the African Union strengthening the capacity of Member States to respond quickly and effectively to disease threats. They are looking to incorporate a mental health strategic plan into their organisational strategy revision, planned for 2022. This was not included in the first 5 year plan (2016-2021), and the result was a relative neglect of the field to date. There is currently strong mental health leadership, a new Mental Health Division, and a commitment to include mental health in the Africa CDC budget based on a strategic plan. Africa CDC asked CBM to help support this project and the Wellcome Trust have given their agreement to support this consultancy project financially whilst the project management will be done by CBM UK.
The key deliverable for this project is a Strategic Plan for Mental Health, that will align to Africa CDC’s overarching strategy and operational processes. It is costed to enable real-world application over five years. Africa CDC have indicated that such a Strategic Plan, presented to the African Union for approval and adoption, is likely to receive funding necessary for its implementation.
|
| 30/09/2021 |
£21,716 |
UNIVERSITY OF EDINBURGH |
To develop and produce a health-environment nexus policy guide that outlines opportunities for global actors to engage with, and link environment and health issues across multilateral environmental agreements (MEAs). This project will target national policy makers, including ministries of health, environment, and foreign affairs.
The guide will:
identify key fora where health and environment issues overlap, provide summaries of relevant priority areas and important policy debates at the environment-health nexus within these fora
focus on the following reference themes: social determinants of health, One Health, and Planetary Health including infectious diseases, non-communicable diseases, mental health, and the climate and biosphere crises, and gender equity
set out negative confluences in climate and health junctures
provide input for the Glasgow Financial Alliance for Net Zero to incorporate planetary health indicators into global financial assessment environmental, social, and governance (ESG) tools
the guide seeks to provide meaningful, succinct, accessible, clear and targeted information to enable health, and environment experts to engage in and follow global processes at a high level, focusing on intersections where policy approaches could incorporate health and well-being issues.
|
| 30/09/2021 |
£25,250 |
UNIVERSITY OF EDINBURGH |
This award supports the expansion of the Malawi Medical Humanities Network (MMHN) through strategic integration within Malawi University of Science and Technology (MUST), Malawi. This new space will facilitate the development of a dynamic research agenda and curriculum, whilst establishing international exchange programmes across the inter-related fields of medical and health humanities and disability studies. MUST's support will position MMHN to engage national collaborators to further pursue interdisciplinary partnerships and develop dynamic learning-based knowledge exchange platforms. This award will enable MMHN/MUST to organise the development of a robust agenda and activities portfolio to 1) facilitate the development of a culturally-informed, translational medical and health humanities approach to address effective modes of community care, 2) to strengthen membership engagement across the country, 3) to promote collaborative and interdisciplinary research projects, 4) to develop competitive scholarship in theory, methods and practice and 5) to showcase national projects that directly address interdisciplinary approaches to public health and community wellness and approach challenging and taboo health issues. Overall, this fund will support the network's transition into a sustainable platform offering greater support to create innovative spaces for interdisciplinary dialogues and define world-leading African crossovers between the arts, humanities, social sciences and health studies.
|
| 30/09/2021 |
£25,750 |
UNIVERSITY OF STRATHCLYDE |
The Society for the Social History of Medicine (SSHM) has a strong record of supporting single and standalone activities organised by our wider community, beyond our biennial and postgraduate/early career researcher events. We have tried and tested criteria for funding to include the necessity to support postgraduate and early career scholars as well as awareness of inclusivity. Wellcome network funding will enable SSHM to direct the Society’s experience into a new and exciting sphere of support: directing funding to networking and networked events. These serial activities promise the space to be both innovative and sustained; a space that has often been limited in the field of the history of medicine and health. What these sustained conversations will do is provide room for creativity and thinking, offering transformative scholarship and assuredly facilitating links and work that would otherwise prove impossible, especially due to our current availability of £1500 per conference funding application, limited so as to support as many activities as possible. We propose to fund between four and seven networks with a maximum of £6000 per award, with two rounds of applications for support.
|
| 30/09/2021 |
£25,750 |
UNIVERSITY OF STRATHCLYDE |
The Society for the Social History of Medicine has a strong track record of providing field-leading conferences in the history of medicine and health, together with postgraduate and early career training and events. Our proposed programme of new and innovative events will allow us to begin new areas of work in the areas of anti-racism, mid-career support, and discussions about career precarity. Wellcome funds will enable scholars to meet at a crucial time for the field, at a time when, with the continuing risk of Covid-19 and other disease outbreaks, the history of medicine has perhaps never been so vital. Bringing scholars together for physical meetings is essential to create the safe space needed for such sensitive discussions as anti-racism, facilitated by a clinical professional and academics experienced in this area, and regarding concerns about careers. The impact of Covid and changes in funding for universities mean many mid-career scholars are in need of support and mentoring, and those without permanent positions are in need of a safe space to discuss the future of the field and the impact on, and potential for, their own work and careers.
|
| 30/09/2021 |
£25,687 |
UNIVERSITY COLLEGE LONDON |
Racism, xenophobia and other forms of discrimination are important and powerful determinants of health that affect populations across the world. The non-profit group Race & Health was set up in 2020 to help combat the adverse health consequences of discrimination through academic work, advocacy and education.
Funding from The Wellcome Trust will enable us to expand the work of Race & Health. We will create a multi-disciplinary global network of experts that will form a ‘Lancet Commission on Racism, Xenophobia and Discrimination’. The commissioners will work collaboratively to produce solutions to improve health. Funding will help establish the network and enable virtual meetings and a physical meeting. Aligned to this, we will work to expand the reach of Race & Health, disseminating our work to the public through our newsletter, and new webinar and podcast series.
|
| 30/09/2021 |
£25,750 |
UNIVERSITY OF ABERDEEN |
Established in 2019, the Menstruation Research Network UK has been able to partake in and document a change in the discourse, policy, and media surrounding menstruation in Britain and the world. Since then, Scotland has passed the Period Product (Free) Provision Act, the UK has formed the Period Poverty Task Force, and the Welsh and Northern Irish governments have outlined similar policies. The network has been involved in these debates, lending interdisciplinary expertise about menstruation to policy makers, academic colleagues, and activists. Today, the continuation of our work is more necessary than ever, as menstrual discourse moves from a focus on products to larger debates about underlying structural issues, such as legal rights, sustainability, and diversity. We propose to continue our network by hosting three blended workshops at the University of Aberdeen, University of St Andrews and Liverpool John Moores University. These events will invite international keynote speakers and diverse stakeholders in and out of academia over the course of four years. Our aim is to strengthen and broaden the network in the UK, link with international colleagues, plan ambitious grant applications, provide mentoring to students and early career academics, and information for policy, media and community engagement.
|
| 30/09/2021 |
£25,438 |
BRITISH SOCIOLOGICAL ASSOCIATION |
We propose the development of a British Sociological Association’s Medical Sociology Study Group ‘research sandpit’, hosted at the group’s annual conference. A facilitated three hour event will enable disciplinary leaders to share opportunities relating to available funding, publication opportunities and disciplinary vacancies, whilst other attendees will have the space to discuss their employment availability, career aspirations and questions about establishing, developing and maintaining a career in Medical Sociology. The Sandpit will be hybrid, hosted online and in person at the wider Medsoc conference location. It will also be available to individuals who are not attending the conference as a free ticketed standalone event.
Discussion, both in person and online, will be stimulated by the display of research posters, and facilitated activities to ensure that attendees are encouraged to engage and maximise the impact of the event. The Sandpit will extend extant networking opportunities provided at the conference, where previous networking innovations have been replicated at the larger BSA annual conference including a well-established mentoring scheme. This event will directly address accessibility brought into relief by the recent pandemic, and our responsibility to ensure that we are creative and innovative in ensuring that Medsoc is a trail blazing organisation for inclusivity.
|
| 30/09/2021 |
£25,750 |
UNIVERSITY OF DURHAM |
Through this Discretionary Award, the Northern Network for Medical Humanities Research (NNMHR) will make funding available to support critical medical humanities research networks. These networks, which involve early career researchers in leading or coordinating roles, will help generate new ideas, methodologies, collaborations and areas of further investigation within the critical medical humanities, nationally and internationally. We will support prospective applicants by running workshops online to explore what makes a successful research network, to reflect upon the benefits and limitations of online working, to address barriers to access, and to share best practice. We will support successful applicants by offering them mentoring, networking resources, and opportunities for profiling their activities. Going beyond the simple distribution of funding, this Discretionary Award will help catalyse exciting and innovative ideas and approaches within the medical humanities research community.
|
| 30/09/2021 |
£25,741 |
UNIVERSITY OF DURHAM |
Extending beyond its geographical focus on the North of England and Scotland, the Northern Network for Medical Humanities Research (NNMHR) now contributes nationally and internationally to development of the critical medical humanities. This Discretionary Award will support the activity of the NNMHR over the next four years, with a focus on
supporting early career researchers to develop, deliver and participate in research-related activities and training;
co-hosting with Durham University’s Institute for Medical Humanities two large-scale international congresses with a significant online component; and
connecting medical humanities researchers with regional cultural institutions in order to forge new collaborations.
|
| 30/09/2021 |
£25,008 |
INSTITUTE OF MEDICAL ETHICS |
The Postgraduate Bioethics Network (the Network) is an interdisciplinary community of bioethics researchers. We strive to connect researchers from all backgrounds, fields and institutional settings.
Our vision is to:
Evaluate, evolve and expand our work to ensure sustainability of the Network and its steering committee.
Provide high quality and accessible network- supporting experiences virtually and in person
Ensure that the Network acts for both a diversity of people and of ideas.
This grant will allow us to achieve our vision by facilitating a range of activities and opportunities for development. We will build on the success of the annual Postgraduate Bioethics Conferences (PGBC) by refocusing on the networking aspects in 2022 and 2023, and incorporating feedback, especially PGBC2021, hosted virtually by Liverpool University.
We will offer further editions of the Bioethics & Media Workshop, oversubscribed in 2021. Two activities that we propose were identified as needs during that workshop: the Bioethics & Media Database and Writing Community.
We seek to build closer relationships with Network alumni by providing space for mentorship and collaboration.
Towards the end of the grant, we will hold a strategic planning event to evaluate our progress in achieving our vision and to plan for the future.
|
| 30/09/2021 |
£251,547 |
INTERNATIONAL CENTRE FOR ANTIMICROBIAL RESISTANCE SOLUTIONS |
ICARS is initiating a project with the Ministry of Health in Zambia aiming to reduce inappropriate antibiotic prescription in Urinary Tract Infections (UTIs), through implementation of a stewardship programme in facilities such as tertiary hospitals, community hospitals, and community pharmacies. The interventions will target prescribers and consider health system factors. However, a gap still exists in current AMR activities in Zambia for engagement with and involvement of the public to address perceptions and practices that impact AMR. This gap is holding back public awareness of AMR issues, as well as building and understanding within the scientific community of the drivers and impact of AMR on communities. This challenge can be tackled through a responsive dialogue process that can address patient perceptions, practices and community-driven solutions. Linkages between the ICARS project and the responsive dialogue process will ensure connections and engagements to ministry officials and policy makers, who are already a part of the ICARS work. This project aims at piloting the Wellcome Responsive Dialogues on Drug Resistant Infections in Zambia. It will be designed by ICARS with input and support from Wellcome, and commissioned to a Zambia-based research institute, with participatory and social research expertise, to design and implement it.
|
| 30/09/2021 |
£2,201,199 |
NEW VENTURE FUND |
Covid-19 exposed major gaps in our ability to aggregate and use data for pandemic prevention, detection, and response. Current approaches require pooled data, which is costly, time-consuming, and legally challenging. Distributed and privacy-preserving methods of analysis are an alternative for generating insight and present new opportunities to use commercially held "health-adjacent" data critical for pandemic analysis and modelling. However, despite the appeal of distributed and privacy-preserving methods of analysis, there are few working examples focused on disease analysis and none that are globally adopted.
This proposal is to build, deploy, and scale innovative solutions – including infrastructure, tools, and analytical techniques to unlock data and enable distributed analysis. Phase 1 will focus on developing the novel software and privacy-preserving methods that will be deployed in Phase 2:
Funding top teams to develop a suite of generalizable, open-source epidemiological software and tools
Challenge funding call to develop privacy-preserving approaches for deployment on commercially sensitive/privately held data, which could be scaled and deployed in Phase 2.
200 Days Architecture Challenge aimed at Big Cloud Providers to design the technical architecture for Phase 2.
data.org will provide the central convening and coordination role, including grant-making, convening interdisciplinary specialists, project management, and strategic communication.
|
| 30/09/2021 |
£649,700 |
DALBERG GLOBAL DEVELOPMENT ADVISORS LIMITED |
See attached document with additional information to answer this question.
|
| 30/09/2021 |
£724,258 |
VILLAGEREACH |
Despite significant progress of the Expanded Program on Immunization in preventing fatal diseases in children in low and middle-income countries, coverage has stagnated over the past decade. We propose a community based participatory and mixed methods research project in diverse settings in Mozambique and Malawi to determine drivers of childhood immunization dropouts as well as context-specific v. scalable solutions to improve full immunization coverage. The research sites will include both urban informal and rural settings. In site selection, we have considered the different ways in which vaccination services are provided. We will implement this study in four-iterative phases:
Identify barriers to childhood immunization access and uptake
Co-develop solutions with communities and understand communities’ roles in generating evidence and solutions
Implement the co-created solutions for up to one year
Evaluate the implementation and early impact of the co-created solutions
We will collaborate with community members, health workers and government stakeholders as participants and partners, and leverage existing partnerships at the global level. Our collaborative approach of engaging caregivers as co-researchers, ensures tailored approaches, which account for context considerations in solution development and promotes community buy-in and commitment to solutions. Tools and learnings will be packaged for broad dissemination.
|
| 30/09/2021 |
£7,323,772 |
DRUGS FOR NEGLECTED DISEASES INITIATIVE |
The COVID Moonshot project focuses on global equitable access to a safe, low-cost oral antiviral treatment that quickly clears SARS-CoV-2 infections and future coronavirus-related diseases. Current therapeutics in clinical trials require intravenous administration and are developed mainly by organizations focusing on a commercial return. This proposal will research an oral treatment to significantly improve patient outcomes in low-resource settings, removing the need for a cold chain or injection and enabling stockpiling of therapeutics for both this and future pandemics We will develop a novel inhibition of main protease (3CL protease) of coronaviruses in order to prevent viral replication, aiming to create a generic drug "straight from the pipeline," facilitating decentralised manufacturing and distribution allowing for rapid patient access. We target effective oral treatment for early stages of disease to reduce viral load, mortality and morbidity (e.g. long COVID). The goal is to progress a compound to Phase I readiness, anticipating clinical trials in 2022. This proposal involves the established Moonshot team complemented by DNDi’s expertise in IP and access strategy, preclinical project management, and drug development. The project aims to maintain the proven open science model adopted from the outset. |
| 30/09/2021 |
£168,401 |
WORLD HEALTH ORGANIZATION, SWITZERLAND |
Not available |
| 30/09/2021 |
£3,136,000 |
ENTHUSE CHARITABLE TRUST |
The ENTHUSE Charitable Trust's charitable purpose is to improve science education, or related subjects, for young people, through the professional development of teachers. Over the period to 2023, ENTHUSE will:
continue to provide science CPD accessible by all teachers and others from state-funded schools, with a particular focus on engaging schools, colleges, teachers and young people most in need of STEM education support so helping close the achievement gap and promote social mobility while raising standards across the board;
build strong, visionary leadership in STEM teaching across primary, secondary and post-16 settings to achieve sustained system-wide improvement, raising standards and expectations;
encourage a culture of career-long, STEM-specific professional learning across the teaching profession, raising morale, and enhancing retention;
significantly raise awareness among schools, colleges, teachers, young people and families of the value of STEM study and STEM-related research and careers, and of the academic, technical and apprentice routes into those roles.
The ENTHUSE Charitable Trust is seeking a budget of £3.136m, with the deployment of Wellcome funding part of a wider mix of income, aligned to the above priorities.
|
| 30/09/2021 |
£1,542,993 |
GAVI, THE VACCINE ALLIANCE |
Vaccine MAPs have significant potential to improve equitable coverage of vaccines, due to their innovative product attributes and anticipated ease of use, which could be very valuable in the fight against enteric diseases such as typhoid. TCV-MAPs could also be an attractive target for the industry because they promise to be technically feasible and may be commercially attractive. To assess and quantify the potential value of a TCV-MAP, this project will develop a Full Vaccine Value Assessment (FVVA) including the potential public health need for a TCV-MAP, its programmatic impact and socio-economic benefit. If the proposed FVVA demonstrates high value for TCV MAPs, it could accelerate TCV-MAP development and preparation for uptake in countries. The processes and methodologies reviewed or developed during this FVVA could be useful for the assessment of other vaccine MAPs or other vaccine-delivery product innovations. |
| 30/09/2021 |
£99,999 |
OPEN LIFE SCIENCE |
Open Life Science (OLS, https://openlifesci.org/) offers a 16-week long cohort-based training and mentoring programme that enables researchers to learn about, reflect on and integrate open science principles in their work. The Open Research Fund will support the continuation of OLS and the delivery of three cohorts of the programme in 24 months. In addition to supporting the volunteer members (up to 30 projects, 30 mentors and 15 experts per cohort), OLS will recruit a full-time staff (1-FTE) for 18 months to conduct a long-term impact study and provide administrative support to the leadership team.
A successfully completed Open Research Fund activity in OLS after 2 years of funding period will have enabled:
(i) research-based evaluation and enhancement of the OLS curriculum, training materials, mentoring formats and value-based approach to community development,
(ii) incentivised integration of contextual (sociotechnical and cultural) knowledge of mentors and project leads in the open science project they develop in the program,
(iii) enhanced representation and equitable participation of health researchers and community builders from the Global South in a shared vision for the global open science through collaboration,
(iv) assessment of the long-term impact of OLS on the careers of the OLS participants and adoption of contextualised open science practices in research work in their regional contexts across low- and middle-income, as well as high-income countries, and
(v) publication of a series of reports capturing different outputs, building open source evidence base and inviting support for the sustainability of OLS over the next 5 years.
|
| 30/09/2021 |
£99,000 |
WITS HEALTH CONSORTIUM (PTY) LTD |
This project seeks to address existing data sharing concerns of African public and population health researchers. It also motivates for the implementation of Africa-led initiatives for data sharing. Using acquired knowledge on global best practices and regional concerns, the project will design sustainable mechanisms to incentivise data sharing. This will involve leveraging our strategic partnerships and adopting artificial intelligence (AI) tools to implement solutions to some of the concerns. We will improve data sharing value chain; simplify access and utilization of data; and strengthen capacity and advocacy towards incentivised data sharing.
Using AI tools, we will develop a virtual and physical environment for active and passive identification and curation of a list of publicly funded research data in public and population health in Africa; link researchers and research institutions to reusable publicly funded data; increase awareness and address fears and misconceptions about data sharing; and advocate for institutions to provide best practice rewards when data is shared.
These activities will result in improved knowledge, attitude, and practices on data sharing by researchers, institutional data custodians and institutional management; increased collaboration and knowledge generation among researchers; and incentivisation of data sharing at institutional level. The project will promote scientific data findability, access, and reusability while simultaneously addressing data governance and trust concerns, fear of data misuse and exploitation, and ensuring compliance with privacy, security, and ethical standards on data sharing.
|
| 30/09/2021 |
£97,867 |
UNIVERSITY OF OTTAWA HEART INSTITUTE |
The completion of the proposed research program will result in two key outputs: 1) a core outcome set of open science (OS) metrics relevant to, and developed by, the biomedical community; and 2) a usable flexible, tailorable, and automated tool, developed using user-centred design best practices, that reports on these core OS metrics.
Establishing a core outcome set of OS metrics is a vital step to move forward discussion around how to measure research(er) quality. Without consensus on what to measure, or how to measure it, even well intended institutions can’t easily consider incorporating metrics beyond those traditionally used (i.e., journal impact factor or number of publications). A core outcome set does not limit organizations from tailoring the collection of OS metrics, but ensures a standard set across organisations to enable national and international standardisation and comparison.
By engaging with the research community at the onset of this program and throughout via an integrated knowledge translation approach, we can ensure that the tool we develop to report on the established core OS metrics meets the needs of the community and considers their concerns. Doing so ensures greater uptake. Further, through embedding considerations of equity, diversity, and inclusion in our design of the OS dashboard, we intend to create a tool that is globally relevant in biomedicine. This will ensure that our impact is as broad as possible and serves the entire biomedical community. By meeting our proposed aims, we will have achieved a ready to implement publicly available OS dashboard.
|
| 30/09/2021 |
£61,203 |
PUBLIC LIBRARY OF SCIENCE (PLOS) |
We aim to have significantly increased the availability of research data associated with peer-reviewed publications in a Findable, Accessible, Interoperable and Reusable (FAIR) manner. By pioneering the seamless integration of a data sharing tool into the scholarly publishing workflow and removing barriers, including cost, to researchers receiving data curation support, in the pathogens community, we aim to increase data repository use by at least 10%. We will also determine if prominent visual cues (links) on publications are an incentive for researchers to share research data in repositories without support from an integrated tool, and determine the ability of these visual cues to support data discoverability and reuse, in multiple communities. The outcomes will enable PLOS, and other scholarly publishers, to make evidence-based decisions about the costs and benefits of increasing sharing of research data in compliance with the FAIR data principles. This will enable PLOS to determine suitability of rolling out these solutions more widely among its journals, which could potentially increase the availability of FAIR data more substantially. We will also understand the attitudes and experiences of researchers in the target community with these two data sharing solutions; determine if these attitudes change after implementation of the solutions, and potentially identify new opportunities to support data sharing and reuse that can be explored in future research or initiatives. The reported outcomes and any accompanying data, such as from user surveys, will be openly available to support decision making by funding agencies, publishers, researchers, institutions and infrastructure providers.
|
| 30/09/2021 |
£463,969 |
YOUBELONG UGANDA |
Summary: Mental health services are most effective and equitable when designed, delivered, and evaluated in collaboration with people with lived experience of mental illness. Unfortunately, people with lived experience are rarely involved in health systems strengthening, and when they are, it is limited to specific components (e.g., peer helpers) rather than across-the-board collaboration in the continuum of health services. We are proposing a novel approach for collaboration with people with lived experience of psychosis that includes involvement at the primary care, community, and home settings. By collaborating on health systems strengthening across these multiple levels, we foresee a more in-depth contribution that can lead to rethinking how best to design and deliver care for people living with psychosis. We will pilot this multi-tiered collaboration with people with lived experience in Uganda because low-income countries represent the greatest gaps in access to evidence-based mental health care. We will conduct a pilot cluster randomized controlled trial of "Strengthening CAre in collaboration with People with lived Experience of psychosis in Uganda (SCAPE-U)". We will train people with lived experience of psychosis using PhotoVoice and other methods to participate at three levels: primary health care, community and home level. The primary objective is to evaluate the feasibility and acceptability of SCAPE-U. This pilot will also be used to prepare a future grant in which we will conduct a fully powered cluster randomized controlled trial that will evaluate health systems outcomes and service user outcomes, including quality of life, lower symptom severity, less disability, lower rates of relapse, and less hospitalization. |
| 30/09/2021 |
£59,735 |
GEORGE WASHINGTON UNIVERSITY |
Mental health services are most effective and equitable when designed, delivered, and evaluated in collaboration with people with lived experience of mental illness. Unfortunately, people with lived experience are rarely involved in health systems strengthening, and when they are, it is limited to specific components (e.g., peer helpers) rather than across-the-board collaboration in the continuum of health services. We are proposing a novel approach for collaboration with people with lived experience of psychosis that includes involvement at the primary care, community, and home settings. By collaborating on health systems strengthening across these multiple levels, we foresee a more in-depth contribution that can lead to rethinking how best to design and deliver care for people living with psychosis. We will pilot this multi-tiered collaboration with people with lived experience in Uganda because low-income countries represent the greatest gaps in access to evidence-based mental health care. We will conduct a pilot cluster randomized controlled trial of "Strengthening CAre in collaboration with People with lived Experience of psychosis in Uganda (SCAPE-U)". We will train people with lived experience of psychosis using PhotoVoice and other methods to participate at three levels: primary health care, community and home level. The primary objective is to evaluate the feasibility and acceptability of SCAPE-U. This pilot will also be used to prepare a future grant in which we will conduct a fully powered cluster randomized controlled trial that will evaluate health systems outcomes and service user outcomes, including quality of life, lower symptom severity, less disability, lower rates of relapse, and less hospitalization. |
| 30/09/2021 |
£49,583 |
UNIVERSITIES UK |
Not available |
| 30/09/2021 |
£261,943 |
UNIVERSITY OF DUNDEE |
Drug discovery is a slow process with a high attrition rate. A key challenge is the optimisation of fragment hits and chemical start points, which requires simultaneous optimisation of multiple parameters – activity, selectivity, physicochemical, pharmacokinetic and toxicological properties. Further only relatively few compounds can be made and profiled in a programme from the vastness of chemical space. Our overall vision is to produce a platform to speed up the drug discovery process to produce clinical candidates with a good developability profile. In this collaboration between the University of Dundee and University of Oxford, we are aiming to produce computational design methods that adequately sample chemical space, driven by prediction of both properties and biological activities of the compounds. The aim will be to rapidly design compounds to make, which have the highest likelihood of satisfying Target Candidate Profiles. This will then feed into a high throughput chemistry platform to rapidly make and test compounds designed, with emerging data being fed back into the design platform. This should reduce the number of design-make-test-analyse cycles and will be tested in Dundee’s Neglected Tropical Disease drug discovery programmes. |
| 30/09/2021 |
£375,808 |
UNIVERSITY OF OXFORD |
Ethical, legal, and social aspects of AI have received unprecedented international attention in recent years. Many technical and organisational tools, such as statistical tests for fairness or ‘Algorithmic Impact Assessments, have been developed to make AI more accountable and trustworthy. However, the efficacy of these tools in practice across different use cases and application types remains unproven. The proposed multi-disciplinary project will develop a ‘trustworthiness auditing meta-toolkit’ to evaluate the efficacy of AI accountability tools in healthcare and scientific research. Over three years we will (1) assess the social and institutional norms, legal mandates, ethical values, and technical constraints guiding the development and governance of trustworthy AI systems; (2) develop the necessary evidence base and technical/organisational tools needed assess the efficacy of AI accountability toolkits; (3) draft policy proposals and best practices that describe standards for effective and trustworthy usage of AI accountability tools; and (4) publish these outputs as an open access meta-toolkit for researchers, civil society, regulators, and industry. Case studies in healthcare and scientific research will be carried out with partner organisations to build and validate all aspects of the meta-toolkit. This project is proposed on a consortium funding basis in partnership with Sloan Foundation and NHSx.
|
| 30/09/2021 |
£277,363 |
UNIVERSITE DE MONTREAL |
Changes in biodiversity, both natural and caused by human activities, are intimately tied to changes in ecosystem status. The environment in which species live will affect their chances of movement, survival, and adaptation; for example, abrupt changes in vegetation cover can modify the risk of predation experienced by some species, and therefore change the relative abundance of their populations. But because species express a variety of biological functions, they too change the status of their ecosystem; for example, harmful algal blooms will disrupt the physical and chemical composition of water, which can lead to localized extinctions, and send rippling effects across the ecosystem. As such, the biological and the ecosystemic are indissociably coupled. Nevertheless, effectively coupling models at these scales has proven difficult, because of three core challenges: differences in scale, differences in how models are built, and volume of data required.
Biodiversity and ecosystem sciences have made progress on these challenges, and developing a field-specific case study to integrate models and pre-existing work will inform about the feasibility of a more general approach to model coupling. We believe this approach to be necessary for accurately identifying emerging challenges and opportunities in global ecosystem sciences, intrinsically tied to human wellbeing.
|
| 30/09/2021 |
£2,013,582 |
ELIFE |
In recent years, eLife has embraced the rise of preprints in the biomedical sciences and adapted its processes to make the review of preprints its central goal. We have developed Sciety, which allows researchers to discover refereed preprints from across the web, to highlight the value of preprint review as an alternative to traditional journal publishing. We aim to create a new publishing model where research is published as a preprint, then reviewed and curated by participating groups.
This proposal outlines the steps required to build out an end-to-end workflow to support this model. Over three years we will develop Sciety to support author submission, peer review management and community curation. Over the first year we will work with a ‘model customer’ to develop the full workflow, then spend two years enhancing and adapting the model for a diverse range of partners, including publishers and funders.
We will work with existing preprint servers such as bioRxiv, open source providers such as Coko Foundation, and journal providers such as PubPub, thereby fitting into the existing ecosystem rather than building a new one. This approach, combined with our existing work to build the community, will ensure the long-term success of the platform.
|
| 30/09/2021 |
£2,000,000 |
EAT FOUNDATION |
EAT is pleased to submit this request for a continuation of Wellcome’s support for EAT knowledge engagement and communications activities. In collaboration with SISTEMIQ, FOLU, and PIK, we continue to progress on the Food System Economics Commission building on the foundational work of the EAT-Lancet Commission, and FOLU’s Growing Better report. . Second, after consulting with numerous EAT partners, including the Wellcome Trust and the Lancet, we are pleased to submit a proposal for a five-year revision of the EAT-Lancet Commission, or the EAT-Lancet 2.0 (EL2.0). This will be a critical revision of the Planetary Health Diet (PHD), amongst other topics, EL2.0 will include: a focus on the diversity of local diets that fall within PHD ranges; a focus on food production practices to complement the important consumption focus work of EL1.0; novel work on the "socially just" dimensions of healthy foods from sustainable production system; and an important IPCC style intermodel comparison. We will invite a third co-chair to join Dr. Willett and Dr. Rockstrom to lead EL2.0 with a focus on the "socially just" elements of the Commission. Third, EAT thanks Wellcome for its continued support, including to core institutional functions.
|
| 30/09/2021 |
£2,284,586 |
UNIVERSITY OF CAMBRIDGE |
The recently emerged SARS-CoV-2 variants of concern (VOC) have altered transmissibility, virulence and susceptibility to neutralising antibodies, leading to concern over the potential for new variants to emerge that have increased resistance to vaccine-induced immunity. This has led to a renewed focus on the deployment of whole-genome sequencing surveillance to detect variants early, to stop or slow their spread, and to enable vaccine programmes to adapt.
However, despite increased genome sequencing, disparity in access to laboratory support and genomic sequencing across the globe has become increasingly evident: to date West and Central Africa produced ~2,000 sequences ( 400,000 from the UK. The VOCs such as P.1 in Brazil and B.1.351 in South Africa can emerge anywhere, further highlighting the urgent unmet need to develop sustainable solutions for COVID-19 sequencing in this underserved region.
This proposal builds on the experience of the ARTIC network and regional collaborators to support SARS-CoV-2 sequencing in West and Central Africa.
The key goals of this proposal are to:
Develop a hub and spoke network of SARS-CoV-2 sequencing labs in West and Central Africa.
Develop a suite of COVID-19 focused training materials and tools for whole-genome sequencing and subsequent data analysis.
|
| 30/09/2021 |
£291,279 |
UNIVERSITY OF BRISTOL |
We propose developing an understanding of how responsible research is conceived and realised, both across disciplines, and across institutions in Europe, grounded in the framework provided by the Singapore Statement on Research Integrity1. The project will include three main phases (described in more detail below):
Phase 1: Scoping responsible research across disciplines and institutions.
Researcher attitudes to responsible research will be assessed via a survey across a range of research disciplines. A similar process will be conducted across institutions, to understand how responsible research is operationalised and linked to training and governance activity.
Phase 2: Developing a responsible research community of practice.
Informed by Phase 1, we will develop a locally embedded and relevant modus operandi for each Responsible Research Steward, and provide infrastructural and governance support (in the form of advice to each of the 18 HEIs).
Phase 3: Implementing and evaluating responsible research stewardship activity.
Local Responsible Research Stewards will coordinate the inventory of research cultures and plural views on responsible research practices at their HEI, thereby informing them of which stimulus and support structures (Phase 2) can help them to build and maintain a diverse and relevant responsible research community of practice.
|
| 30/09/2021 |
£455,998 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
Antivenom treatment of snakebite is failing to reduce the annual 138,000 deaths - predominantly in impoverished tropical communities. With a focus upon the most medically-important African and Indian snake venoms, we are developing toxin-neutralising, recombinant, humanised, thermostable monoclonal antibodies (mAbs) that will be more dose- and polyspecifically-effective, affordable and safer than antivenoms, and possess critical economies of scale and manufacturing incentives to secure sustained production/delivery.
We have collected sera and B cells (producing immunoglobulins of distinct structure and therapeutic/mAb-development promise) from:
multi-envenomed humans
cows, camels, baboons, mice immunised with the most pathogenic African and Indian venom toxins
horses used to manufacture African or Indian antivenoms.
Using High-Throughput platforms, we will rank B cells producing these globally-unique animal and human antibodies by in vitro toxin-binding affinity and toxin-function neutralisation, prioritising cross-generic/continental functionality. Genes from top-ranked B cells will be processed into recombinant mAbs (220-500).
Subsequent rounds of in vitro and in vivo (neutralisation of venom-induced lethality in a mouse model of envenoming) down-selection will output 20-40 mAbs for gene-manipulation to deliver ‘humanised’ and thermostable mAbs.
A final round of in vitro/in vivo selection will deliver 5-10 mAbs/3 mAb mixtures of proven pan-Africa/India polyspecific efficacy for downstream preclinical manufacture and clinical trials.
|
| 30/09/2021 |
£477,083 |
INSTITUTE OF EPIDEMIOLOGY DISEASE CONTROL & RESEARCH |
Our proof-of-concept study used MinION (Oxford Nanopore Technology), "Lab in a suitcase" to generate genomic data that we combined with mobility data mobile phone operators to provide an early picture of the dynamics of the COVID-19 epidemic in Bangladesh. We showed evidence of repeated introductions by returning migrant workers and international travelers leading to the emergence and rapid country-wide dissemination of SARS-CoV-2 lineages or variants. Bangladesh urgently needs an integrated genomics network suitable to identify and track known or novel variants. Our proposal is to establish a country-wide network for SARS-CoV-2 genomic surveillance. We will do this by extending the number of MinION-based sequencing platforms to seven federated sites linked to the Ministry of Health and Family Welfare, representing facilities in different administrative areas (6 of 8) comprising Bangladesh. The advantage of these devices is their portability and ease of use, and the flexibility of the platform beyond SARS-CoV-2 in the context of future epidemics. We will use the expertise we have developed to train researchers, adopting a "train the trainer" model of capacity building, in sequencing, bioinformatics, and epidemiological modeling, such that we are able to respond to COVID-19 as it evolves, as well as to future pathogen threats.
|
| 30/09/2021 |
£100,000 |
WELLCOME SANGER INSTITUTE |
In 2020 The Pan American Health Organization (PAHO) established and now coordinates the COVID-19 Genomic Surveillance Regional Network. It includes 21 collaborating countries of which 10 do not have any appropriate in-country sequencing capacity and instead send their samples externally for sequencing to the network reference laboratories in Brazil and Chile. Here we propose to build direct sequencing and analytical capacity in all participating laboratories to generate relevant genomic data that can be used for public health decision making. Where batch sequencing capacity already exists we propose to use MinIon platforms to extend the within-country capacity to investigate changing patterns of disease. Combined, this will dramatically increase our understanding of the known and new SARS-CoV-2 variants circulating in this region. We will develop a hub-and-spoke organization with PAHO at the center forming the hub for coordination, training and data flow and the Network laboratories forming the spokes. Laboratories with existing genomics expertise will help build genomics surveillance capacity in those that don’t. Combining local and international expertise we aim to develop a regional network able to produce actionable SARS-CoV-2 data now with the potential to become a sustainable network able to track other diseases of regional importance in the future.
|
| 30/09/2021 |
£998,810 |
STEM LEARNING LIMITED |
Our vision for Explorify: is to be a sustainable and dynamic resource that is a core part of the primary science teacher’s toolkit – enabling teachers and school leaders to develop primary science as a strength, and inspiring children to engage with science.
Explorify has established itself as a substantial and influential part of the primary science environment – particularly for teachers taking their first steps in teaching primary science. We will build on this, expanding its reach, impact and long-term sustainability through:
Maintaining the current Explorify user experience so that it remains free of charge, simple to register, easy to navigate and requires minimal teacher preparation;
Updating content and adding activities in response to changes in primary science education and UK curricula, reflecting topical issues, and in response to feedback and suggestions;
Increasing the reach of Explorify, engaging more users through our established networks and partners, whilst seeking opportunities to create new associations and outlets through which to raise awareness of Explorify;
Positioning Explorify alongside wider professional development opportunities to develop a comprehensive and flexible CPD journey for Explorify users, including science subject leaders;
Developing a sustainable business model which enables Explorify to remain free to UK audiences.
|
| 30/09/2021 |
£1,406,528 |
CSIR- INSTITUTE OF GENOMICS AND INTEGRATIVE BIOLOGY |
The global challenges posed by COVID-19 are best tackled through global cooperation between researchers, clinicians and funding agencies. One such challenge is generating timely, high-resolution monitoring of the SARS-CoV-2 viral evolution and using such data to guide public health response in a timely manner. The discovery of current variants of concern (VOC) in UK, South Africa and Brazil is because of a high quality sequencing program (UK) or vaccination related investigations (South Africa, Brazil). Indian SARS-CoV-2 Genomic Consortia (INSACOG) is revealing the possibility of local VOC driving fresh outbreaks.
We proposes a network of satellite genomic sequencing MicroLabs in India, Bangladesh and Sri Lanka that will be integrated by virtual cloud-based workflows as well as physical linkages to national MegaLabs for quality assurance and operational support. This would help scale up global monitoring of emerging SARS-CoV-2 strains in one of the world’s most populous region and guide global R & D efforts for COVID-19 diagnostics, vaccines and therapeutics.
Given the relevance of SARS-CoV-2 surveillance to especially the diagnostics and health systems pillars of WHO’s ACT-Accelerator, partners such as Wellcome Trust can play an important role in furthering this effort. There is an urgent need to create distributed local capacity via MicroLab hubs.
|
| 30/09/2021 |
£388,926 |
UNIVERSITY OF COLOMBO |
The global challenges posed by COVID-19 are best tackled through global cooperation between researchers, clinicians and funding agencies. One such challenge is generating timely, high-resolution monitoring of the SARS-CoV-2 viral evolution and using such data to guide public health response in a timely manner. The discovery of current variants of concern (VOC) in UK, South Africa and Brazil is because of a high quality sequencing program (UK) or vaccination related investigations (South Africa, Brazil). Indian SARS-CoV-2 Genomic Consortia (INSACOG) is revealing the possibility of local VOC driving fresh outbreaks.
We proposes a network of satellite genomic sequencing MicroLabs in India, Bangladesh and Sri Lanka that will be integrated by virtual cloud-based workflows as well as physical linkages to national MegaLabs for quality assurance and operational support. This would help scale up global monitoring of emerging SARS-CoV-2 strains in one of the world’s most populous region and guide global R & D efforts for COVID-19 diagnostics, vaccines and therapeutics.
Given the relevance of SARS-CoV-2 surveillance to especially the diagnostics and health systems pillars of WHO’s ACT-Accelerator, partners such as Wellcome Trust can play an important role in furthering this effort. There is an urgent need to create distributed local capacity via MicroLab hubs.
|
| 30/09/2021 |
£3,069,373 |
DIAMOND LIGHT SOURCE LTD |
Not available |
| 30/09/2021 |
£3,000,000 |
UKRI-EPSRC |
This partnership between Wellcome and UKRI will support the Physics of Life funding call. Which aims support internationally leading research that requires collaborative, interdisciplinary working to address key challenges at the interface of physics and life sciences.
The call will fund high-quality proposals that demonstrate deep integration of cutting edge experimental, theoretical and/or computational physics within life sciences research to advance our understanding of living systems in biological or biomedical contexts. |
| 30/09/2021 |
£3,728,812 |
UNIVERSITY OF OXFORD |
We propose to set up and validate a pharmacometric platform to provide quantitative assessment of antiviral effects in low risk adult patients with recent onset uncomplicated COVID-19 and high viral burdens. This assessment is based on measurement of oropharyngeal viral clearance rates. This will be a randomised, open label, group sequential adaptive platform trial to quantitate the antiviral activity of currently available potential (i.e. repurposed) treatments in low-risk adult patients with early COVID-19, through adjusted qPCR of serial oropharyngeal samples. It will be a mainly outpatient study conducted in three locations; one each in the Americas, Europe and Asia. The interventions to be evaluated in this first phase are hydroxychloroquine, lopinavir/ritonavir, ivermectin, miglustat, remdesivir, intranasal heparin, with the Regeneron monoclonal antibody cocktail or Peginterferon-lambda as a positive control. This will identify drugs with a > 90% probability of accelerating virus clearance compared to no treatment and will reject drugs with |
| 30/09/2021 |
£277,163 |
CENTRO DE ESTUDOS DO INSTITUTO DE PSIQUIATRIA |
The first goal of this award is to achieve an inexpensive, accessible and scalable
solution to detect clinical high risk for psychosis in individuals within the general
population. This solution will be based on an algorithm that analyses an individual’s
speech collected by means of a mobile smartphone or by over-the-web recorded
interviews. This algorithm will deliver a high accuracy score ( > 80% accuracy) that can
detect whether an individual is at clinical high risk for psychosis. The second goal is to
establish an algorithm that can predict whether individuals at clinical-high risk transition
to psychosis. In the longer term these tools will enable early detection of psychosis. |
| 30/09/2021 |
£3,828,366 |
OPHIREX |
Ophirex seeks funding from the Wellcome Trust to support an India-focused Phase 2 human trial to evaluate the safety, tolerability, and efficacy of oral varespladib-methyl with standard of care after venomous snakebite in subjects aged 5 years and older.
Technical Goals:
Goal 1. Qualify and on-board 4 – 8 trial sites in India.
Goal 2. Complete trial start-up activities including trial database, training, DSMB, and project operations.
Goal 3. Complete regulatory submission and approval from Drug Controller General-India (DGCI).
Goal 4. Complete trial and Clinical Study Report
The program will advance broad-spectrum treatments for snakebite based upon Ophirex’s privately developed toxin-targeting portfolio and provide affordable, superior care to rescue life and limb. All tasks are focused on supporting eventual New Drug Application submissions in India and, separately the US to enable file transfers to other regulatory authorities (such as individual countries in Asia and sub-Saharan Africa as well as via WHO precertification).
Key attributes of this First-In-Class antidote are:
1) Broad spectrum sPLA2 inhibition for first-line treatment of snakebite
2) Excellent safety profile for population at risk
3) Ease of use and administered anywhere
4) Shelf-stability for at least one-year
5) Low cost of manufacture compared to biological products
|
| 30/09/2021 |
£856,768 |
UNIVERSITY OF GOTHENBURG |
Antibiotic resistance surveillance is critical for guiding empirical treatment and evaluating interventions. As current methods rely on analyses of bacterial isolates from many individuals, surveillance is resource-demanding and thus absent or very limited in most low- and middle-income countries (LMICs). We hypothesize that microbiological analyses of sewage, containing excreted bacteria from thousands of people, can be a resource-efficient complement for population-level antibiotic resistance surveillance with particular value in LMICs. This is supported by our recent European studies showing good correlation between resistance rates in clinical and sewage E. coli isolates. Here we aim to further develop the sewage monitoring system by targeting additional clinically important bacteria in sewage and investigating the value of including gene-based analyses. We also aim to validate the methodology in three sub-Saharan African countries by benchmarking to local clinical surveillance data generated during the project. The relationship between sewage and clinical ESBL-producing strains, one of the most urgent resistance threats, will be studied in more detail by applying whole genome sequencing. By also engaging relevant stakeholders, the overarching goal is to pave the way for future implementation of sewage monitoring, which could significantly increase the basic data for surveillance of antibiotic resistance in LMICs.
|
| 30/09/2021 |
£999,674 |
UNIVERSITY OF OXFORD |
There does not exist currently a clear pathway for the pharmacometric evaluation of new Chagas disease treatments, and thus evidence-based drug and dose selection. Compounds currently in pre-clinical development (Wellcome HIT NTD flagship) cannot be assessed for efficacy in vivo in an efficient way. This project will provide a platform for phase 2 assessment of these new compounds. The success of our project could accelerate clinical development substantially and, by ensuring evidence-based dosing, will reduce the risks and improve the value of the phase 3 trials. This could have an enormous impact on the treatment of Chagas disease. |
| 30/09/2021 |
£318,039 |
WORLD HEALTH ORGANIZATION, SWITZERLAND |
Critically ill patients require a continuum of care spanning from early recognition and system activation through facility-based care in emergency and intensive care units. There are few resources to support critical care strengthening in low- and middle-income countries (LMIC); existing tools have largely been designed in and for high-income settings and are poorly suited to the distinct resource and capacity constraints, disease burdens, and ways of organizing and delivering critical care in LMICs. WHO proposes to address this by developing a Critical Care Toolkit composed of two major elements. First, an expansion of the Essential Resources for Emergency Care to encompass the spectrum of emergency and critical care: a guidance document for policymakers, planners, and health professionals developing and improving critical care systems. This will explicitly define the elements needed to establish key critical care functions. The second will be a training course oriented to LMICs. The course will teach the basics of critical care delivery across the continuum, strengthening provider capacity. The toolkit will support effective critical care systems, those that integrate mechanisms to ensure a systematic approach to every patient, provide rapid access to equipment and supplies, and use structured processes for timely recognition and management of threats. |
| 30/09/2021 |
£449,970 |
NEOPENDA PBC |
Through user-centric design, Neopenda aims to create needs-based solutions that benefit underserved populations, enable high quality patient care, and provide nuanced data insights for stakeholders. With the funding requested for this project, we will modify a wireless vital sign monitoring system for health facilities into a vital sign measurement tool for lower level health facilities and community health workers. |
| 30/09/2021 |
£5,041,583 |
YORK UNIVERSITY (CANADA) |
Drug-resistant infections have the potential to threaten tens of millions of lives, yet, in many countries, efforts to promote sustainable antimicrobial use and implement national action plans have stalled. As the antimicrobial resistance (AMR) threat grows, it is increasingly important to integrate scientific evidence into the national and global AMR responses. We propose to develop a Virtual Policy Think Tank that serves as a bridge between AMR science and policy, leverages global science and insights, and delivers relevant and rigorous evidence that responds to urgent global policy needs. The Think Tank will undertake three streams of work to build coordinated and innovative progress toward global AMR goals. A rapid response stream that responds to rapid evidence requests from governments and other actors will support the implementation of robust, evidence-informed AMR action plans. A capacity-building stream will support the regular use of scientific evidence in AMR policymaking processes. A policy proposal stream that engages academics from around the world will build new solutions for intractable AMR policy challenges. The Think Tank will act as a global leader and resource for evidence-informed AMR policy with the aim of ensuring sustainable antimicrobial use for all.
|
| 30/09/2021 |
£533,825 |
MAKERERE UNIVERSITY |
Much of critical care revolves around respiratory support. Indeed, AHRF contributes the highest proportion of intensive care admissions worldwide. Therefore, any strategy to optimise critical care in Africa begins with care of the patient with Acute Hypoxemic Respiratory Failure.
This study provides an opportunity to introduce a cost-effective intervention that would also constitute a significant component of holistic frugal critical care in Africa.
This study is a pilot in the following manner, in addition to answering the primary question of which intervention is suitable, it will provide insights to the logistics of applying such interventions in places with under-staffed healthcare workers. In addition, use role of newer and safer lung diagnostics such as lung ultrasound shall be employed to ensure quicker diagnosis and to assist in patient stratification.
These answers shall inform preparations for larger multi-country trials that will test the efficacy of either one of the interventions (BREATHE) or their combination (COSTA). This is also likely to be the first adult acute respiratory trials network in sub-Saharan Africa.
This work has the potential to impact care of the critically ill patient in Africa.
|
| 30/09/2021 |
£2,639,537 |
BETH ISRAEL DEACONESS MEDICAL CENTRE |
With this funding, we hope to achieve a decrease in mortality for the 20 million critically ill adults in sub-Saharan Africa with acute hypoxemic respiratory failure.
In the setting of COVID-19, governmental and nongovernmental organizations are working toward improving oxygen availability through large PSA plants and bedside oxygen concentrators. While sources of oxygen are increasing, what remains unknown is the impact of using different delivery systems for oxygen, which include low flow nasal cannula and facemasks, HFNC, CPAP, and invasive ventilation. Low flow systems are limited in the degree of oxygen support they can provide and are therefore only appropriate for mildly hypoxemic patients; non-invasive CPAP carries a significant aspiration risk for patients with altered mental status and requires close monitoring by trained staff; mechanical ventilation requires even more significant infrastructure, consumables, and human resources to operate safely. In HICs, HFNC has been shown to reduce the need for mechanical ventilation, and in some cases reduce mortality. In LICs, where safe mechanical ventilation is largely unavailable, we predict a robust mortality reduction.
This funding will yield definitive evidence for HFNC’s impact on mortality, and develop the resources to widely disseminate that evidence, including comprehensive strategies for implementation and scaling.
|
| 30/09/2021 |
£6,783,629 |
CARDIFF UNIVERSITY |
First-in-Human, Phase 1 safety, tolerability, pharmacokinetic and pharmacodynamic/target engagement studies of MDI-478, a positive allosteric modulator (PAM) of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid subtype of ionotropic glutamate receptor (AMPAR). The aim is to demonstrate that MDI-478 is safe and well-tolerated and demonstrate pharmacodynamic effects and/or target engagement sufficient to support Phase 2 efficacy studies". |
| 30/09/2021 |
£15,613,391 |
EUROPEAN BIOINFORMATICS INSTITUTE |
Ensembl is the world’s most comprehensive genome informatics resource. We have powered genomic analyses for over twenty years through our data, know-how, software and deep ties to the research community. Today, as genomic medicine is scaling up across the world and the effects of the sixth mass extinction become increasingly apparent, genomics has a critical role to play in addressing key societal challenges. To meet these challenges and stay relevant in a fast paced environment, we are preparing for landmark innovations in our processes, including (i) a transition to the graph-based human reference genome; (ii) an increased use of cutting-edge technologies including machine learning to more accurately annotate genomes; (iii) an expansion of the number of supported genomes from hundreds to tens of thousands; (iv) an extensive redevelopment of our comparative genomics infrastructure; (v) a complete overhaul of our release cycle to release data as quickly as we can annotate it; (vi) the launch of our new website; and (vii) the release of new APIs that will replace our Perl API for external users.
Keywords: genome annotation, bioinformatics, database, biodiversity, functional interpretation of genetic variation, model organisms, genome regulation, agricultural genomics, FAIR data, open source software, open and reproducible science.
|
| 30/09/2021 |
£2,532,166 |
UNIVERSITY OF DUNDEE |
"Schistosomiasis is a neglected tropical disease, caused by parasitic worms that live in the blood vessels around the intestines or bladder. Approximately 230-440 million people are currently infected and the disease causes approximately 300,000 deaths per year, either directly or indirectly, and many other health related problems due to chronic infection, including cognitive development issues with children and exacerbation of the effects of other infectious diseases. There is only one drug, praziquantel, registered to tackle this disease, creating an urgent need for the development of new drugs to treat this disease, to improve the efficacy and also in case of resistance developing to praziquantel. Furthermore, there is little known about drug discovery for this parasite. In this Project the University of Dundee, Aberystwyth University and Cardiff University are developing new assays and optimising existing assays to facilitate the drug discovery process. The team has discovered a series of chemical start points through previous work which will be progressed through the improved pathway with the eventual aim of discovering a late lead, a molecule that has the potential to be developed for treatment of schistosomiasis." |
| 30/09/2021 |
£1,968,101 |
ST GEORGE'S, UNIVERSITY OF LONDON |
The overall goal of this project is to develop simple tools to help individual countries make the best use of their own AMR surveillance data to inform local action. The project will use a range of modelling methods of existing global data sets that include information on clinical infection management and outcomes, antibiotic resistance, consumption and use. The proposal aims to learn from the development of clinical surveillance networks in other disease areas such as tuberculosis (TB) and will use a public health approach to provide a conceptual framework for future surveillance implementation and policy goals.
This project combines research expertise on antimicrobial resistance, usage modelling and policy development. It aims to model the existing data sets to provide a framework for future clinical patient centred AMR surveillance that can inform empiric prescribing guidance and support local individual country policy decisions on future targets and ambitions. The proposal has been developed to link closely with current and planned WHO initiatives and the work of other key stakeholders. The project includes an early pilot phase, developing and testing the models in collaboration with multiple partner countries.
|
| 30/09/2021 |
£335,050 |
UNIVERSITY OF OXFORD |
The global community has mobilised in an unprecedented way to deliver research in response to the threat of COVID-19. In February 2020, priority areas for research were advanced under a coordinated mechanism convened by the World Health Organisation. For social science a cross cutting research agenda was proposed in recognition of the vital role played by individuals, communities and populations worldwide in slowing disease tranmssison and providing care for COVID-19 and beyond. Research initiatives, including over 300 social science studies funded by GloPID-R members alone, have been advanced against these social science priorities. Building on earlier successes in supporting epidemic-relevant research, the research arm of GOARN, the Global Outbreak Alert and Response Network, has actively coordinated this work with WHO. There is a pressing need to properly resource coordination and knowledge mobilisation of epidemic-relevant social science research. Further, there is an important opportunity to leverage the reach and expertise of GOARN and establish infrastructure for the COVID-19 response as well as for future scenarios to ensure that structures for epidemic-relevant research can take hold: the well worn phrase of building the ship while we sail it is unsustainable as an effective and efficient research response to infectious disease epidemics.
|
| 30/09/2021 |
£2,815,184 |
UKRI-MRC |
The UKPRP is an inter-disciplinary national initiative supported by an alliance of UK charities, Research Councils and the UK Health Departments, and established in recognition of the need for research into population-level strategies that will prevent non-communicable diseases (NCDs) and reduce inequalities in health. |
| 30/09/2021 |
£245,428 |
UNIVERSITY OF LIVERPOOL |
We will engage new parents and children and young people and their families in the Liverpool City Region through a series of highly interactive arts-based initiatives to understand how people perceive health, health inequalities and how data are used to inform policy, and to foster the ownership of the Children Growing up in Liverpool (CGULL) study in the wider community.
We will co-create engagement activities via engaging and creative arts, participatory research methods and events, and through a network of public engagement co-leads. We will create CGULL characters in books and digital media, host a museum installation on "Growing up in Liverpool", and conduct workshops on health inequalities and data use.
We will take activities, research and outputs to the communities that we serve. This public engagement work will enrich the core work of the cohort, enabling us to coproduce the next phase of the study and its engagement.
Working in collaboration with our partner organisations, including through Liverpool’s UNICEF Child Friendly Cities programme, Liverpool Health Partners Starting Well programme, local council and NHS trusts, we will provide a springboard for capacity across the city for trustworthy research and public engagement focussed on children and young people and health inequalities.
|
| 30/09/2021 |
£238,930 |
UNIVERSITY COLLEGE LONDON |
Research has indicated that the future use of emerging, data-driven, technologies in surgery is dependent on ensuring these technologies are designed with, and for, the public and patients.
Accordingly, we propose ‘In Theatre’- an interactive public installation and arts-based community engagement programme. This will use arts-based approaches to discuss challenging topics and break down barriers to engagement in a two stage project.
Stage 1: Deep listening – This will use societally engaged arts and creative practice to explore concepts of robotics and A.I. in surgery to better understand the public’s concerns, identify what they want to know more about and what they would like researchers to consider in future work. Learnings and outputs from this stage will inform the content, experience and overall design of the public installation.
Stage 2: Installation – Working with The Liminal Space, experts in public engagement delivery, we will create a three-week pop-up installation which will help residents in Tower Hamlets build their own understanding of these technologies and shape how they should be developed. This intervention will also make a valuable ‘learning environment’ for clinicians and researchers to gain further insights into the relationship people have with surgical technology beyond the clinical environment.
|
| 30/09/2021 |
£81,528 |
UNIVERSITY OF CAPE TOWN |
Total number of current applications in progress for LMICSSs by Administering Organisation (for all Programmes they administer): 1
Total number of current applications in progress for LMICSSs to be held at the AAP/Centre to which the application relates: 1
|
| 30/09/2021 |
£249,701 |
UNIVERSITY OF OXFORD |
Not available |
| 30/09/2021 |
£1,484,750 |
SAVE THE CHILDREN (ELHRA) |
Not available |
| 30/09/2021 |
£31,219 |
MQ TRANSFORMING MENTAL HEALTH |
Interest payable to MQ |
| 30/09/2021 |
£2,000 |
PANOS PICTURES |
Produce, print and install an exhibition of photographs by Tom Pilston documenting University College Hospital (UCH) staff working on the Covid pandemic. Exhibtion to be in UCH lobby in Euston Road
|
| 26/08/2021 |
£17,827 |
UNIVERSITY COLLEGE LONDON |
The feminisation of HIV is an increasing issue of concern, especially amongst Latin American migrant populations. As the predominant demographic of those living with HIV in the region are men-who-have-sex-with-men (MSM), there is a gendered Diversity & Inclusion gap. Women living with HIV have different needs & experiences than MSM, however due to gender-based constraints (e.g.childcare, home-based-working) they are less present/visible in my research environment, as well as within local NGO activities/projects.
How the activity will look:
Working alongside the United-Nations-Population-Fund (UNFPA), this two-day participatory workshop will bring female migrants living with HIV in Peru together to discuss and ‘story-tell’ specific experiences and needs that may be overlooked due to lifestyle constraints limiting participation in research and NGO projects. Relevant stakeholders will be invited and, learning horizontally from the experiences of migrants, we will collaboratively discuss how to address the feminisation of HIV in migrant populations.
We will professionally produce an informative-animation to disseminate outcomes/stories widely and easily through social-media. This will ensure that a) research environment and NGO activities are more hospitable to the gender-specific barriers to participation faced by migrant women; b) migrants themselves have opportunities for their voices to be heard and fed-back into research and NGO activities.
What we will achieve for:
Diversity & Inclusion Initiatives: Greater understanding of the migrant-based feminisation-of-HIV amongst relevant stakeholders, and greater inclusion of women in research where they are often left-out due to practical constraints.
Participants/Collaborators: Prioritisation of experiences and voices of female migrants living with HIV, thereby empowering them.
|
| 26/08/2021 |
£19,500 |
KING'S COLLEGE LONDON |
Similarly to other universities in the UK, in the Faculty of Life Sciences and Medicine (FoLSM) we see that the diversity of our post graduate research (PGR) community is inconsistent with the undergraduate (UG) population we have at King’s College London and, whilst students on our UG courses are diverse in ethnicity and socio-economic background, our PhD students are predominantly white Europeans and rarely the first in family to get a university degree. This an area in great need of levelling up.
The proposed Research Enrichment activity will tackle some of the barriers students from under-represented backgrounds face when pursuing PGR. The combination of a mentorship scheme, visits to research laboratories and a series of talks will endow students with essential transferable skills, contacts and support that will demystify the PGR recruitment process and help them progress to PGR and research-related jobs, including academic careers. Additionally, we will raise awareness of issues related to equality, diversity and inclusion within our current cohort of PhD students and research staff, empowering them to drive the change needed to create an inclusive research culture in academia. We will employ a mixed-method approach to collect quantitative and qualitative information to evaluate the activity’s effectiveness and will share our findings with our Centre for Doctoral Studies and WP division, other Schools within FoLSM as well as with the other Health Faculties within King's. Other dissemination activities will include electronic media such as blog posts and publication of a summary report of the outcomes.
|
| 26/08/2021 |
£8,838 |
UNIVERSITY OF YORK |
Due to geographical distance, and difference in wages and funding opportunities for scholars in Sudan, there has been limited direct engagement with the Sudanese colleagues during the applicant’s project, for which Sudan is the core area of research. Owing to the close links between past and present heritage crafts and their impact on health, it is paramount the project reaches the scholars and the public in Sudan. The project aims to deliver a ‘hands on’ multidisciplinary ‘summer camp’ at the University of York, for the Director of the first Bioarchaeology laboratory in Karthoum, Sudan, Dr Mohamed Saad, and one of his students. Such a laboratory, created by the British Museum (Dr Antoine), is the first laboratory of its kind in the region, aimed to empower a new generation of scholars in Bioarchaeology. A multidisciplinary team in York, led by the applicant and the visiting scholars, will prepare an open access ‘road map document’ to implement the inclusion and diversity of scholars and the public in the field of Bioarchaeology and Medical humanities in East Africa. This will be achieved with the full support of the applicant’s Department, which hosts a Centre of Excellence in African Archaeology (Dr. Wynne-Jones, Dr Stump). The road map document will be shared across a wide network of scholars involved in traditional knowledge, sustainability and health in East Africa. The visit will culminate with the participation of the scholars to the final project workshop (a 3 days event) planned for June 2022 at the British Museum.
|
| 26/08/2021 |
£20,000 |
ELIFE |
We will develop sustained capacity for scholarly peer review among early- and mid-career African researchers. To this aim, we propose to develop resources and a dissemination strategy for the delivery of a Best Practices in Scholarly Peer Review workshop, materials that once openly released can be adapted and replicated across research communities in Africa.
The proposed programme will follow three milestones. We will develop materials and teaching resources for a three-part workshop (M1) where African researchers are invited to join a path of guided learning to build their profile as constructive peer reviewers. To ensure scalability and maximize impact, we will implement a "Train the trainer" model (M2). We will leverage joint networks of all partners to recruit the first cohort of ten African researchers and invite them to train as trainers, co-create the materials and help adapt the resources to their needs and contexts, and c) deliver the workshop to their research community (M3).
In addition to peer-review training, workshop participants will be invited to join the eLife Early-Career Reviewers Pool, and offered support and onboarding materials to build a public profile as preprint reviewers as part of new reviewing communities on PREreview and Sciety.
As a result of this programme, the visibility of African researchers will increase, as will the recognition for their constructive peer-review contributions. Those, coupled with supportive journal policies, will help establish a rich representation of African scholars among reviewers in the traditional as well as the ‘publish, then review’ system of scholarly communication.
|
| 04/08/2021 |
£504,703 |
UNIVERSITY OF DUNDEE |
Cryptosporidium is a waterborne, protozoan parasite that is a significant cause of child morbidity and mortality in low- and middle-income countries. Cryptosporidiosis causes severe diarrhoea in children that leads to approximately 200,000 deaths per year and is a major contributor to malnutrition and growth stunting. There are no effective medicines for the treatment of malnourished children and immunocompromised adults suffering from cryptosporidiosis. The aim of this project is to develop a new way to test drugs for their ability to kill Cryptosporidium that more closely mimics the actual intestinal environment in patients. This more biologically realistic environment will allow us to discover new chemical start points for drug discovery. We will use human intestinal organoids, "miniature organs", that replicate the environment of the intestine in the lab. We will test compounds on a largescale, collect the data using microscopy, and evaluate the results using artificial intelligence. |
| 04/08/2021 |
£751,510 |
I3S - INSTITUTO DE INVESTIGAçãO E INOVAçãO EM SAúDE, UNIVERSIDADE DO PORTO |
Healthcare-Associated Infections (HAI) affect ~1.7M people in USA and 4.1M in Europe, contributing to 99,000 and 37,000 deaths/yr, respectively. Catheter-related infections are the most frequent cause of HAI, leading to life-threatening complications and colossal medical costs. Current prevention/treatment options – lock solutions, systemic antibiotic administration – are inefficient and lead to bacterial resistance, a huge threat to public health. We propose the development of "SmartCap", the first light-activated cap for catheter sterilization. Unlike standard catheter caps that are just used as physical barrier, the SmartCap kills 99% of bacteria without using antibiotics, hampering bacterial resistance. This reusable system is fully integrated in the cap and can be adapted to any catheter, standing out as a safe, long-term antimicrobial solution to prevent catheter infections. The SmartCap will contribute to patient well-being and quality of life, reducing associated risks, reintervention procedures, and hospitalizations, having a huge economic impact on the healthcare system. |
| 04/08/2021 |
£697,119 |
UNIVERSITY OF OXFORD |
Brain injury commonly affects young people after trauma or stroke. Minimally Conscious State (MCS) is a devastating consequence where wakefulness is minimal, leading to poor quality of life, and dependence on healthcare services (Bernat J). There are currently no treatments that improve arousal and care is restricted to nursing and supportive care. In MCS, brain electrical rhythms are disrupted. We have demonstrated that deep brain stimulation (DBS - implanting electrodes in the brain) can increase arousal by altering these rhythms. We have developed a bespoke DBS system that responds to sleep/ wake cycles. Our next step is to modify the technology to respond to abnormal brain rhythms and test its effects in MCS patients. The advantage of this approach is that stimulation can be adjusted to wakefulness or time of day. This is a platform technology which has implications for both disorders of consciousness and sleep disorders. |
| 04/08/2021 |
£504,942 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
Delayed parasite clearance and treatment failures with first-line artemisinin-based combinations are widespread in Southeast Asia and alarmingly resistance markers have been detected in several African countries. New antimalarial drugs with novel mechanisms of action, active against resistant strains are urgently needed. We have identified potent inhibitors of malaria parasite phosphodiesterase (PDE) enzymes. They kill asexual blood stage parasites that cause disease, and two of our sub-series also kill gametocytes which mediate transmission, a property absent from most antimalarials. Our inhibitors act at a similarly rapid rate to chloroquine. Importantly, PDEs have been targeted successfully and safely to treat a range of human disorders and importantly our series has excellent selectivity against human PDEs. One of the attractions of the chemotypes we are developing here is that their profile in terms of drug-drug interactions is particularly benign. Thus, a new antimalarial targeting PDEs has clear potential in combination therapy. |
| 04/08/2021 |
£470,113 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
Worldwide, there are approximately 150 million cases of Shigellosis annually, which is exacerbated by increasing resistance to the antibiotics used to treat Shigellosis. The WHO has highlighted that there are no currently effective vaccines for any Shigella species. The O-antigen, a sugar that coats Shigella cells is a validated vaccine candidate, particularly when conjugated to a carrier protein, but current methods to achieve this are complex and costly. Using our glycoengineering technology, we will multiply conjugate Shigella O-antigens to novel conserved immunogenic Shigella proteins we have validated to produce broad-spectrum Shigella glycoconjugate vaccines. These "double-hit" Shigella vaccines will be expressed in E. coli cells that act as mini-factories to produce affordable vaccines. Our Shigella-plus vaccine will be (i) safe, (ii) effective, (iii) broad-spectrum to cover all Shigella species and (iv) low-cost so that it can be deployed where it is most needed, providing an effective global solution to Shigellosis. |
| 04/08/2021 |
£501,078 |
UNIVERSITY OF CAMBRIDGE |
Non-alcoholic fatty liver disease (NAFLD) is defined as hepatic fat accumulation that exceeds 5% of liver weight. Accumulation of lipids in the liver in NAFLD plays a key role in the progression of cirrhosis and hepatocellular carcinoma, a hard-to-treat cancer and it is becoming the major reason for liver transplantation in the world. NAFLD is associated with obesity, type 2 diabetes and metabolic syndrome and estimated 25% of adults worldwide suffer from it. No effective treatment, apart from a significant change in lifestyle, exists for NAFLD. We propose to develop a drug that will reduce the production of lipids in the liver and thereby stop and reverse the progression of the disease. Our drug target is pyruvate kinase, an enzyme that is critical for lipid synthesis. We will improve our early inhibitors to be more potent and specific and thereby pave the way for the first pharmacological treatment for NAFLD. |
| 04/08/2021 |
£348,280 |
UNIVERSITY COLLEGE LONDON |
Glaucoma and trachoma are leading causes of blindness worldwide, with a combined > 200M people affected and close to 10M at immediate risk of permanent sight loss. For both diseases, surgical treatment success is directly dependent on the avoidance of postoperative scarring. However, there is no treatment to prevent scarring in trachoma and the current drugs used to prevent scarring following filtration surgery for glaucoma can have serious blinding side effects. We have designed an innovative product consisting of biodegradable microparticles loaded with doxycycline, a common drug, for local delivery at the time of surgery to achieve safe, targeted and sustained anti-scarring action. These have shown remarkable anti-scarring efficacy in laboratory tests, and we propose to evaluate their effectiveness in an animal model of post-surgical ocular scarring. The successful completion of this project will allow us to develop this treatment towards clinical trials, with a potential benefit to millions worldwide. |
| 04/08/2021 |
£286,964 |
UNIVERSITY COLLEGE LONDON |
Scoliosis surgery involves insertion of screws in the spine (called pedicle screws). Current techniques to insert these screws are not completely accurate. Even in international experts’ hands, 25-30% of the screws are misplaced. Misplacement of screws has a high risk of bone weakening, injuries to the spinal cord, nerve roots or blood vessels. Getting screw placement wrong has long term health implications for young patients, including lifelong disability. More accurate methods use computer navigation or image guidance techniques. However, these involve using more radiation (X-rays, CT scans) before and/or during the surgery. Surgeons and parents are concerned regarding the long term effects of ionising radiation in young patients. Our work helps to address this unmet health need by developing MRI based imaging techniques to design patient specific pedicle screw placement devices, which improve the accuracy of placing screws in the spine and removing the need for ionising radiation. |
| 27/07/2021 |
£394,010 |
UNIVERSITY OF EDINBURGH |
Studying neurobehavioural and metabolic disease requires precise measurement of movement/behaviour, energy balance, and systemic metabolism in living animals. Current platforms are imprecise, and mice are often studied under conditions compromising fidelity of disease modelling (e.g. "normal" room temperature imposes a thermal challenge, confounding modelling of human energy balance). We now seek a 16 cage indirect calorimetry system with environmental cabinet and 8-cage stable isotope module for precise, integrated quantification of murine metabolism, energy balance and behaviour. This offers:
5x faster cage flow rate than competitors, sampling every 2.5 minutes for respirometry at 0.001%/0.0001% (O2/CO2) resolution, allowing analysis in hypometabolic states (caloric restriction/thermoneutrality/small or aged animals). Ambient in-cage CO2 minimises hypercapnic compromise of behavioural testing, and home cage environment minimises acclimatisation/downtime.
Direct water balance measurement.
Laser-based, multiplexed detection of 13CO2/C18O2/CO2/H2O, permitting synchronised, rapid measurement of oxidation of > 10,000 substrates.
Behaviour capture at 1Hz, resolving disease-relevant abnormalities invisible to legacy systems. Outputs include behaviour time budget and position probability mapping. 1Hz integrated mass measurement detects feeding and drinking to 0.002 grams, quantifying "microfeeding" (c.30% food intake).
Computer architecture configured in a standalone network supporting synchronised metabolic/behavioural analysis even in large, long term experiments, increasing statistical power and permitting multiple hypothesis testing.
|
| 27/07/2021 |
£1,000,000 |
UNIVERSITY OF DUNDEE |
Cryo-electron microscopy (Cryo-EM) has become a powerful method to determine three-dimensional (3D) structures of macromolecular complexes. The technological developments to electron microscopes, detectors and processing software have enabled researchers to achieve high-resolution structures. Hence Cryo-EM has revolutionized structural biology to provide unprecedented insights into protein structure and function. Substantial investment has established national centres for data collection at the eBIC facility in Harwell and at the SCMI facility in Glasgow. To ensure that only the highest quality samples are selected for ultimate resolution data collection at the national facilities, it is equally important that the institutes that feed into them have excellent instrumentation for sample screening. To meet growing demand for Cryo-EM in Dundee this proposal requests support for the purchase of a Glacios Cryo-TEM with 200 kV X-FEG optics with an Autoloader for cryogenic sample manipulation and Falcon 3EC detector (or similar). In addition to efficient sample screening, this system supports high resolution data acquisition for single particle analysis, sample quality assessment, tomography, and other applications. This microscope will provide high quality screening for optimizing cryo-EM samples prior to data collection at National facilities, but also can determine structures at sub-3 Å resolution in house.
|
| 27/07/2021 |
£103,508 |
UNIVERSITY COLLEGE LONDON |
The IsoPlexis IsoLight platform is a unique, highly multiplexed single-cell microchip proteomics technology applicable to both basic and clinical research. Quantitative measurement of secreted proteins associated with a broad range of functional profiles is derived from over 1000 live single cells using intracellular protein detection via high-density antibody barcode arrays. It can precisely dissect the functional heterogeneity ('polyfunctionality') of immune cells with genetically and phenotypically identical signatures and several studies have shown that polyfunctionality determined at the single-cell level can identify critical effector cells associated with durable immunity against infections and cancer. Isoplexis analysis of polyfunctionality in the cell therapy space reveals that phenotypically similar T-cells can have heterogeneous functions and that the 'polyfunctionality index' can provide predictive signatures for toxicity and response to treatment. This state-of-the-art equipment will be housed at the UCL Royal Free Campus and will be used primarily for disease-focused and translational immunology research spanning the disciplines of immunotherapy, autoimmmunity, immunodeficiency, infection (including COVID-19) and cancer. This breakthrough single cell proteomics analysis platform will enable immunology and immunotherapy scientists at UCL to further enhance their understanding of endogenous and engineered human immune cells subsets in the pathophysiology of disease and in the response to treatment.
|
| 27/07/2021 |
£842,649 |
UNIVERSITY OF LEEDS |
The goal of this proposal is to establish a cutting-edge in-cell structural proteomics platform at the Astbury Centre that will enable the characterization of biomolecular structure and function in a cellular context. This will inform on the architectures of proteins and protein complexes, including interactions with nucleic acids and small molecules, directly in their native environment. We are requesting funding for the centrepiece of this platform, an Orbitrap Eclipse mass spectrometer with extended mass range and advanced fragmentation technologies. This equipment will enable us to deploy the suite of structural proteomics methods we have developed for in vitro protein studies directly to the cell. These approaches include in-cell covalent labelling to probe protein structure, such as by hydroxyl radical footprinting, and in-cell chemical crosslinking, including using bespoke photocrosslinkers, for interactome analyses. Such methods can only be implemented utilising the most sensitive mass spectrometry instrumentation available, and require advanced fragmentation methods to achieve the highest possible structural resolution. The proposed equipment will transform our ability to study molecular mechanisms of health and disease directly in the cell, and will result in translational opportunities, by identifying novel proteins, complexes and interactions that could be biomarkers or drug targets.
|
| 27/07/2021 |
£373,813 |
UNIVERSITY COLLEGE LONDON |
The requested equipment is a state-of-the-art multiwavelength photoacoustic imaging scanner for non-invasively imaging mice. Its distinguishing advantage over conventional optical imaging is that it avoids the deleterious impact of light scattering; it can therefore provide high resolution 3D images with molecular contrast at much greater depths (cm-scale) than light microscopy (
To benefit the widest possible range of users, it will be installed in the UCL Centre for Advanced Biomedical Imaging, a preclinical imaging centre that provides open access to a wide range of mouse models and state-of-the-art small animal imaging systems including ultrasound, SPECT/CT, MRI, bioluminescence and optical-projection-tomography.
|
| 27/07/2021 |
£340,339 |
QUEEN MARY UNIVERSITY OF LONDON |
In order to remain world-leading in the fast moving arena of single-cell approaches, UK researchers need access to the latest technology. Single-cell genomics and transcriptomics have fuelled an unmet need for affordable, single-cell, multiplexed protein maps that maintaining tissue architecture and integrity in a multi-user, high-throughput and flexible manner.
Launched in April 2020, The Cell DIVE Imager provides an automated solution for multiplexed immunofluorescence with industry-leading high content image analysis software enabling the visualisation, identification and integrated quantification of 60+ markers at the protein level. This equipment represents a new research capacity. Thus, our key goal is to establish the first multi-user Cell DIVE Imager platform available to researchers outside the USA.
We believe that the requested equipment satisfies all the technical requirements for accuracy, sensitivity and specificity. It also currently offers best value with respect to throughput, assay flexibility and cost, and enables multiple projects to be parallel tracked to support a multi-user base. Under the guidance of the lead applicant, the experienced QMUL Phenotypic Screening Core Facility will operate and maintain the equipment ensuring fair access to the 20 named co-applicants and collaborators and beyond, if capacity allows.
|
| 27/07/2021 |
£811,161 |
UKRI-MRC |
We are requesting funds to acquire a focused ion-beam and scanning electron microscope (FIB-SEM) with a cryo transfer system and an attached mass spectrometer for investigating biological material in three dimensions (3D) at high spatial resolution with chemical specificity. This cryo-FIB-SEM will be used for the three distinct purposes -
Firstly, serial block face sectioning and imaging of vitreous samples will provide images of key regions of tissues at unprecedented resolution (~5 nm). Secondly, this instrument will enable thick vitreous biological samples to be precisely thinned at cryogenic temperatures, producing lamella at high throughput with automation, which will be used in cryo-tomography applications for in situ structural cell biology. Thirdly, the instrument will have a secondary ion mass spectrometer attached, which will support molecular identification of the specimen, adding chemical specificity to high-resolution EM pictures. This versatile instrument will therefore provide a link between molecular structural data to 3D ultrastructure of cells and tissues, a complete transformational advance for the research of the MRC Laboratory of Molecular Biology (MRC-LMB).
This instrument will enable study of the structure and function of molecules in their native environment inside cells, providing insights into fundamental problems related to molecular biology and medicine.
|
| 27/07/2021 |
£1,204,973 |
THE FRANCIS CRICK INSTITUTE |
To understand how metabolites and drugs function in our bodies, it is essential to map their distributions accurately within tissues and cells. Secondary ion mass spectrometry (SIMS) is emerging as a powerful technology for this. We and others have collaborated with industry to improve SIMS instruments so that it is now possible to image tissues at micron spatial resolution with high mass resolution ( > 240,000 at m/z 200) and in situ detection sensitivity by at least an order of magnitude. We now propose three technology development aims with the goal of removing critical remaining obstacles to the wide adoption of SIMS in the biomedical sciences and pharmaceutical industry:
1) To optimise instrumentation and sample preparation for submicron-resolution cryo-OrbiSIMS.
2) To develop a toolkit of cryo-OrbiSIMS-visible chemical and genetically-encoded markers for cells and organelles.
3) To validate the OrbiSIMS marker toolkit across another SIMS platform - NanoSIMS.
|
| 27/07/2021 |
£928,892 |
UNIVERSITY OF EDINBURGH |
Bioimage analysis helps answer scientific questions by applying computational methods to images comprising millions – or, increasingly, billions – of pixels. As imaging technologies advance, new software tools are required to interpret these complex images.
QuPath (http://qupath.github.io) was created specifically to address the image analysis challenges of one emerging imaging modality: whole slide imaging. Whole slide images (WSI) are ultra-large digital scans (up to 50 GB), typically representing histological samples containing a wealth of information relating to health and disease. QuPath’s native support for WSI and intuitive combination of image processing and AI have established the software as a de facto standard for digital pathology and an essential tool for basic research.
The aims of this project are to:
Expand the range of algorithms available in QuPath to maximize the value of imaging data
Improve workflow development, validation and sharing to aid the translation of image analysis and AI towards clinical practice
Extend QuPath to new imaging modalities and applications to address unmet needs across a wide range of bioimaging applications
Together these represent a major upgrade to the software, transitioning QuPath from being primarily 2D and pathology-focussed into becoming an advanced bioimage analysis platform for next generation multidimensional imaging.
|
| 27/07/2021 |
£1,000,339 |
KEW ROYAL BOTANIC GARDENS |
Products derived from plants have scientific, medical, and economic significance.
Effective research, regulation, quality control, and consumer safety require precise, unambiguous references to these products. Regulations, databases, and research, however, employ contradictory, imprecise terminologies undermining integrity, retrieval, and exchange. Complex plant mixtures, for example, are regulated inconsistently as ‘drugs’ and ‘supplements’. Local terminologies duplicate effort, are inconsistent, and fail to reflect advances in molecular plant taxonomies.
Plants for Health (PfH) addresses the quality, interoperability, and findability of research and regulatory datasets concerning natural products by collating the terms used for ingredients, products, adulterants, and substitutes and mapping them to a scientific ontology. PfH will enable the detection and resolution of ambiguous terms and improve how research is targeted (eg. novel molecules) and reported.
"Medicinal Plant Names Services" is the default reference for herbal drugs. PfH will become so for all plant-derived products (c. 50,000 plants, 1.3 million terms) and serve many more audiences. PfH will include key traits, link to critical references, and provide digital accessibility.
10 institutional partners from diverse domains (e.g. WHO and WIPO) will help design, test, and deploy PfH, ensuring impact within their communities.
Health outcomes worldwide will improve through enhanced research, regulation, and knowledge exchange.
|
| 27/07/2021 |
£1,544,774 |
EUROPEAN BIOINFORMATICS INSTITUTE |
The PRIDE database, established in 2004 at the European Bioinformatics Institute (EMBL-EBI), is the world-leading proteomics data repository. PRIDE is also the leading partner in the ProteomeXchange Consortium, standardising public proteomics data submission and dissemination worldwide. PRIDE stores ~83% of all ProteomeXchange datasets, with ~5,300 datasets submitted during 2020 alone.
We request support to extend PRIDE, enabling the appropriate handling of clinical sensitive human datasets, through implementing controlled-access (CA) data capabilities. We will leverage infrastructure implemented for CA DNA/RNA sequencing data in the European Genotype Archive at EMBL-EBI, to create PRIDE-CA. Additionally, we will adapt the Beacon framework (developed for genetic variation at the DNA level) to support genetic variation data at the protein level, which is increasingly relevant in personalised medicine studies.
We will also develop the PRIDE Knowledge-Base (PRIDE-KB), a complementary resource to PRIDE, to store and disseminate high-quality proteomics data re-analyses, to generate new biological insight. We will implement proteogenomics data as the first use case supported in PRIDE-KB, reporting protein variants, isoforms and novel coding events for personalised proteomics approaches. To support this, diverse components will be developed and integrated, including new data archiving infrastructure, web interface, open data analysis pipelines and data inclusion guidelines.
|
| 27/07/2021 |
£981,393 |
UNIVERSITY OF LIVERPOOL |
The Tick Cell Biobank (TCB), the world’s only dedicated culture collection for cell lines derived from ticks and other arthropods, was founded in 2009. The TCB houses > 60 cell lines derived from ticks of medical and veterinary importance. We also generate and supply cell lines from neglected insect vectors including sand flies, biting midges, tsetse flies, triatomid bugs and mosquitoes. We supply arthropod cell lines to researchers all over the world and provide training in their maintenance, greatly increasing the chances of successful transfer and subsequent application in recipient laboratories. TCB Outposts in Asia (Malaysia), Africa (Kenya) and South America (Brazil) facilitate uptake of these valuable research tools in lower and middle-income countries.
This new project will
substantially enhance the existing collection through genomic and phenotypic characterisation of our novel, medically-important insect and tick vector cell lines
support, with the TCB Asia Outpost, continued generation and characterisation of novel arthropod cell lines with emphasis on human disease vectors (mosquitoes, sand flies, midges and mites)
extend the availability of the TCB and TCB Outposts as a global biomedical resource underpinning UK and international vector-borne disease research until 2026.
|
| 27/07/2021 |
£1,521,990 |
UNIVERSITY OF EDINBURGH |
We propose to develop the first miniaturised microscopes for high-speed (kHz) voltage imaging in freely moving animals. Voltage changes that mediate neuronal computations, and electrical signalling in non-neuronal tissues, are too fast to observe with miniature microscopes currently used for imaging in freely moving animals. To address this, we will build miniature microscopes that use Single Photon Avalanche Diode (SPAD) sensor technology to obtain frame rates > 10 fold higher than existing systems.
Our proof-of-principle ex-vivo data shows that SPAD sensors can image sub-threshold and spiking activity of neurons reported with genetically encoded voltage indicators (GEVIs). As the sensors used for these experiments have a similar footprint to the standard CMOS sensors in current miniature microscopes, it will be feasible to use SPADs to image fast electrical signalling even in freely behaving animals.
Our goals are: 1. To develop miniature microscopes that incorporate our established SPAD technology, along with custom made drivers and control software, to image 10s of neurons in freely moving animals. 2. To develop a second system using state-of-the-art SPAD sensors to image 100s of neurons in freely moving animals. 3. To validate the systems by recording from genetically identified neurons during spatial exploration and action selection.
|
| 27/07/2021 |
£1,338,559 |
UNIVERSITY OF EDINBURGH |
Drosophila is the only model organism with complex adaptive behaviours for which we also have a powerful genetic toolkit and extensive connectomic and transcriptomic coverage of the nervous system. This offers unparalleled opportunities to reveal the mechanisms by which brains control complex behaviour. Virtual Fly Brain provides a uniquely integrated, queryable view of Drosophila neuroscience data. Established pipelines with all major data providers enable rapid integration of new bulk data. Powerful UI and API allow users to find neurons and reagents from many sources, explore connectomes, visualise and download 3D image data. VFB provides an essential system ensuring key data is released openly and rapidly following FAIR data standards. However, it must cope with rapid increases in data scale and richness.
The next phase will:
Massively scale-up integration of multiple connectomics datasets, enhancing tools for search query and, via APIs, integration with analysis pipelines.
Integrate comprehensive single cell transcriptomics data and exploration tools.
Incorporate data-driven cell-type definitions and automated tools to map cell types across datasets, and annotate and share data.
Develop and integrate text mining pipelines to ensure complete mapping of papers and reagents to neuron types.
Extend APIs to empower users to analyse, annotate and share huge datasets
|
| 27/07/2021 |
£1,036,355 |
EUROPEAN BIOINFORMATICS INSTITUTE |
Established in 2018, the PDBe Knowledge Base (PDBe-KB, pdbe-kb.org) is a community-driven resource providing FAIR access to experimental and predicted 3D structure models and enhanced structural and functional annotations e.g. predicted functional sites. PDBe-KB supports fundamental biology, biomedicine, biotechnology and bioenergy by enabling atomic-level understanding of macromolecular function through its novel, consolidated presentation of all the available structural data and enriched annotations by means of "aggregated views". The PDBe-KB consortium has established common data standards for structural and functional annotations to improve data interoperability extending the impact of structural data e.g. to rationalise the impacts of disease-associated mutations, and thereby assist diagnostic and therapeutic strategies.
In this project we will:
Grow the PDBe-KB consortium to broaden the structural and functional annotations with specific emphasis on integrating residue mutation data in human and pathogen genomes.
Establish a new and comprehensive 3D-fold structure domain library (3D-SCAfold) through integration of CATH and SCOP domain data.
Ten-fold increase in the structural coverage of the sequence space using 3D-SCAfold for enhanced structure-based annotations with a specific focus on disease genotype data from human disease and pathogen proteins (e.g. SARS-CoV-2, Mycobacterium tuberculosis).
Develop novel visualisation tools, and a collection of aggregated views.
|
| 27/07/2021 |
£659,982 |
UNIVERSITY COLLEGE LONDON |
Our goal is to establish and validate a non-invasive imaging system capable of concurrently mapping brain and spinal cord electrical activity, non-invasively, at millisecond temporal resolution, during natural movement.
The proposed system will exploit novel magnetic sensing technology in the form of optically pumped magnetometers (OPMs). Using this technology, we have successfully developed a 100 channel wearable optically pumped magnetoencephalography (OP-MEG) system in a dedicated laboratory and shielded room at UCL. With OP-MEG, we have demonstrated that it is possible to make reliable measures of human brain function, even under challenging conditions such as participant movement or mapping deep structures, e.g. cerebellum or hippocampus. Yet all of this has been achieved with precision exceeding conventional MEG technology.
Building on this experience, we will augment OP-MEG with the ability to simultaneously record from the spinal cord – something that is not possible with existing technologies. The proposed wearable magneto-encephalography and spinography (MESG) system would be a world first. Concurrent imaging of brain and spinal cord electrophysiology, during natural human movement, and in diverse patient groups, would offer unprecedented opportunities for basic and clinical investigation of the human central nervous system in its entirety.
|
| 27/07/2021 |
£928,849 |
ROSALIND FRANKLIN INSTITUTE |
We will address the urgent and unmet need within the biomedical community for effective agents to combat the existing threat from coronaviruses and to be prepared for those that will arise in the future. We will also deliver a pipeline that will be applicable to other high threat respiratory viruses (Disease X). We propose to build a nanobody screening strategy that targets cross-reactivity from which we anticipate identifying (pan)-coronavirus binders. The pipeline will combine nanobody technology, structural biology and virology making use of the Diamond synchrotron at Harwell for X-ray data collection and the CL3 facilities in Oxford and Liverpool for handling live viruses. Together the results will enable the structure-activity relationships of anti-coronavirus nanobodies to be determined providing information that will guide sequence changes to increase nanobody binding and counter the effects of virus escape mutants or natural variants on virus detection and neutralisation. The demonstration of in vivo potency to SARS-CoV-2 and other than coronaviruses(cross therapeutic) is a key aim of the proposal and we will test any new potent neutralising nanobodies in an appropriate disease model.
|
| 27/07/2021 |
£1,435,494 |
UNIVERSITY OF BIRMINGHAM |
Membrane proteins provide a multitude of functions essential to the life of the cell, and yet extracting them in an active form remains exceptionally challenging. In recent times an amphiphilic polymer, poly(styrene-co-maleic acid) (SMA) has gained significant traction as an effective agent for extracting and stabilising membrane proteins in phospholipid nanodiscs. Unlike conventional methods based on detergents, the method also extracts the lipids surrounding the protein, helping to preserve native activity. Although the original SMA polymer provided a good solution for demonstrating the utility of this approach it is becoming increasingly clear that further development of the polymer is required to fully capitalise on the unique aspects of the method.
This project aims to address this by providing a technical resource for the community for generating improved, bespoke polymers matched to end users need allowing them to:
1) Tune the lipid environment within the nano-particle to optimise protein activity by introducing a variety of comonomers, including aromatic, linear aliphatic and branched aliphatic into the established maleic anhydride copolymer
2) Harness functionalised plug-n-play polymers that allow researchers to easily modify the polymers for downstream applications
These polymers will be tested by the community and delivered through an integrated commercial supply chain.
|
| 27/07/2021 |
£1,561,404 |
DIAMOND LIGHT SOURCE LTD |
We propose a Membrane Protein Laboratory (MPL) as a national resource focused on integrating, developing and harnessing new technologies to drive membrane protein biomedicine and structural biology. This proposal will build upon 15 years of MPL research excellence, technical developments at Diamond Light Source, and complement the strategic aims of Diamond-II and the Rosalind Franklin Institute. Integrative in situ outcomes spanning atomic to cellular scales will be central to technologies developed including time-resolved structural biology for drug discovery, single-particle and live-cell imaging. The MPL experimental platforms located in the Research Complex at Harwell (RCaH) will be vital to these efforts, delivering biomedically important membrane protein samples to drive technological developments, create new access routes for Diamond users and engage experts on the Harwell campus with the wider membrane protein community. Through an integrative technologies user access programme, we will support challenging, high-impact projects that have exhausted current strategies. Rapid-access proposals and INSTRUCT-ERIC (European Infrastructure for Integrated Structural Biology) will support MPL facilities access for the wider membrane protein community. In parallel Diamond and the Franklin will work with the MPL to establish a sustainability plan to enable core MPL activities to be independent of responsive mode funding.
|
| 27/07/2021 |
£1,560,057 |
EUROPEAN BIOINFORMATICS INSTITUTE |
DECIPHER’s mission is to lead an international collaborative effort to collect, annotate, share and aggregate genotypic and phenotypic data on rare disease patients in order to catalyse the discovery of new disorders and to improve clinical diagnostic interpretation of genome variation. It is the only online data-sharing platform which provides live, rich contextualisation of genomic variation and phenotype data in patients undergoing research and diagnostic testing globally, including for underserved areas of the world. Since 2004, collaborating rare disease genomics projects and clinical genetic diagnostic centres have uploaded and openly shared consented data on more than 38,000 patients.
Our plans to improve DECIPHER include driving increased global sharing and aggregation of clinical and research data; integrating relevant new research datasets to accelerate discovery science; developing functionality to support variant interpretation of the non-coding genome; and improving gene-phenotype-disease modelling to drive discovery research and drug development.
We will migrate DECIPHER from the Wellcome Sanger Institute to EMBL's European Bioinformatics Institute (EMBL-EBI), taking advantage of EMBL-EBI's rich resource environment and expertise in delivering web services and training. DECIPHER will operate and grow in an efficient and sustainable manner, providing an essential bridge to research resources to strengthen their clinical impact.
|
| 27/07/2021 |
£1,385,864 |
EUROPEAN BIOINFORMATICS INSTITUTE |
SureChEMBL is a large-scale, fully automated, chemical-structure-enabled database providing the research community with open, free and FAIR access to the patent literature. SureChEMBL contains ~140 million patents with ~50,000 added monthly. Of these, ~50 million patents are chemically annotated with more than 20 million unique chemical structures. Around 80,000 new compounds are extracted and stored monthly. The data in SureChEMBL can currently be accessed via a web interface that enables users to perform text and chemical structure queries, filter the output and then display the results. The complete set of chemical structures and patent associations are also available for download.
In this proposal we plan to significantly enhance SureChEMBL, enabling a wider selection of questions and use cases to be addressed, by: expanding annotations to include biological entities; developing methods to assess the relevance of information identified in patents and enable more accurate data retrieval and analysis; significantly improving the technical infrastructure and web interface with enhanced stability and usability; providing programmatic access through development of a RESTful application programming interface (API). The new, upgraded SureChEMBL will provide the broader life sciences research community with unparalleled access to a large and rich source of information and knowledge.
|
| 27/07/2021 |
£237,623 |
UNIVERSITY OF SOUTHAMPTON |
We will generate saturation transposon mutagenesis libraries of human pathogenic Chlamydiae (C. trachomatis (trachoma and LGV) and C. pneumoniae) and the 'model' species C. muridarum using TraDIS methodology. This approach has been successfully developed during my current Technology Development Grant with urogenital C. trachomatis. We have now refined the method so it will be straightforward to apply to other species, the application of the technology to generate a new series of key resources will greatly accelerate research. Our ultimate aim is to develop an ordered library of mutated/knock-out chlamydia isolates akin to the E. coli Keio collection. These mutants (knock-outs of non-essential genes) will be genome-sequenced in Southampton to mitigate off-target mutations. The collections will provide a unique and important biomedical resource, along with the saturation mutagenesis libraries and transposon delivery vectors. The transposon delivery vectors will form the basis for the development of further vectors for other chlamydial species. All resources generated during this project will be made available to the research community via the Chlamydia Biobank (www.chlamydiabiobank.co.uk) (BMR 101502/Z/13/Z). This will enable other researchers to test their hypotheses in the pursuit of gene function ascertainment - a critical step in identifying novel targets for drug or vaccine development.
|
| 27/07/2021 |
£919,761 |
UNIVERSITY OF BRISTOL |
We have created a prototype system – "U-RHYTHM" (Fig 1) – which enables, for the first time, circadian and ultradian rhythms to be investigated in free-moving individuals in their own home or work environment. Now that we have regulatory guidance from the MHRA Innovation Office that we can provide other centres with our current U-RHYTHM system for research use, we want to work with scientists from different research communities to enable them to develop important new lines of research for which there are no current enabling methodologies. We now need:
a) A much more user friendly version of U-RHYTHM that can be readily used both by the research
community and clinicians. The current version is very reliable in experienced hands but needs
specially trained personnel and would not be suitable for commercialisation.
b) To demonstrate its value in three new specialties:
Chronobiologists using its ability to measure dynamic changes in tissue metabolome, melatonin and glucocorticoids
Cardiovascular scientists who can utilise our ability to measure catecholamines, aldosterone and cortisol to improve diagnosis and pathophysiological understanding of hypertension.
Inflammation biologists needing to measure dynamic changes in tissue inflammatory mediators.
|
| 13/07/2021 |
£197,441 |
UNIVERSITY OF EXETER |
The project tackles the question of how digital technologies (DTs) are being adopted and adapted throughout the pork production and consumption process in China.
It explores the opportunities and challenges of using DTs, their effect on disease management practices, and their implications for food safety and OH challenges in Shanghai, Zhejiang and Jiangsu.
The project analyses the current conditions (behavioural, regulatory, economic and material) and interactions (institutional, human-animal) that drive or hinder the adoption and adaptation of DTs. It scrutinises how political and scientific discourses about the adoption of DTs are constructed, valued, and promoted to shape the uptake of DTs, and how DTs are being adopted, by whom, for what purposes, and to what effect.
The project focuses on farmers, vets, policymakers, high-tech companies, retailers and consumers to understand how the uptake of DTs transforms farmers’ and vets’ behaviours expedite a reduction in antimicrobial use, and how the adoption of DTs affects consumer and market practices.
The project adopts ethnographic approaches to examine the adoption of DTs by employing document analysis, in-depth interviews, participant observation and mapping methods to engage with key participants, thereby producing a geographically-specific dataset to advance the field and policies of OH and digital farming.
|
| 13/07/2021 |
£190,287 |
UNIVERSITY COLLEGE DUBLIN |
Keywords: Heroin, drugs, Ireland.
By 1990 heroin had devastated working-class communities across Dublin and, in some families, wiped out entire generations. But how did things reach that stage when three decades previously heroin was only known in Ireland as a symbol of distant, undesirable, foreignness?
This project will explore the history of heroin in Ireland, from its first public discussion (1918) to the end of the first heroin epidemic (1990). It will approach the history from two directions. First, analysing the public discourse about the drug. This will reveal, inter alia, different ways that heroin was used as a symbol of dissolute otherness, and how this shaped health policy and provision. Secondly the project will collect 100 oral histories to investigate how heroin affected everyday life in the communities at the centre of the heroin epidemic of the 1970s and 1980s. Finally, the project will use reception theory to integrate these approaches and achieve three key goals:
To understand how the public discourse shaped community members’ interaction with each other, the wider world, and healthcare providers.
To give marginalised communities a voice in the production of their own history.
To produce the first history of heroin-use in Ireland.
|
| 13/07/2021 |
£165,923 |
UNIVERSITY OF DURHAM |
This project is the first in-depth geographic examination of relationships between fatness, masculinities, and everyday life of diverse Filipino men situated in the uneven urban geographies of Metro Manila in the Philippines. Drawing hybrid connections from contemporary work on critical fat studies, critical masculinities, and Southern urban political ecology, I investigate urban cityscapes as complex obesogenic environments that shape the subjective experiences and everyday embodiment of fat amongst men. My approach combines textual and image-based analyses of ethnographic interviews to articulate the multiple ways by which fat is embodied in everyday practices of fitness and leisure as well as food and diet. Recognising the distinct contexts wherein Filipino masculinities are constructed, the overall goal of the project is to deepen situated knowledges of fat and masculine politics as integral to the reproduction, contestation, and transformation of urban ecologies.The importance of this intellectual intervention is aimed towards transforming gender and fat politics and rebuilding everyday equitable and holistic health among diverse groups of men in the city.
|
| 13/07/2021 |
£245,064 |
GOLDSMITHS, UNIVERSITY OF LONDON |
This research project is an inquiry into how caste structured medical discourses on alcohol between 1860 and 1950 in colonial South India. It examines the conceptualization of two local drinks, toddy and arrack as contaminating within medical theories and tracts that produced stigma. It focuses on two communities, Adi-Andhras and Adi-Dravidas (Telugu and Tamil speaking Dalits) in Madras Presidency as they bore intense forms of stigmatization. It examines the part played by medical ‘publics’ and ‘counter-publics’ – where the former served as liberal sites for voicing public opinion and the latter as forums for oppositional discourses of subordinated groups – in consolidating and contesting caste stigmas around alcohol. It investigates processes by which medical publics composed of surgeons, chemists, missionaries, Congress nationalists configured these two communities as polluted agents of drink. It critically inquires into multiple public health pedagogies employed by counter-publics comprised of Dalit communities who fought to purge themselves of alcohol-driven stigmas. The project explores the empowering possibilities of medical discourses on alcohol when driven by a regionally and globally informed Dalit social consciousness. While grounding Indian debates, it delves into how concepts of ‘publics’, ‘counter-publics’ and ‘stigma’ travelled across global drinking cultures and medical landscapes of alcohol.
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| 13/07/2021 |
£197,042 |
UNIVERSITY OF LEEDS |
This project will establish the fundamental methods for the study of Byzantine disability, an area that has received almost no attention. Focusing on two pillars of power, the Church and the Court, it will examine how representations of diverse human capacities and appearances, including restricted mobility, blindness, and dwarfism, changed between 1000 and 1200, depending on gender, race/ethnicity, social and religious status. It will reveal how norms of able-bodiedness were reproduced, while emphasising the potential for disability gain that arose from disabled bodies and their relational configurations with other humans, animals, and technology.
This project will expose ableist historiographical assumptions by uncovering the beneficial effects of a Church that valued spiritual sensation above the physical senses and a Court in which the bodies of powerful emperors and eunuchs disrupted expectations of perfection and integrity. More broadly, it will examine what Byzantine disability can tell us about what it means to be human, focusing on the place of autonomy/heteronomy in a world that was more connected with animals than our own.
These Byzantine findings will be placed in dialogue with Classical and Western medieval sources, challenging existing understandings of premodern disability and creating new avenues for interdisciplinary work.
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| 13/07/2021 |
£195,286 |
UNIVERSITY OF STRATHCLYDE |
The illegal drug Ecstasy (3,4-Methylenedioxymethamphetamine (MDMA)) arrived in Britain in the mid-1980s. Initially associated with, and assumed to be a catalyst for the nascent ‘rave’ scene, by the mid-1990s Ecstasy had transcended its subcultural origins and was a mass intoxicant. Despite government campaigns, harm reduction programmes, and the high-profile deaths of young people such as Essex teenager Leah Betts, by the turn of the millennium Ecstasy had joined the ranks of alcohol and cocaine as ‘party’ intoxicants that were a feature of British nightlife and leisure activities.
This project places consumers and consumption at the heart of an original historical account of the impact and legacy of this novel psychoactive substance. Using a combination of archival research and oral histories to explore representations of Ecstasy by public health and medical circles, in mainstream media, and in wider cultural discourse, it promises important new perspectives on how far consumers drive markets for psychoactive substances in contemporary societies. It brings recent developments in the history of emotions into investigations of drugs and intoxicants for the first time. Finally, it will take these conclusions about Ecstasy consumers into debates about the changing relationships between ‘pleasure’, ‘risk’ and ‘health’ in Britain since the 1980s.
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| 13/07/2021 |
£375,164 |
UNIVERSITY COLLEGE LONDON |
The NHS is challenged to provide effective psychological services for traumatised populations. Iranians comprise the largest number of asylum seekers in the UK, with some having experienced torture, which results in enduring psychological distress for the victims.
This study aims to improve mental health services for traumatised refugees by exploring moral injury from the perspective of Iranian torture survivors.
Moral injury, a concept for survivors’ responses to the transgression of their moral beliefs, seeks to address trauma’s lasting impacts – examples are loss of a sense of self-worth, and the belief in a benevolent world as well as mistrust in all forms of relationships. This concept, however, lacks empirical data from victims and refugees.
I will undertake a phenomenological study to explore the impact of morally injurious events in Iranian torture survivors in the UK. Using snowball sampling, I will recruit and collect life-history narratives. This will be followed by focus groups with healthcare professionals and support workers to determine the clinical and policy implications of moral injury.
The findings will contribute to a culturally sensitive approach to therapy for torture survivors. To influence policy and practice, the advisory group will include torture survivors, trauma experts, and refugee community organisations.
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| 13/07/2021 |
£238,155 |
UNIVERSITY OF EDINBURGH |
This comparative research investigates how care relationships and identities are (re)configured through the development and use of Socially Assistive Robots (SARs) by tracing AI and robotics innovation for care from the laboratory to final users, and focusing on embodied experiences of SARs across different cultural contexts. The study lies at the intersection between medical sociology, anthropology and STS, while scrutinising how robots may be used to assist a range of healthcare workers. It investigates: (1) the ways in which emotionality and sociability are being algorithmically configured in SARs; (2) how care recipients do and might perceive and respond to such algorithmic sociability, and what aspects of human care relationships they may want robots to mirror; (3) how our understandings of the role and value of human care may influence the development of SARs - and how might such care in turn be influenced, as ‘caring machines’ come into our world. This research will create knowledge of how SARs may shape and be shaped by different understandings of the role and the value of human care, and potentially transform how care is understood, approached, managed, and experienced. Ultimately it will contribute to conceptual frameworks needed to analyse and understand these transformations.
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| 13/07/2021 |
£1,905,653 |
UNIVERSITY OF GLASGOW |
Malaria remains a major global health threat with over 200 Mio cases and 400’000 deaths annually, the majority of them due to infection by Plasmodium falciparum. Malaria elimination depends on strategies to eliminate the parasite reservoir and prevent its onward transmission to mosquitoes. Production of transmission stages (or gametocytes) is variable across parasite species and strains, conditions as well as being environmentally sensitive. Studies in P. falciparum revealed that epigenetic mechanisms regulate the plasticity in gametocyte production in response to changes in the within-host environment. Specifically, we discovered that limiting levels of the serum phospholipid LysoPC are translated into transcriptional upregulation of alternative metabolic pathways for phosphatidylcholine biosynthesis and the transcription factor ap2-g. Epigenetic activation of the transcription factor, ap2-g in turn triggers the transcriptional program for sexual development. LysoPC is an immune metabolite and reduction in systemic LysoPC levels is the result of inflammation, for example due to acute malaria. How exogenous LysoPC levels regulate both, expression of metabolic enzymes and the epigenetic switch underlying stage conversion in the parasite is the subject of the current proposal.
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| 13/07/2021 |
£3,743,939 |
UNIVERSITY OF OXFORD |
The development of improved therapies for Parkinson’s disease (PD) requires new knowledge of why certain types of neuron dysfunction and die. Midbrain dopaminergic neurons (DANs) are particularly impacted by PD, and offer valuable opportunities for comparative investigations of factors underpinning vulnerability. Our interdisciplinary collaboration will address the overarching hypothesis that compartmentalised, activity-dependent Ca2+ handling in DANs is cell-type-specific, perturbed by disease burden, and contributes to preferential vulnerability in Parkinson's.
We will collectively deliver a step change in the understanding of calcium dynamics and related dopaminergic signalling in DANs. We will be the first to define cytosolic and organellar calcium dynamics throughout the whole extent of DANs during physiologically-relevant activity patterns. Our programme brings together leading scientists with complementary expertise, and integrated experimental platforms spanning mouse models and human stem cell-derived models, to identify the key mechanisms involved. Progressing from correlation to causation in the contexts of health and PD, we will define how and when calcium enters susceptible and resistant DANs, its handling by organelles in light of their other functions, and the importance of compartmentalised calcium for how DANs cope with PD burden. Our collaborative approach is strongly positioned to transform understanding of selective neuronal vulnerability in PD.
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| 13/07/2021 |
£1,598,460 |
UNIVERSITY OF BIRMINGHAM |
I will test the hypothesis that a shared molecular mechanism drives brain structural plasticity and degeneration throughout life. Structural plasticity enables the brain to adapt to the environment, whereas structural homeostasis constrains change. This balance breaks down in brain disease – psychiatric, neurodegenerative - and aging, and stressors such as isolation, lack of stimulation and stress cause a degenerative drive. Discovering the molecular and circuit mechanisms underlying experience-dependent plasticity and degeneration, and their link to behaviour, is urgently needed to understand human brain health.
Building on my discovery of the Drosophila neurotrophin system – comprising neurotrophins, Tolls and kinase-less Trk-like Kek receptors – I will use Drosophila to link molecules, neural circuit modification and behaviour.
I will ask:
How does experience and behaviour alter the brain?
What is the molecular switch between structural plasticity and neurodegeneration?
Key goals are:
(1) To establish a molecular mechanism regulating structural brain plasticity, focusing on DNT-2 and -3 and their circuits involved in sensory experience, motor output and neuromodulation.
(2) To test a key molecular switch between structural plasticity and degeneration, focusing on Wek.
(3) To test and reverse with DNTs a neurodegenerative drive caused by isolation, immobility and lack of stimulation.
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| 13/07/2021 |
£1,718,251 |
UNIVERSITY COLLEGE LONDON |
Allergic reactions to food and environmental substances affect more than 40% of the UK population, resulting in a major health burden and potentially fatal anaphylaxis. Many of the clinical symptoms are caused by overproduction of allergen-specific IgE antibodies. Interestingly, the IgE responses are normally low, transient and lack classical immunologic memory. Using new genome-wide approaches, we have discovered molecular mechanisms, which naturally inhibit the differentiation of IgE-switched B cells into antibody-secreting cells and limit their lifespan. These inhibitory mechanisms are triggered by spontaneous intracellular signalling by the IgE B cell receptor expressed on the surfaces of IgE-switched B cells and plasma cells and are different from the control of other antibody isotypes. We hypothesise that this suppressive signalling defines the self-limiting character of IgE responses and that its failure contributes to allergic disease. We will investigate this by elucidating the molecular mechanisms and dynamics of this signalling, and by determining its role in responses to allergens and in primary hyper-IgE syndromes. Our comprehensive characterisation of the molecular pathways underlying the behaviour of IgE-switched cells will illuminate the unique character of IgE responses and provide new therapeutic targets to selectively inhibit IgE production in allergic disease.
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| 13/07/2021 |
£1,387,077 |
UKRI-MRC |
AMPA receptor (AMPAR) operation underlies learning, while receptor malfunction is associated with various diseases. Their uniquely versatile signalling arises from numerous auxiliary subunits that assemble into functionally diverse receptor super-complexes. The combination and stoichiometry of these components, and how they shape neuronal response properties, remains a central open question.
We will elucidate the pathways leading to activation of a predominant AMPAR, building on our cryo-EM structures of this receptor, associated with two structurally diverse auxiliary subunits. Using cryo-EM, MD simulations and single-channel recordings, we will assess the differential contribution of core- and auxiliary subunits to the receptor’s characteristic activation time course.
We will also investigate the mechanism of leading neurotherapeutics on gating, capitalising on our AMPAR structures associated with these ligands, and study the role of the receptor’s lipid environment through reconstitution into liposomes. We will complement these studies with time-resolved cryo-EM of gating intermediates, and structures of native AMPAR complexes, isolated from mammalian synapses.
These experiments will uncover the principles underlying AMPAR organisation and activation. We will derive a comprehensive kinetic model, delineating how activation is modulated by auxiliary subunits, lipids and neurotherapeutics. Elucidating the conformational states selectively targeted by these ligands will facilitate targeted structure-based drug design.
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| 13/07/2021 |
£1,619,132 |
THE FRANCIS CRICK INSTITUTE |
Toxoplasma gondii infects any nucleated cell of any warm-blooded animal and ~30% of the human population. Why some Toxoplasma strains cause disease in humans but not in other species and vice versa is poorly understood, but linked to effector proteins the parasite secretes to remodel its host cell. A substantial proportion of host cell remodelling occurs on the transcriptional level, but which of Toxoplasma’s ~200 putative effector proteins mediate these changes, and how they affect different cell types and hosts is largely not known. We will use a novel technology we devised (EffectorSEQ) to correlate host cell transcriptomic changes to infection by various Toxoplasma mutants in a highly multiplexed manner. We will i) identify most, if not all, Toxoplasma effectors important for host cell transcriptional responses in different cell types and species and ii) use bioinformatics approaches to identify those that promote anti-inflammatory immune responses. iiI) We will investigate in detail the effector proteins that change infected immune cells signalling behaviour and thereby promote an immune environment that favours parasite growth and pathogenesis. Our result will lead to a comprehensive understanding how this important pathogen infects and causes disease in such a broad host range.
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| 13/07/2021 |
£1,810,041 |
KING'S COLLEGE LONDON |
Macrophages are best known for their immune functions, but they also play important roles in development and tissue homeostasis – often referred to as trophic functions. There are two distinct lineages of macrophages that populate mammalian tissues; embryo-derived tissue-resident macrophages (TRM) maintain themselves in adult tissues by proliferation and self-renewal and coexist with monocyte-derived macrophages (MDM) from adult bone marrow. We recently showed that TRM form a niche that promotes the metastatic spread of cancer cells, suggesting TRM have specific functions linked to tumour progression. We hypothesise that TRM maintain hard-wired trophic functions that support the malignant progression of cancer cells and tumorigenesis. It’s therefore critical to determine the unique features of TRM and the mechanisms that maintain their homeostasis and functional programming during tumour development. In this project we will perform high-dimensional single cell analysis of TRM in mouse models and human cancer. We will develop new genetic tools to dissect the specific functions of TRM during tumorigenesis and the mechanisms that maintain their homeostasis and functional programming. These studies will give new insights into the biology of TRM and their roles cancer that may reveal new targets for therapeutic intervention.
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| 13/07/2021 |
£1,416,647 |
UNIVERSITY OF EXETER |
This research will use novel insights from genomic analysis of individuals with congenital hyperinsulinism to provide new mechanistic understanding of the regulation of insulin secretion. Through preliminary studies I have identified non-coding mutations that affect the regulation of HK1, a housekeeping gene which is silenced within the beta-cell. These mutations pinpoint the first element to be discovered that regulates beta-cell specific silencing and highlights the role of ‘disallowed’ genes in pathophysiology.
To discover further regulatory mutations affecting the expression of a beta-cell ‘disallowed’ gene I will integrate genomic data with epigenomic annotation in my unique cohort of ~2000 hyperinsulinism patients with known causes excluded. I will study the impact of mutations in affected pancreatic tissue to gain insights into 1) the mechanism(s) by which they disrupt insulin-secretion and 2) the regulatory networks that are critical for maintaining tissue-specific suppression of genes. The results from these studies may be leveraged to discover novel targets to better treat hyperinsulinism and will improve knowledge of the role of the non-coding genome. This will be important for genetic discovery in other monogenic conditions where the major focus has been on the discovery of coding mutations in genes highly expressed within the disease tissue.
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| 13/07/2021 |
£2,002,780 |
UNIVERSITY OF EDINBURGH |
Background: rapid advances in our understanding of psychiatric disorder genetics within European ancestries are leading to mechanistic insights, more accurate risk stratification and stronger causal inferences, but there is growing concern that these findings may not generalise to African ancestries and those who reside in low and middle income countries. We need to urgently address this knowledge gap if we are to reduce growing health disparities.
Vision: drawing on the substantial strengths of the UK Psychiatric Genomics Consortium (PGC) and a network of African investigators, we will develop processes for rapid sample collection and address critical scientific and clinical questions about the genetic architecture of depression in non-European populations.
Research plans: using state-of-the-art ancestry-aware genetic methods, we will address whether the genetic architecture of major depressive disorder in different African countries is similar and whether it mirrors that of European ancestry populations. We will develop a network of UK and African partners in the best clinical research practices. We will adopt a pragmatic approach to data collection and analysis through a combination of new sample collections and genotyping and analysing existing samples; building capacity at each stage of the research process.
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| 13/07/2021 |
£1,031,556 |
KING'S COLLEGE LONDON |
Background: rapid advances in our understanding of psychiatric disorder genetics within European ancestries are leading to mechanistic insights, more accurate risk stratification and stronger causal inferences, but there is growing concern that these findings may not generalise to African ancestries and those who reside in low and middle income countries. We need to urgently address this knowledge gap if we are to reduce growing health disparities.
Vision: drawing on the substantial strengths of the UK Psychiatric Genomics Consortium (PGC) and a network of African investigators, we will develop processes for rapid sample collection and address critical scientific and clinical questions about the genetic architecture of depression in non-European populations.
Research plans: using state-of-the-art ancestry-aware genetic methods, we will address whether the genetic architecture of major depressive disorder in different African countries is similar and whether it mirrors that of European ancestry populations. We will develop a network of UK and African partners in the best clinical research practices. We will adopt a pragmatic approach to data collection and analysis through a combination of new sample collections and genotyping and analysing existing samples; building capacity at each stage of the research process.
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| 13/07/2021 |
£960,918 |
CARDIFF UNIVERSITY |
Background: rapid advances in our understanding of psychiatric disorder genetics within European ancestries are leading to mechanistic insights, more accurate risk stratification and stronger causal inferences, but there is growing concern that these findings may not generalise to African ancestries and those who reside in low and middle income countries. We need to urgently address this knowledge gap if we are to reduce growing health disparities.
Vision: drawing on the substantial strengths of the UK Psychiatric Genomics Consortium (PGC) and a network of African investigators, we will develop processes for rapid sample collection and address critical scientific and clinical questions about the genetic architecture of depression in non-European populations.
Research plans: using state-of-the-art ancestry-aware genetic methods, we will address whether the genetic architecture of major depressive disorder in different African countries is similar and whether it mirrors that of European ancestry populations. We will develop a network of UK and African partners in the best clinical research practices. We will adopt a pragmatic approach to data collection and analysis through a combination of new sample collections and genotyping and analysing existing samples; building capacity at each stage of the research process.
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| 13/07/2021 |
£1,659,251 |
UNIVERSITY OF EDINBURGH |
My work during the Covid outbreak has shown that genetic associations with critical illness can predict therapeutic targets, and that therapies targeting the host response improve outcome in carefully-defined subgroups of critically ill patients. I propose to extend this work to bridge the gap between genetic discovery and therapeutic application. In doing so I will build on established infrastructure and lay the foundations of a system for rapid identification and assessment of candidate drugs for respiratory critical illness. To achieve this I will:
Use genome-wide association studies to identify host genes associated with critical illness in viral pneumonia (Covid-19: 20,000 cases; influenza: 3000 cases).
Identify targets using computational approaches including integrated functional genomics and Mendelian randomisation.
Complete proof-of-principle analysis to test for differential genetic effects in new patient subgroups.
Refine and test candidate causal variants in vitro.
Establish technology for distal lung regional microdosing to validate targets in vivo in critically ill humans.
At the end of this fellowship I will have established a programme of translational genomics in critical care medicine going from genomic discovery to experimental medicine in humans.
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| 13/07/2021 |
£1,764,240 |
UNIVERSITY OF OXFORD |
The endoplasmic reticulum (ER) is the largest membrane-bound organelle in cells, playing numerous essential functions including the biogenesis of secreted and membrane proteins, lipid synthesis and assembly of the nuclear envelope. A long-term goal of my lab is to dissect how these functions are coordinated and ER homeostasis achieved. Proteolysis through the ER-associated degradation (ERAD) pathway has emerged as key in maintaining ER homeostasis and this proposal aims at understanding its mechanistic basis, with a particular focus on membrane protein substrates.
ERAD is organized in multiple branches, thereby targeting a broad range of luminal and membrane substrates. The mechanisms by which luminal substrates are selected and processed by the ERAD machinery are well established. In contrast, the mechanisms by which ERAD targets membrane substrates are mysterious and several fundamental questions remain: (1) what are the preferences of the various ERAD branches for membrane substrates? (2) what are the molecular basis for their recognition? (3) how are membrane substrates translocated to cytosol for degradation? Addressing these issues will reveal key mechanisms of membrane protein quality control by ERAD. Given that defects in protein quality control are linked to various pathologies, from developmental diseases to neurodegeneration, our studies may have clinical relevance.
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| 13/07/2021 |
£1,791,993 |
UNIVERSITY OF OXFORD |
Neuropathic pain (NeuP) affects almost 10% of the general population and current therapies are inadequate. Ion channels are key determinants of excitability within the sensory nervous system and so are attractive therapeutic targets. We need to understand the mechanisms by which ion channels drive hyper-excitability and NeuP in humans. Ion channel variants have been associated with rare Mendelian pain disorders; we have recently found that variants in ion channels also act as risk factors for more common NeuP disorders such as painful diabetic neuropathy. I will investigate ion channels (and their variants) identified from human genetic studies of NeuP. These will include voltage-gated sodium channels and, recently implicated targets, such as channels which maintain neuronal homeostasis in response to sodium. I will determine how these genes regulate excitability within the sensory nervous system and their interaction with environmental stressors (such as extremes of temperature) using electrophysiology, human-iPSC and animal models. These models will also provide a platform in which to screen potential treatments. I will explore the relationship between pathogenic variants, clinical and sensory phenotype. This will lead to new understanding of the pathophysiological mechanisms driving NeuP, facilitating identification of new treatment targets and better targeting of existing therapies.
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| 13/07/2021 |
£3,723,378 |
UNIVERSITY COLLEGE LONDON |
This project will reveal how neural activity is structured in brainwide patterns to support diverse behaviors, using powerful techniques that record and interpret the activity of a myriad individual neurons. The brain is a high-dimensional system, but coarse measurements of macroscopic brain activity - from EEG, fMRI, LFP, and widefield imaging - reveal a surprisingly simple low-dimensional structure. By recording from large neuronal populations across the mouse brain we will determine: 1) how macroscopic activity patterns are organized across brain structures at the level of individual neurons and neuronal cell classes; (2) how they interact with the high-dimensional activity patterns that encode sensory signals, and modulate the transmission of signals across brain regions; (3) how they depend on the performance of different behaviors, and evolve over time as animals learn a task. The results will provide a new understanding of how neural activity is organized across a myriad individual neurons into the brainwide patterns that shape behavior.
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| 13/07/2021 |
£1,896,758 |
THE FRANCIS CRICK INSTITUTE |
Cancer immune control relies on cytotoxic T cells that are primed against tumour antigens by crosspresenting type 1 conventional dendritic cells (cDC1s). We have found that the cDC1 receptor, DNGR-1, promotes crosspresentation of dead cell-associated antigens through a novel cell biological mechanism that involves signalling for phagosomal rupture. We propose to screen for further components of the DNGR-1–phagosomal rupture pathway with a view to harnessing them in anti-cancer immunity. Notably, DNGR-1 detects dead cells by binding to F-actin exposed by cell corpses, an activity opposed by secreted gelsolin (sGSN) circulating in plasma or produced by cancer cells. We will examine how the interplay between DNGR-1 and sGSN regulates anti-tumour immunity, including testing the hypothesis that DNGR-1-mediated crosspresentation selects tumour neoantigens associated with the actin cytoskeleton. Finally, as cDC1 are rare in tumours, we will assess the benefit of broadening DNGR-1 expression to other myeloid cells, either genetically or chemically. The latter will involve arming Fcgamma receptors, which may also signal for phagosomal rupture, with the DNGR-1 extracellular domain. Altogether, the proposed work will reveal fundamental mechanisms by which the antigenicity of dead cells is translated into anti-tumour responses and suggest avenues to exploit these mechanisms for cancer therapy.
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| 13/07/2021 |
£2,099,101 |
WELLCOME SANGER INSTITUTE |
BACKGROUND
Despite impressive progress over seven decades, the prognosis of many childhood cancers has now stalled. Novel treatments are required, which may be derived by studying the foetal origin of childhood cancer. My goal is to provide an exact phylogenetic and quantitative molecular understanding of the roots of childhood cancer that may be clinically exploited, for example, by revealing foetal specific antigens, mechanisms of subverted differentiation, or markers for screening.
HYPOTHESIS & QUESTIONS
My overarching hypothesis is that childhood cancer formation represents a perturbation of human development that extends beyond individual cells, which I will address through two questions:
(i) Do childhood cancers arise from pre-cancerous clonal expansions?
(ii) Do embryonic cancer-disposed lineages contribute to non-transformed tissues?
APPROACH
I will reconstruct from resection and post-mortem tissues the embryonic phylogeny of tumours from somatic DNA mutations and interrogate the molecular differences between normal, pre-cancerous, and cancerous tissues through mRNA and methylation sequencing at the resolution of individual histological units.
ANTICIPATED OUTCOMES
This work will reveal embryonic precursors of specific tumour types and molecular features of malignant transformation. Moreover, it will provide a blueprint for studying the origin of the entire spectrum of childhood cancers and other genetic developmental diseases.
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| 13/07/2021 |
£2,019,718 |
THE FRANCIS CRICK INSTITUTE |
A relatively small number of proteins have been suggested to act as morphogens, molecules that spread within tissues to organize cell fate decisions and tissue repair. Among them are Wnt proteins, which, surprisingly for signalling molecules, are relatively insoluble because of a palmitoleate moiety that is essential for signalling activity. A number of proteins are dedicated to Wnt secretion and transport in the extracellular space. In particular, Wntless escorts Wnt from the ER to the cell surface, and Dlp-class glypicans shield the Wnt lipid in the extracellular space before it engages with signalling receptors of the Frizzled family. We will combine structural, biophysical, and genetic approaches to characterise the key interactions that Wnt proteins and their lipid engage with during this journey. Thus, we will determine how Wnts are released from Wntless in secreting cells and allowed to form a complex with Dlp-class glypicans. We will determine the glycosaminoglycans that support the formation of the Wnt-glypican complex before elucidating the complex’s structure and identifying the key determinants of affinity. These measurements will lead to a mechanistic understanding of Wnts’ extracellular transport and subsequent hand-over to Frizzleds and form the foundation of a realistic mathematical model of Wnt gradient formation.
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| 13/07/2021 |
£4,055,445 |
UNIVERSITY OF CAMBRIDGE |
Efficient brain network computations rely on suppressing cell excitation—a process known as inhibition that involves neurotransmitter activity. GABA is the primary inhibitory neurotransmitter in the brain and is known to play a key role in learning and brain plasticity. Yet, our understanding of the role of GABA in regulating the brain network dynamics that support learning has been hampered by technology limitations and a fundamental disconnect between work in animal models and humans. To tackle this challenge, we propose an integrated work programme that bridges across species (mice, humans) and scales (local circuits, global networks).
We will a) match behavioural training protocols in humans and mice, focusing on perceptual learning, b) validate non-invasive Magnetic Resonance Spectroscopy (MRS-GABA) imaging capitalising on the precision afforded by neuroengineering tools (optical GABA sensors, electrophoretic GABA/drug delivery), c) combine GABA imaging with calcium imaging and electrophysiology to test the link between GABAergic inhibition and network activity, d) marry modelling and interventions (optogenetics, neuropharmacology) to test the mechanistic functions of inhibitory brain networks.
Our work programme will 1) advance understanding of the inhibitory brain dynamics that mediate learning across species, 2) decipher the origins of MRS-GABA, 3) optimise GABA imaging, enhancing potential for clinical translation.
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| 13/07/2021 |
£1,377,893 |
UNIVERSITY OF LEEDS |
The human genome encodes 40 genes for myosin that can be grouped into 12 different classes based on their sequence similarities. Many are implicated in disease from cardio- and myo-pathies and blood clotting deficiencies (Class 2), to deaf-blindness (class 7) and neuronal and gut disorders (class 5). Each myosin is specifically adapted for its cellular role, with adaptations to the motor and lever domains dictating how the myosin interacts with actin filaments to generate motility and adaptations to the tail dictating its cellular cargos. However, we lack an understanding of how the activity of these motor proteins is regulated. Here I plan to focus on class 2, 5 and 7 myosins, to uncover how myosin-2 function is regulated by filament assembly and disassembly, how myosin-5 and 7 function is regulated by the formation of compact inhibited structures, how strain affects myosin structure, modulating its ATPase, a broad mechanism that regulates the behaviour of all myosins, and I plan to discover when and where myosin is switched off in in cells, a fundamental question in biology.
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| 13/07/2021 |
£3,984,636 |
IMPERIAL COLLEGE LONDON |
Those responsible for the healthcare sector in countries in Eastern, Central and Southern Africa must decide what to do with limited resources to generate the greatest possible benefit to the health of the people they serve. We propose to develop new methods and collect new data to characterize the means by which the healthcare system produces health benefits in the context of a complex and evolving pattern of demand for healthcare. Our proposed approach is to build a detailed and theoretically-principled simulation model that couples a ‘Healthcare Production Module’ with an agent-based ‘Epidemiological Module’, that together would represent the mechanisms by which resources create healthcare that lead to health gains. We will use these methods to examine: how can the currently available resources (budgets and non-financial resources) for health be used to generate the greatest health gains; how could greater gains be achieved with more financial resources; and how should the healthcare system adapt in response to evolving burdens of diseases. We will work closely with national and regional institutions to translate the insights into strategic planning and policy and facilitate the routine usage of these methods by governmental analysts throughout the region.
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| 13/07/2021 |
£2,105,903 |
UNIVERSITY OF CAMBRIDGE |
Stem cells in tissues as varied as the blood, gut, and brain spend much of their time in a reversible, mitotically dormant state called quiescence. Quiescent stem cells can be reactivated to resume proliferation in order to fulfil the needs of the organism during development and in adult life. A key point of regulation is the decision to switch between quiescence and proliferation. The response of stem cells to changing physiological conditions is mediated by inter-organ signalling, ensuring that growth and patterning are coordinated throughout the organism and that homeostasis is maintained. Uncovering the molecular mechanisms that control stem cell behaviour is crucial for understanding tissue regeneration under normal and pathological conditions and may make it possible to activate quiescent NSCs to regenerate neurons after injury or disease.
My goal is to understand the control of stem cell quiescence and reactivation in the brain, unravelling the steps that lead from systemic signalling, through inter-organ communication, to stem cell proliferation and the generation of new neurons and their circuits. Using Drosophila as a model system, it will be possible to deduce, in vivo, the sequence of events at the level of the organism, tissue, cell, and finally genome.
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| 13/07/2021 |
£1,224,434 |
UNIVERSITY OF OXFORD |
The interferon (IFN) immune response induces an antiviral state by triggering the expression of IFN-stimulated genes and is the primary line of defence against infection. The proteins encoded by these genes fulfil a variety of functions, including degradation of viral RNA and reduction in protein translation. Unsurprisingly, viruses have evolved compensatory mechanisms to suppress the IFN response. One such family of viruses is Coronaviridae, responsible for the current COVID-19 pandemic. Suppression of IFNs by Coronaviridae has been attributed to the macrodomain module present within the multidomain Nsp3 protein. The macrodomain functions as an ADP-ribosylhydrolase to neutralise the actions of the antiviral members of the poly(ADP-ribosyl)polymerase (PARP) family. However, the mechanisms through which antiviral PARPs and macrodomains impact the IFN response remain unclear. This proposal will provide a molecular understanding of how antiviral PARPs suppress coronavirus infection and how SARS-CoV-2 macrodomains oppose their activity to evade IFN signalling and promote viral replication. Furthermore, comparative analyses of the macrodomains from different coronaviruses and their impact on interferon response may explain the variations in their pathogenicity. Collectively, our studies will inform interferon-based disease management strategies to prevent spread within and between infected hosts and provide novel biomarkers of susceptibility and antiviral drug targets.
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| 13/07/2021 |
£1,202,559 |
UNIVERSITY OF EXETER |
Transcriptional regulation is critical for all cellular processes. It is usually studied by asking how RNA polymerase II (Pol II) is recruited to gene promoters then activated for elongation. This programme focuses on promoter-proximal termination (PPT) of Pol II in mammals that I hypothesise as a general means of transcriptional control, the evasion of which is required to produce functional mRNA. I will dissect two major PPT pathways in the first two aims, one of which we recently discovered. I will use genetically encoded degrons to study the relevant protein factors at high temporal resolution. Cutting-edge nascent RNA analyses will be employed to scrutinise their impact on transcriptional control, define their mechanisms and uncover their substrates. I will then transfer this approach into mouse embryonic stem cells to ask whether PPT regulates developmental gene expression during the transition between naïve and formative pluripotency. In the final aim, I will uncover the proximal Pol II proteome to reveal why polymerases are susceptible to PPT. I will also identify the RNA binding proteins that distinguish PPT products from other transcripts. My overall goal is to uncover how PPT controls RNA biogenesis and the extent to which it regulates gene expression.
|
| 13/07/2021 |
£4,215,495 |
UNIVERSITY OF CAMBRIDGE |
Despite > 60 years of antitubercular chemotherapies, tuberculosis (TB) has been the leading infectious cause of death. My laboratory pioneered the zebrafish - Mycobacterium marinum tuberculosis model to better understand TB pathogenesis. It enabled surprising discoveries about tuberculosis with immediate implications for new therapeutic modalities. Here, we will use the zebrafish to discover genetic alterations that impact upon immunity and inflammation in early TB. This will uncover human genetic susceptibilities to tuberculosis and druggable pathways underlying them. Our key goals are to:
- Map and characterize hypersusceptible zebrafish mutants identified in a forward genetic screen. We will identify their causative lesions and characterize which infection step is altered in them and how, so as to understand how these genes modulate infection.
- Identify gene-regulatory networks involved in early granuloma formation. RNA-seq analyses will provide a blueprint of gene expression changes associated with tuberculous granuloma formation, which we will link dynamically and functionally to the individual processes involved to determine their consequences.
- Determine mechanisms of human primary immunodeficiencies to mycobacterial infections using the zebrafish. We will model in the zebrafish known human genetic mutations that increase human susceptibility to mycobacterioses to determine their susceptibility mechanisms, particularly in early infection.
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| 13/07/2021 |
£1,610,225 |
UNIVERSITY OF OXFORD |
Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality globally. However, current prevention and treatment strategies for CVD are inadequate. In response there is a growing interest in wearable sensors that offer the potential to continuously, noninvasively, and painlessly measure key attributes of relevance to cardiovascular health - such as physical activity, sleep, and atrial fibrillation - in patients’ everyday lives. In this fellowship, I propose a new programme of research to use wearable sensors to provide novel insights into cardiovascular disease (CVD), with respect to its prediction, discovery of target mechanisms, and new methods to prioritise and assess the impact of potential treatments on day-to-day physical activity and sleep. This research will harness the power of reproducible machine learning in large-scale wearable sensor and human genomic datasets to advance the understanding of CVD. My research will provide the basis for new methods, target mechanisms, and tools to reduce the burden of CVD.
|
| 13/07/2021 |
£2,602,647 |
UNIVERSITY OF OXFORD |
In the final three years of my Principle Fellowship I wish to complete studies to improve the treatment and elimination of malaria. To counter the threat of antimalarial drug resistance emerging from the Greater Mekong sub-region I have recommended a switch to triple artemisinin combination treatments and developed the methods to conduct targeted malaria elimination in endemic areas. I propose a series of studies to assess the safety, efficacy and overall benefit of these new approaches. To support control and elimination I will develop and evaluate better methods of identifying, measuring and monitoring antimalarial drug resistance. To prevent relapses of vivax malaria (the main therapeutic challenge and obstacle to elimination) I will investigate safer methods of giving primaquine, and identify the optimum dose of tafenoquine. I will improve methods for the pharmacometric assessment of antimalarial drugs and I will apply similar proven principles to the assessment of much needed treatments of Chagas disease and COVID-19. I will develop a pharmacometric platform based on assessment of parasite and virus clearance rates respectively for assessing and comparing new drug treatments. This is necessary to inform the choice of drug and dose in larger phase 3 assessments, accelerating their development.
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| 13/07/2021 |
£2,136,164 |
UNIVERSITY OF EDINBURGH |
A role for 3D gene structure in regulating transcription has been hypothesised, but direct evidence remains limited. This restricts our understanding of the mechanisms through which chromatin misfolding leads to disease. To understand the relationship between structure and transcription in human cells we will integrate molecular biology approaches and cutting-edge mechanistic polymer models of chromatin. Such models are well-suited to explore parameter space, predict molecular properties, and generate hypotheses to provide a framework for laboratory experiments. Using minimal bioinformatic data, a new polymer model to predict gene structure and transcriptional activity in healthy or diseased cells will be developed and experimentally validated. We will then assemble the first genome-wide, 3D gene structure compendium and use it as a foundation to determine if structure has evolved to regulate transcription. Polymer models predict a range of possible structures. We will combine simulations and experiments to test whether such intra-gene structural heterogeneity regulates transcriptional noise and will identify the mechanisms involved through locus engineering. Finally, as the protein SAF-A interacts with RNA to regulate gene architecture, we will incorporate RNA fields into simulations and experimentally investigate the concept that protein/RNA gels can impact transcription, thereby characterising a novel feedback between structure and function.
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| 13/07/2021 |
£1,813,055 |
UNIVERSITY OF GLASGOW |
The adult intestine is a major barrier epithelium and coordinator of multi-organ functions. Stem cells constantly repair the intestinal epithelium by adjusting their proliferation and differentiation to tissue intrinsic as well as micro- and macro-environmental signals. How these signals integrate to control intestinal and whole-body homeostasis is largely unknown. Addressing this gap in knowledge is central to an improved understanding of intestinal pathophysiology and its systemic consequences.
Combining Drosophila and mammalian model systems my laboratory has discovered fundamental mechanisms driving intestinal regeneration and tumourigenesis and outlined complex inter-organ signalling regulating health and disease. Building upon new findings from our research, here we propose to:
Identify and characterise stem cell intrinsic metabolic adaptations underpinning intestinal regeneration and tumourigenesis.
Elucidate interactions between the intestine and its vascular microenvironment influencing intestinal regeneration and tumourigenesis.
Characterise the role of enteroendocrine signals in the intestine and the whole-body in health and disease.
The work outlined in this proposal will reveal new drivers of intestinal regeneration and cancer and key processes through which the intestine coordinates multi-organ responses. This knowledge holds great potential to inform the design of integrative regenerative and anti-cancer therapies.
|
| 13/07/2021 |
£3,313,863 |
UNIVERSITY COLLEGE LONDON |
Our overarching hypothesis is that mechanistic insights from preclinical models of Huntington’s disease (HD) and their genetic treatment are valid for early human pathogenesis and can therefore be realised as the foundation for transformative, preventive, clinical trials. A major obstacle to treatment is that degenerative conditions are usually diagnosed once compensatory mechanisms have been exhausted and irrecoverable cell death has occurred. TREAT-HD shifts the focus to mechanisms underlying earlier and asymptomatic stages of pathogenesis as a better time to initiate treatment. We test our hypothesis through three inter-linked aims (Figure 1) that establish the earliest consequences of mutant huntingtin protein (mHTT) in cells, mice and humans with the aim of developing novel therapeutics to delay or prevent symptom onset.
Aims:
1. Determine molecular mechanisms associated with somatic CAG-repeat expansion as targets for novel therapeutics by examining agents targeting DNA repair pathways in cellular and mouse models of HD
2. Determine early systems-level pathology and impact on symptomatology in young adult HD mutation carriers to test the hypothesis that neurodevelopmental effects on brain structure occur before progressive neurodegeneration
3. Integrate molecular and systems-level insights for therapeutic benefit by identifying and validating target engagement and efficacy markers for future clinical trials
|
| 13/07/2021 |
£1,560,578 |
UNIVERSITY COLLEGE LONDON |
I aim to understand the molecular and cellular mechanisms regulating HIV-1 replication and spread in T-cells and how the virus manipulates cells to create a permissive niche. HIV-1 most efficiently disseminates between T-cells by cell-cell spread (CCS) that dominates infection. We have recently discovered CCS triggers target T-cells to become vastly more susceptible to infection, allowing HIV-1 to replicate in resting T-cells that are usually non-permissive for infection. By using CCS infection to bypass the need to mitogenically stimulate target T-cells (a process which drastically changes T-cell biology), we have discovered HIV-1 transcriptionally and phenotypically reprogrammes T-cells to induce a tissue-residency-like phenotype via Vpr, revealing new consequences of HIV-1 infection. Our key goals are now to:
Determine how CCS drives HIV-1 replication in resting T-cells, defining key viral and cellular factors and mechanisms.
Determine how HIV-1 navigates innate immune defences to infect resting T-cells, how this shapes permissivity, and how sensing operates in T-cells.
Dissect how HIV-1 reprogrammes T-cells, Vpr mechanism and the consequences for T-cell fate and function.
Our work will advance mechanistic understanding of how HIV-1 manipulates its most important target cell to drive replication and persistence, uncover exciting new biology and inform future therapeutic innovation towards cure.
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| 13/07/2021 |
£1,288,633 |
UNIVERSITY COLLEGE LONDON |
This research programme explores the cellular and molecular mechanisms responsible for metabolic support of neuronal computation in the brain. Experimental studies are designed to answer the following fundamental questions: (Q1) What are the mechanisms responsible for on-demand delivery of metabolic substrates to support the variable level of neuronal activity? (Q2) What are the mechanisms underlying metabolic control of cerebral blood flow? (Q3) What are the brain mechanisms of adaptation to acute metabolic insufficiency? These questions are addressed by focusing on three metabolic mechanisms/signalling pathways: (i) mediated by cAMP in astrocytes, (ii) underlying the effect of CO2 on brain vasculature, and (iii) responsible for mitochondrial production of nitric oxide by astrocytes in low oxygen conditions. Key identified component(s) of the hypothesised mechanisms will be blocked genetically, followed by two-photon optical recordings of the activities and interactions between neurons, astrocytes and cerebral vasculature, electrophysiological assessment of synaptic function, recordings of cerebral blood flow and cerebrovascular reactivity using MRI, physiological and behavioural phenotyping in experimental animals (rats and mice). This research is expected to advance our understanding of brain energy metabolism and may prove to be important for the development of preventive and therapeutic strategies to maintain cognitive health and promote brain longevity.
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| 13/07/2021 |
£1,852,668 |
UKRI-MRC |
We wish to determine how the cytosolic antibody receptor and E3 ligase TRIM21 uses its potent antiviral and immune signaling activity to prevent infection by diverse viruses. We will use our newly developed protein deletion technology ‘Trim-Away’ to determine the ubiquitin machinery necessary to synthesize the diverse ubiquitin chain types that allow TRIM21 to drive proteasomal degradation of viruses and trigger innate immunity. We will build on our structural studies of TRIM21 to define the mechanism by which its pro-inflammatory signaling is regulated and how other ligases and deubiquitinases are recruited. We will exploit our recent discovery that TRIM21 promotes antigen presentation, by investigating its role in targeting antigens for proteasomal degradation and stimulating protective T cell responses during LCMV, Influenza and SARS-CoV-2 infection. Together this work will define new roles for TRIM21 in host immunity and decipher how TRIM21 uses ubiquitin to provide antiviral protection. The insight we learn from these natural mechanisms will further the development of new technologies like Trim-Away and may inform future antiviral and vaccine development.
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| 13/07/2021 |
£523,653 |
NATIONAL UNIVERSITY OF IRELAND GALWAY |
Nucleoli form around rDNA arrays at nucleolar organiser regions (NORs) located on the five acrocentric chromosome p-arms, providing positional cues for 10 of the 46 chromosomes in diploid human cells. Thus, nucleoli are a paradigm for two general features of genome organisation; specific associations between multiple chromosome territories and internal organisation of nuclear bodies involving multiple chromosomes. Exploration of this organisational paradigm is complicated by the shared DNA-sequence composition of acrocentric p-arms. Recently we have devised a methodology for genetic manipulation and functional testing of individual p-arms/NORs. Efficient ‘scarless’ genome-editing of rDNA is achieved on ‘poised’ human NORs within mouse mono-chromosomal cell-hybrids. Subsequent transfer to human cells introduces ‘active’ NORs yielding readily discernible functional customised ribosomes. We propose exploiting this transformative methodology to identify p-arm elements that drive acrocentric co-location at large nucleoli. We further aim to determine how rDNA arrays from multiple NORs partition within nucleoli. NOR genome-editing will also facilitate exploration of rDNA genome-stability and links with cellular senescence. Finally, we propose using top-down chromosome-engineering to construct minimal NOR-bearing chromosomes as a platform for future research. These studies will advance our understanding of the relationship between acrocentric chromosomes and the largest functional sub-domain in the human nucleus.
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| 13/07/2021 |
£2,065,070 |
UNIVERSITY OF YORK |
The life cycle of the Leishmania parasite requires transition between insect and mammalian hosts, where temporal cell type differentiation allows adaptation to changing environments. We have recently identified a number of Leishmania protein kinases and ubiquitination enzymes that are essential for successful differentiation and establishment of infection, regulating cell signalling and cellular remodelling. We will now tackle two fundamental processes that are fundamental to the parasite’s biology: The regulatory mechanism(s) that control cellular remodelling during differentiation and the requirement of co-regulation of the cell cycle and differentiation to enable establishment of infection To address this we will decipher the protein kinase-dependent signalling pathways controlled by activators and repressors intrinsic to successful differentiation, as well as the signalling pathways regulating kinetochore assembly during differentiation-induced re-initiation of the cell cycle. We will investigate cellular remodelling through characterisation of E3 ubiquitin ligases essential for differentiation. These studies will lay the foundations for developing proteolysis targeting chimeras and protein kinase tool compounds for investigating Leishmania biology and for drug discovery. The expected output of the project will be novel insights into the cross-talk between cell signalling and cellular remodelling through the co-ordinated action of phosphorylation and ubiquitination post-translational modifications.
|
| 13/07/2021 |
£2,150,992 |
UNIVERSITY COLLEGE LONDON |
The molecular mechanisms causing neuronal death in many neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease, are poorly understood. The key consequence of our incomplete understanding of disease pathogenesis is that there is a complete dearth of effective symptomatic treatments for these widespread global disorders, prompting the necessity for a step-change in treatment strategies to fight these pathologies.
In this view, we are investigating ALS as a disease paradigm to identify new, common targets for pharmacological intervention in these devastating pathologies. In work leading to this proposal, we uncovered alterations in axonal transport of several cytoplasmic organelles at pre-symptomatic stages of ALS pathogenesis, suggesting that these impairments may play a causative role in disease onset and progression. Crucially, we have restored axonal transport to physiological levels at early symptomatic stages of disease, thus demonstrating that these pathological changes are fully reversible. Our program of work aims to identify novel signalling nodes that modulate axonal transport in healthy and ALS motor neurons. This will allow us to test the hypothesis that counteracting axonal transport deficits observed in ALS and other neurodegenerative diseases, represents a novel, effective therapeutic strategy towards treating these currently incurable pathologies.
|
| 07/07/2021 |
£1,249,141 |
UNIVERSITY COLLEGE LONDON |
Much of the global population now live in an obesogenic environment, characterised by ready availability of the ultra-processed, high-fat and high-sugar foods comprising the modern ‘Western diet’. This diet is a deleteriously effective trigger of the evolutionarily-conserved drive to maximise energy intake during periods of food abundance, leading to the chronic overconsumption driving the obesity epidemic. Overconsumption can be caused by impaired function in the neurobiologically-distinct processes of satiation and/or satiety. Satiation processes ultimately elicit meal termination, via a poorly-understood interaction of neuronal and hormonal gut-brain signalling pathways, respectively mediated by vagal afferent neurons, and blood-borne peptide hormones and endocannabinoid-like lipoamines. I will use the TRAP2 system for activity-dependent Cre-recombinase expression, combined with systems neuroscience techniques including chemogenetics and optogenetics, to map and selectively manipulate Western diet-recruited gut-brain neurocircuits in an unbiased manner. I will combine this model with single-nucleus transcriptomics, and targeted HPLC-MS/MS lipidomics, to functionally interrogate how neuronal and hormonal gut-brain neurocircuits recruited by Western diet interact to orchestrate meal termination at the cellular, molecular and behavioural levels in lean mice. I will then identify the molecular mechanisms driving dysfunction in this circuitry resulting from chronic Western diet consumption, to identify new approaches to prevent and treat obesity.
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| 07/07/2021 |
£1,382,660 |
UNIVERSITY OF LEEDS |
The proteostasis network is at the forefront of cellular defence against protein misfolding diseases and its decline with age is directly associated with cell death. Chaperones of the Hsp70 family are the workhorses of the proteostasis network and their powerful refolding capabilities are crucially directed to specific clients by Hsp40s(DNAJs). However, the mechanisms that Hsp40s use to regulate Hsp70 functions and how they recognise specific toxic substrates remain unknown. Here, using the DNAJB6b isoform (that is related to neurodegeneration and myopathies) and utilising/developing NMR methods ideal to study dynamic/transient events, I will reveal how Hsp40s drive the multifunctionality of the Hsp70 machine using long, low-complexity regions. In addition to cooperating with Hsp70, DNAJB6b is able to inhibit protein aggregation on its own. The mysteries of DNAJB6b substrate antiaggregation functions are encrypted in its self-oligomerisation properties. By combining in vitro NMR, MS, and cryo-EM data with cellular assays and organismal models, I will reveal the origins of DNAJB6b self-assembly and how it interferes with toxic aggregation of client proteins. The interdisciplinary approach of this proposal will unravel the molecular origins of DNAJB6b specificity and will open the way to engineering optimised chaperones and therapeutic agents tuned to target different disease-related substrates.
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| 07/07/2021 |
£963,821 |
UNIVERSITY OF MANCHESTER |
Knee replacement surgery (KRS) is commonly performed (~100,000/year in UK) in patients with severe osteoarthritis. Despite a good outcome for most patients, 20% of patients experience chronic pain afterwards and 4.4% require revision surgery within 10 years for a variety of reasons.
My goal is to develop a software system to predict poor outcome and early revision in KRS. The system will facilitate (i) informed decision-making about surgery, enabling targeted interventions such as preventive pain management; and (ii) the identification of patients that need closer follow-up post-surgery, enabling more remote monitoring of patients.
Radiographic knee shape has been shown to be a predictor for the outcome of KRS. I have developed the BoneFinder®-technology, an internationally leading technology to automatically outline structures in radiographs. Using machine learning methods, a system will be developed to automatically measure the knee in pre-/post-operative radiographs, and to predict poor outcome based on the radiographic measurements, clinical and patient-reported data.
To facilitate implementation of such a system for patient benefit, it will serve as a use case to create a sustainable toolkit for translating medical imaging solutions in particular and digital healthcare solutions more broadly; aiming to reduce the translational gap between research and clinical practice.
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| 07/07/2021 |
£1,041,010 |
UNIVERSITY OF BIRMINGHAM |
Prosocial behaviours – decisions that help others – are essential for health and society. However, these behaviours can change across the lifespan and in mental health disorders, most prominently in adolescent conduct disorder. To support healthy development and guide intervention we must understand the basic mechanisms. Across three workstreams, I will use two novel paradigms to test hypotheses about fundamental aspects of prosocial behaviour and how they can be changed. Crucially, I will be able to link these behaviours to brain function through fMRI-MEG ‘fusion’. This approach can uncover the spatiotemporal dynamics – where and when - prosocial behaviours are computed, for the first time. I predict that prosocial decisions will be distinctly represented from self-benefitting decisions early in temporo-parietal and later in prefrontal brain areas. These findings will inform when to apply brain stimulation to temporal-parietal and prefrontal areas, to examine their causal influence on prosocial behaviour. Finally, I will translate these findings to understand changes in prosocial decisions and neural mechanisms in the transition from adolescence to adulthood and in conduct disorder. These integrated experiments will uncover the neurocomputational mechanisms of prosocial behaviour across health, development and disorder, laying a necessary foundation for interventions to foster prosocial behaviour.
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| 07/07/2021 |
£1,084,360 |
UNIVERSITY OF OXFORD |
Subcortical brain regions are critical for motivation and decision-making but work in humans has largely focused on prefrontal regions. Important subcortical structures such as amygdala and hypothalamus have typically been treated as homogenous, despite consisting of multiple nuclei with differing functions. This is because human neuroimaging has lacked the resolution and signal-to-noise required for studying precise nuclei, and available causal techniques have been unable to modulate activity at the required depth.
Here, I will exploit recent technical advances and Oxford’s expertise in high-field neuroimaging and transcranial ultrasound stimulation (TUS), a non-invasive technique for focally stimulating deep-brain regions, to test whether nuclei-specific limbic-prefrontal subcircuits have dissociable functional contributions to complex motivation and decision-making in humans.
First, I will develop in-vivo parcellations for nuclei within amygdala and hypothalamus, permitting study of their differential functional contributions. Second, I will use computational modelling, 7T-neuroimaging and TUS to establish the causal contributions of nuclei-subcircuits to motivation and decision-making. Finally, I will compare decision-making and nuclei-connectivity between healthy and depressed cohorts. My work will allow translation between work in animals and humans and provide a new framework for understanding neural circuit dysfunction and behavioural change in depression, which affects precisely the circuits and behaviours studied here.
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| 07/07/2021 |
£718,737 |
UNIVERSITY OF OXFORD |
Severe malaria remains a major cause of preventable childhood mortality in sub-Saharan Africa. Improved understanding of human genetic susceptibility to severe disease and the effect of therapeutic interventions will save lives. A major difficulty for all quantitative research in severe malaria is the evaluation and classification of the severe malaria phenotypes in areas of high transmission. The diagnosis of severe malaria in young children and the distinction from bacterial sepsis is imprecise. I will develop a biomarker based diagnostic model of severe malaria that can be used as a research tool to improve the quality and accuracy of quantitative analyses. The biomarker model will be validated using Mendelian randomisation (natural experiment using genetic polymorphisms with known protective effects). I will then apply the biomarker model to evaluate the effect of blood transfusion in severe malaria and re-evaluate the role of glucose-6-phosphate dehydrogenase deficiency in the protection against severe illness. Underpinning all of the work will be the development of new statistical methods for case-control studies which have phenotypic imprecision in the case definitions. These methods will improve genome-wide association studies in severe malaria and help guide the design of early phase evaluations of new therapeutic interventions.
|
| 07/07/2021 |
£810,761 |
UNIVERSITY COLLEGE LONDON |
My fellowship will test the hypothesis that academic pressure is a common, modifiable causal risk factor for adolescent depression, self-harm and suicide. If my hypothesis is correct, academic pressure could be modified in whole-school interventions and through longer-term changes to policy.
I will test my hypothesis using advanced methods from epidemiology, data science and causal inference, to triangulate evidence across different settings, samples and designs. I will also collaborate with a multidisciplinary network of key stakeholders, to inform my research and translate my findings into school and policy interventions.
The key goals of my project are to:
1. Conduct the first longitudinal studies of whether academic pressure increases the risk of depression and self-harm and is therefore a novel candidate for prevention.
2. Investigate how timing within the school year relates to clinical presentations for depression, anxiety and self-harm, and adolescent suicide rates
3. Work with key stakeholders to:
Complete patient and public involvement
Define the components of academic pressure and its sources and drivers
Investigate what schools currently do to mitigate the impact of academic pressure on the mental health and well-being of students and teachers
Achieve knowledge mobilisation
Key words: adolescent, depression, self-harm, suicide, prevention, epidemiology, schools.
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| 07/07/2021 |
£1,340,337 |
UNIVERSITY OF OXFORD |
Chromatin is partitioned into functional domains. Nucleosomes within these domains contain specific histone variants and post-translational modifications (PTMs) that modulate chromatin structure and dynamics. During DNA replication, parental nucleosomes are disassembled ahead of the replication fork, followed by their restoration on daughter strands from recycled parental and new histones. Local histone recycling at the replication fork is central to epigenetic inheritance but the molecular mechanisms underlying this process are poorly understood.
I have developed a real-time single-molecule imaging platform that allows simultaneous visualisation of parental histones and replication forks as they navigate through the nucleosomal environment of individual DNA molecules in Xenopus egg extracts. Using this approach, I showed that, upon collision with forks, histones can be locally recycled, evicted from the DNA, pushed by forks over tens-of-kilobases and even stall forks. Importantly, I found that free histone concentration is a key modulator of parental histone recycling at the replication fork.
I will exploit this novel single-molecule technology, and combine it with biochemical and biophysical methods, to uncover how histone variants and PTMs affect nucleosome dynamics during DNA replication. My work will provide mechanistic insight into replication-coupled histone inheritance and shed light on how chromatin structures are maintained.
|
| 07/07/2021 |
£1,326,121 |
UNIVERSITY OF CAMBRIDGE |
Flaviviruses such as Zika virus, dengue virus and yellow fever virus transmit their RNA genomes between arthropods and humans, causing widespread pathology and death. During infection, the viral RNA genome resides inside the host cells’ cytoplasm. However, whether the viral genome folds differently inside human and arthropod cells, and whether it interacts with the hosts’ own RNA remain largely unexplored. The aim of this proposal is to dissect the dynamics and function of the flaviviral RNA interactome. I will employ my recent developed COMRADES method to investigate the base pairing capacity and function of two related flaviviruses: Zika virus and yellow fever virus, and to address the following little-explored aspects in their biology: (i) Do viral genomes base-pair with host RNAs? What are the roles of host-virus RNA base-pairing? (ii) Do viral genomes base-pair differently inside different hosts? What are the functional implications?
The results will cast light on how RNA viruses utilise RNA base-pairing to enhance their replication and pathogenicity; offer new opportunities to develop antiviral therapeutics targeting the host-virus RNA-RNA interactome; and establish a new role for RNA base-paring in zoonosis.
|
| 07/07/2021 |
£1,347,093 |
KING'S COLLEGE LONDON |
Using an innovative cross-disciplinary approach, I will directly explore the pathophysiology, function, and mechanisms of respiratory motor recovery following severe spinal cord injury (SCI) and determine if restoration of this activity is sufficient to mitigate increased rates of morbidity and mortality caused by acquired infections.
Treatment strategies for SCI have focused on restoring spinal neuronal circuitry. I will determine if a novel treatment strategy which targets both neural growth/plasticity in the spinal cord and muscle mitochondrial activity, can restore systemic respiratory motor function after severe SCI. I will use innovative techniques including bi-planer X-ray videography and ventilatory pattern variance to assess the pathophysiology of the respiratory system following injury and recovery. Further, in physiologically relevant conditions, I will assess cyclical power generated by respiratory muscles, alterations in neuronal circuitry, and model changes in muscle oxygen transport to determine the systemic mechanisms behind respiratory deficit and recovery. Finally, most SCI patients show increased morbidity and mortality with reduced functional activity due to post-injury acquired pneumonia infections. For the first time, I shall assess whether my combined treatment strategy can overcome the deleterious effect of pneumonia infection and the mechanisms through which sustained systemic functional respiratory recovery can occur.
|
| 07/07/2021 |
£626,065 |
THE PIRBRIGHT INSTITUTE |
Viruses that use a single strand of positive sense RNA (+ssRNA) as their genomes number a breadth of human pathogens including Zika virus (flavivirus), poliovirus (picornavirus), norovirus (calicivirus) and SARS-CoV2 (coronavirus). A number of key, fundamental questions regarding how these viruses regulate usage of their genomes remain. Answering these questions not only provides new biological insights into host-pathogen interactions but could prove critical in identifying new strategies for control. These viruses use the same molecule of RNA for protein expression and as a template for replication. However, these processes occur in opposing directions i.e. translation in a 5′-3′ direction and replication in a 3′-5′ direction. This therefore necessitates a "lifestyle switch" for any single RNA molecule in a cell, the details of which are unknown. We will use a multidisciplinary approach including in vitro reconstitution, cell biology and infection studies to determine how lifestyle switching of genome usage is regulated during infection by +ssRNA viruses. This work will lead to a new paradigm in our understanding of the evolution of genome organisation and function in an important class of pathogenic viruses.
|
| 07/07/2021 |
£712,398 |
UNIVERSITY OF EXETER |
A major source of emerging infectious disease are virus host shifts, where a pathogen jumps into a new host species (e.g. HIV, Ebola, SARS-CoV-2). Research to date has focused on the role of host genetics. Here I will examine the role pathogen genetics (relatedness) and ecology (interactions between microbes) play in emerging infectious diseases, which will be critical to predict future host shifts.
The first goal is to understand how patterns of susceptibility correlate amongst different pathogen taxa. I will infect hosts with different viruses and other pathogens to test the importance of the host phylogeny in determining susceptibility for each pathogen. For example, if a host is susceptible to one virus, are they also susceptible to other types of virus, or is susceptibility pathogen specific? This is critical for understanding whether the characteristics of an emerging pathogen can be predicted based on our knowledge of other related pathogens.
Next, I will investigate how interactions between microbes can alter the likelihood of pathogen emergence. I will examine whether the outcomes of co-infection and microbiome-pathogen interactions are the same or different across host species. This has important consequences for understanding how biotic interactions could alter the outcomes of pathogen host shifts.
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| 07/07/2021 |
£601,131 |
UNIVERSITY OF MANCHESTER |
Cellular responses to changes in the environment depend on Receptor Tyrosine Kinase (RTK) signalling and are tightly regulated. Such regulation is lost in diseases, including breast cancer. Importantly, different ligands binding to the same RTK, including Fibroblast Growth Factor Receptor 2b (FGFR2b) in breast cancer cells, elicit distinct cellular responses (proliferation vs. migration). The molecular basis by which FGFR2b signalling generates such functional selectivity is poorly understood, information that is crucial to develop better targeted therapies against deregulated FGFR2b signalling in breast and other cancers. Here, I will investigate whether each FGF/receptor pair initiates unique responses right from receptor activation at the plasma membrane to determine specific long-term outputs. I will combine structural proteomics, proximity methods to study localised signalling, phosphoproteomics, and functional assays in breast cancer cells to reveal whether each FGF induces unique structural re-arrangements of FGFR2b at the plasma membrane, over and above receptor dimerization, that recruit specific signalling partners; what ligand-specific signalling modules are recruited to FGFR2b; and how these signalling modules regulate the long-term effects of FGFR2b functional selectivity. Overall, this project will lead to breakthrough in understanding cell signalling specificity and reveal new signalling nodes amenable for therapeutic intervention in breast and other cancers.
|
| 07/07/2021 |
£818,932 |
UNIVERSITY OF CAMBRIDGE |
Despite decades of research, little is known as to how we can improve epithelial regeneration. Mounting evidence suggests that the physical changes taking place during tissue remodelling are critical to regulate cellular behaviour. However, it remains unclear how different cell populations sense and synchronise their response to mechanical cues in order to adequately adapt to tissue perturbations.
Using the oesophagus as a tractable model, my laboratory has provided new insights into the mechanisms regulating epithelial cell behaviour. Our work identifies naturally occurring changes in tissue mechanics as a central regulator controlling the establishment of adult homeostasis after birth. In the proposed extension, we will use an interdisciplinary approach combining in vivo lineage tracing techniques, single cell transcriptional analysis and organ culture systems to investigate whether these mechanical cues (i) coordinate the behaviour and cross-talk of different cellular compartments, and (ii) contribute to the regenerative decline described in adult tissues.
This work will lay the foundation to understand how mechanical cues orchestrate cell fate at the whole organ level and to help develop novel clinical therapies to improve wound healing, an unresolved aspect of modern medicine.
|
| 30/06/2021 |
£50,000 |
UNIVERSITY OF CAMBRIDGE |
The proposed work is – to our knowledge - the first integrated economic analysis of a single policy intervention and its potential to influence three interlinked threats: the global health crises of both non-communicable diseases and new infectious diseases such as Covid-19, as well as environmental degradation, including biodiversity loss and climate change.
The work will comprise modelling the consequences of carbon pricing, set at a level compatible with keeping climate change within planetary boundaries, with outcomes including land-system change, agricultural production, food prices, diets and health outcomes, and effects on infectious disease and biodiversity. The analysis will consider potential differential effects of carbon pricing across socio-economic groups, and between high, medium and low-income countries, as a basis for considering policy interventions to mitigate inequitable outcomes.
This analysis will contribute to the goal of The Lancet-Chatham House Commission which is to identify actions that can impact positively across the shared drivers of the three threats to human and planetary health described above. Importantly it will provide novel evidence for the ways in which co-benefits and
co-costs of interventions might form a significant part of the political and economic cases for intervening at national and international levels and optimising policy design.
|
| 30/06/2021 |
£128,102 |
THE ASSOCIATION FOR SCIENCE EDUCATION |
The purpose of the project is to test the impact and value of delivering subject-specific CPD in upper primary, lower secondary science through ‘bite-sized’ online courses linked to micro-accreditation. It will:
develop three online CPD units focusing on teaching more challenging ideas in science to pupils at upper primary and lower secondary level (ages 9-13)
test ‘proof of principle’ that a structured online CPD course comprising ‘bite-sized’ CPD units supports teachers of primary and lower secondary science in strengthening their subject knowledge (SK) and their pedagogic content knowledge (PCK); and indirectly improves pupils’ understanding of difficult ideas in science;
enable teachers using the CPD resources to gain micro-accreditation in those topics, recognising and certifying their skills and knowledge, and explore ways to promote the value of this accreditation to senior leadership and more widely, including as evidence towards other accreditations such as Chartered Science Teacher (CSciTeach);
test the ‘buy-in’ to the value of micro-accreditation by senior leadership in building up a pool of teachers who are skilled, confident (and ultimately deployed) to teach age and stage appropriate topics of the science curriculum; and as a tool to inform individual professional learning needs, promotion; and support targeted recruitment and retention strategies.
|
| 30/06/2021 |
£153,054 |
SHEFFIELD HALLAM UNIVERSITY |
There is a strong evidence base on effective continuing professional development (CPD) for teachers, but in spite of this evidence, there has been limited sustained change towards the goal of all teachers being able to participate in high quality professional development throughout their careers. To address this, greater understanding is needed of how to make change happen: the implementation of innovations and programmes in relation to policy and entitlements and the school environment; and the mechanisms and processes which underpin change.
Applying insights from implementation science and theory-based evaluation, our proposed research will identify a series of ‘mechanisms for change’ applicable to teacher CPD policy and practice in school environments in England, to guide CPD practice by schools and policy-makers. Four complementary project strands (a systematic evidence review; STEM CPD policy analysis; investigating effective change implementation in CPD, through mixed methods of survey and case studies; stakeholder engagement and dissemination) will lead to evidence-based guidance for effective implementation of CPD in England at multiple system levels, whether a local system (e.g. a single department or school CPD), larger system (e.g. programmes for a specific teacher subject group or phase) or the whole education system (e.g. increasing access to CPD).
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| 30/06/2021 |
£137,623 |
HUMBOLDT UNIVERSITY OF BERLIN |
Mindscapes Curatorial Research Fellow
Full-time position with CARMAH, reporting to the Director
This post-doctoral fellowship appointment will assist with the research and development phase of a new project looking at aspects of mental health with a specific focus on Berlin. Alongside pursuing self-directed research, the fellow will work closely with members of Wellcome’s International Cultural Programmes team and Wellcome’s Germany Office under the direction of the International Cultural Producer Danielle Olsen to:
- Develop external partnerships across the city with partner organisations on the theme of mental health in Berlin investigating potential archives, collections, institutions and community led organisations that could provide a focus for transdisciplinary research
- Serve as connector across participant spaces and places, developing creative new links with international city partners (in Bengaluru, New York and Tokyo) as the project develops
- Assist in developing interdisciplinary and inclusive methods and processes between and across the Arts and Sciences on a mental health theme
- Participate in a launch meeting in July 2021 on a mental health theme with a Berlin City focus
- Explore crossover and hybrid experimental curatorial possibilities utilizing original creative work, events, and public programming.
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| 30/06/2021 |
£132,988 |
UNIVERSITY OF NOTTINGHAM |
Schooling in England is complex and evolving. Large-scale academisation has fragmented local landscapes and created multiple models for knowledge exchange, increasing the risk that continuing professional development (CPD) for teachers becomes variable in terms of quality, equity of access, and impact. More recently, national CPD frameworks have been made more coherent, while local areas are being encouraged to coordinate CPD offers through new Teaching School Hubs.
Understanding how this systemic process of fragmentation and re-formation is impacting on CPD for schools and teachers is a pressing concern. The EQuaLLS project will focus on ‘local learning systems’ (LLS): place-based localities encompassing a mix of school structures and hub arrangements for teacher CPD.
Using primary mathematics as a case study, we will research 'to what extent, and how, do LLS operate to provide high quality, inclusive professional learning for schools?' In four phases, we will: i) harness existing knowledge; ii) identify three representative localities and 18 schools for study; iii) investigate equity and quality of primary mathematics CPD; and iv) analyse findings, identify implications and disseminate these widely.
The findings will inform policy and practice, helping school and system leaders to shape and navigate high quality, inclusive and effective local CPD systems.
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| 30/06/2021 |
£140,158 |
UNIVERSITY OF OXFORD |
Antibiotic resistance in Vietnam is amongst the highest in the world, driven by high levels of antibiotic use for human and animal health. Community understanding and perceptions about antibiotics and antibiotic resistance is poor, and antibiotics are often prescribed inappropriately in healthcare settings. There is limited evidence for the effectiveness of public engagement approaches to promote appropriate antibiotic use, compared to more traditional education-based methods, or for understanding the pathways and facilitating conditions for successful behaviour change.
We will facilitate community-wide change in the way people prescribe and use antibiotics for human and animal health. We will compare three different One Health approaches to change behaviour: training for human and animal health-workers; a public information campaign for communities and farmers; and participatory action research groups. Activators in communities and healthcare settings will guide groups through a four-phase action cycle similar to Wellcome’s Responsive Dialogues approach, covering: 1. Understanding the problem of antibiotic resistance; 2. Planning and implementing strategies; 3. Monitoring strategies and generating evidence; 4. Evaluating strategies and planning future actions. We will evaluate the impact on knowledge and behaviour through qualitative and quantitative methods. We will engage local researchers and policymakers through formative discussions and dissemination meetings.
|
| 30/06/2021 |
£35,000 |
SANDPAPER FILMS |
My Planet Now is a cinematic short film and feature documentary for worldwide release that seek to break new ground and provide a genuine moment of global coming together on the climate crisis.
The films will tell the global story of the climate crisis in a uniquely human way by inviting ordinary citizens from around the world to film and share their personal stories of their relationship to the planet and experience of climate change. By making these people our co-directors and enabling viewers to experience the world through them, they will offer a sense of connection to the crisis that is unfiltered, intimate and immediate – strikingly different from typical climate crisis documentaries.
The films will marry stories from the frontlines with stories that offer hope and offer a constructive way forward. Critically, they will also bring attention, insight and understanding to the relationship between health and climate, in alignment with Wellcome’s strategic objectives.
The feature documentary’s large-scale, multi-pronged impact campaign will target global and national decision-makers, key stakeholders and the public (including specific target communities). A central theme will be the relationship between climate and health, and we have enjoyed positive initial discussions with WHO about this prospect.
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| 30/06/2021 |
£6,880 |
MQ TRANSFORMING MENTAL HEALTH |
The MQ Mental Health Science Summit, in collaboration with Wellcome, is an interdisciplinary mental health science conference. It brings together people from all disciplines and sectors, focused on transforming mental health. Key to this is the involvement of people with lived experience of mental illness, early career researchers, and delegates from LMICs.
Attendance at the Summit is ticketed. Many delegates are attending in a work capacity, and so are both salaried and have their costs covered by their organisation. For certain groups of key delegates, the ticket price is prohibitive. This is particularly true for people with lived experience who often attend such events in a voluntary capacity and some of whom are insecurely employed, early career researchers who often do not have research grants available to cover conference attendance, and delegates from LMICs who are economically less able to have such funds available.
Following Wellcome' Cat Sebastian’s contributions to the organising committee, we are applying for £4,000 to enable subsidised places for delegates from these three groups to attend the Summit. This will enable 30 delegates to attend. Aa agreed, any funds not spent on bursaries for this year’s Summit will be used to widen access at subsequent events.
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| 30/06/2021 |
£98,806 |
BOSTON UNIVERSITY |
Pharmaceutical companies understand the need for modeling stochasticity, by which we can improve the reliability and effectiveness of drugs across the whole population. Our 2020 review in Trends in Pharmacological Sciences, one of the highest impact journals in pharmacology, argued that deterministic models that ignore stochasticity bias clinical and pre-clinical trial analyses. The quantitative systems pharmacology (QSP) groups within drug companies are the core units that model and predict patient outcomes, dramatically reducing the research and development timeline by predicting which drugs will fail before clinical trials begin. These groups have recently adopted stochastic dynamical models in order to better achieve their goals. Discussing with CJ Musante, Global Head of Pharmacology at Pfizer, the main reason that stochastic models are not more widely used is due to a lack of software that addresses the needs of QSP modelers. Stochastic models are more predictive of patient outcomes, but computationally expensive. Moreover, turnaround times needed by QSP teams are too short to make use of stochastic models with current software. This proposal addresses this problem, proposing to build software tooling which automates the construction and solution of stochastic models in a way that is orders of magnitude faster than what exists today.
|
| 30/06/2021 |
£2,135,985 |
WORLD HEALTH ORGANIZATION, SWITZERLAND |
Not available |
| 29/06/2021 |
£7,433,739 |
BRADFORD HOSPITALS NHS TRUST |
Adolescence and transition into adulthood are periods shaping life-long mental health, cardiometabolic risk, and inequalities. However, they are poorly studied and understood. By extending and expanding the Born in Bradford (BiB) cohort study through this period using innovative, co-produced approaches to collect and analyse data, we aim to understand better the interplay of factors that influence health and wellbeing, and inform/evaluate interventions to improve them and reduce inequalities.
Age of Wonder will be the only large whole city cohort capable of capturing the contemporary lived experience amongst multi-ethnic adolescents progressing into young adulthood, linked to their earlier life. It will build on a world-leading birth cohort situated the 5th largest metropolitan district in England with high levels of deprivation, ethnic diversity, supported by a connected routine data infrastructure covering 600,000 citizens.
We will collect repeated data from existing BiB participants and their peers (N~30,000). In-school assessments, clinical assessments plus online data collection and electronic linkage will capture information on mental, reproductive, sexual, neurocognitive and cardiometabolic health. Remote collection will continue to age 21. Repeat qualitative interviews and ethnographic observations will explore lived experiences.
We will collaborate internationally to broad-ranging research and discovery science and promote rapid application to policy/practice.
|
| 23/06/2021 |
£60,000 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
Schistosomiasis, a trematode infectious disease, is highly endemic in Malawi. Approximately 40-50% of the population are at risk of being infected with urinary and intestinal schistosomiasis, with transmission being dependent on humans encountering an intermediate freshwater snail host. As such, the spatial pattern in disease risk is strongly influenced by the natural environment. The overarching goal of this project is to combine remotely sensed and georeferenced snail survey data to quantify the relationship between the snail host and the environment, and to understand the impact of environmental changes such as land-use and climate change on transmission risk. Focusing on the highly endemic region of Southern Malawi, I will use geospatial statistical methods and publicly available satellite imagery to generate habitat suitability maps over a 30-year period (1990-2020) to visualize the changing patterns in transmission risk over time. Data on various climate change scenarios will be used to predict future changes in snail habitat for the region. I will undertake snail surveys and drone image capture to generate snail habitat suitability maps which complement the ongoing epidemiological surveys. Outputs generated will provide valuable insight into the spatial patterns in schistosomiasis risk, and mitigating future risk caused by environmental and climatic changes.
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| 23/06/2021 |
£60,000 |
KEMRI-WELLCOME TRUST RESEARCH PROGRAMME |
Private retail pharmacies are the first point of contact for most people seeking treatment for minor illness in LMICs. They play a significant role in delivery of public health interventions (PHIs). In Kenya, for example, retail pharmacies are involved in the provision of family planning services, HIV counselling and testing services and malaria treatment. Despite the role private retail pharmacies play in delivering PHIs, there is limited evidence on the attributes of PHIs that community pharmacists (pharmacists working in private retail pharmacies) value and the trade-offs they would be willing to make. Moreover, private retail pharmacies have competing interests aimed at maximizing profits. It is therefore essential that the contracts policy makers design for them are aligned with their incentives.
The proposed study aims to elicit the preferences of community pharmacists for attributes of PHIs in Kenya, utilizing a discrete the choice experiment (DCE) approach. A DCE is a stated preference method used to elicit individuals’ preferences for goods and services using hypothetical scenarios. The mixed-method study will involve 350 participants from 4 counties. Data will be analyzed using thematic analysis and conditional-logit model. Findings will inform policy makers in design and implementation of PHIs through private retail pharmacies.
|
| 23/06/2021 |
£261,547 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
Transmission of ESBL-E in humans occurs through diverse routes. However, the relative contributions of each are poorly understood, especially in low- and middle-income (LMIC) hospital settings. Furthermore, attempts to quantify effects of transmission risk factors in LMICs have been challenged by inadequacies in data quality and/or modelling approaches.
In this Fellowship, I will investigate pathways to transmission of ESBL-E at Queen Elizabeth Central Hospital (QECH) in Blantyre, Malawi to:
To characterise changes in patient and carer gut microbiota during hospitalisation;
Determine hospital reservoirs of ESBL-E and routes of transmission;
Explore the causal relationship of antimicrobial use, patient and hospital hygiene factors with gut microbiota diversity and acquisition of ESBL-E.
I will sequence the genomes of isolated bacteria and whole populations from stool samples of admitted patients and carers at QECH and analyse the genetic data and participants metadata using bioinformatic and causal modelling approaches to investigate pathways to hospital acquisition of ESBL-E.
The output from this study will inform the design of interventions for controlling ESBL-E transmission and provide a framework understanding nosocomial AMR transmission to enable generalisation of methods from to this study to other sites.
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| 23/06/2021 |
£43,372 |
WELLCOME SANGER INSTITUTE |
Transmission of ESBL-E in humans occurs through diverse routes. However, the relative contributions of each are poorly understood, especially in low- and middle-income (LMIC) hospital settings. Furthermore, attempts to quantify effects of transmission risk factors in LMICs have been challenged by inadequacies in data quality and/or modelling approaches.
In this Fellowship, I will investigate pathways to transmission of ESBL-E at Queen Elizabeth Central Hospital (QECH) in Blantyre, Malawi to:
To characterise changes in patient and carer gut microbiota during hospitalisation;
Determine hospital reservoirs of ESBL-E and routes of transmission;
Explore the causal relationship of antimicrobial use, patient and hospital hygiene factors with gut microbiota diversity and acquisition of ESBL-E.
I will sequence the genomes of isolated bacteria and whole populations from stool samples of admitted patients and carers at QECH and analyse the genetic data and participants metadata using bioinformatic and causal modelling approaches to investigate pathways to hospital acquisition of ESBL-E.
The output from this study will inform the design of interventions for controlling ESBL-E transmission and provide a framework understanding nosocomial AMR transmission to enable generalisation of methods from to this study to other sites.
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| 23/06/2021 |
£416,392 |
CENTRE FOR SEXUAL HEALTH AND HIV AIDS RESEARCH ZIMBABWE |
There is an urgent need to promote positive masculinity among boys in Africa, where negative gender norms underpin many areas of public health concern including unwanted pregnancy, HIV and violence. I aim to co-develop and evaluate a peer-delivered gender-transformative intervention for younger adolescents (aged 10-14 years) to promote positive masculinity and sexual health in Zimbabwe. Gender-transformative interventions can successfully promote gender-equitable identities especially in early adolescence when attitudes and behaviours are still malleable. The ultimate goal is to develop an effective scalable model to influence constructs of positive masculinity. The project will include both girls and boys, but with special focus on boys. I will first conduct research to identify and prioritise the gender norms to be targeted. I will then work with younger adolescents and other stakeholders to co-develop an intervention targeting the prioritised harmful gender norms and then pilot and refine the intervention. I will also develop context-specific and valid quantitative tools to measure gender-related social norms, attitudes and behavioural norms. I will conduct a feasibility trial of the intervention with in-depth process evaluation to explore feasibility and acceptability to inform the design of a randomised effectiveness trial (assuming that pre-specified criteria for feasibility are met).
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| 23/06/2021 |
£278,810 |
MOCHTAR RIADY INSTITUTE FOR NANOTECHNOLOGY |
In Indonesia, a patch of Eastern Bornean forest remains the home of the last active hunter-gatherer group in the region, the Cave Punan (Punan Batu), who live under karstic rock-shelters. They continue to hunt on a daily basis, primarily using dogs and spears, and to gather a range of forest tubers and fruits. However, deforestation is forcing the community to transition away from their traditional lifestyle towards a more sedentary and partially agricultural one. The transition from hunting and gathering to agriculture involves a radical shift in diets and physical activity levels, and could disrupt long-standing biology likely to have been shaped by natural selection, eventually leading to increased risk for lifestyle disease. Hence, the aims of this project are i) to characterize genomic adaptation to a foraging lifestyle in the Cave Punan, ii) to study the biological impact of lifestyle transition by observing the changes at the RNA and epigenetic level in communities along this lifestyle gradient, iii) and to contrast the gut microbiome diversity in communities with different lifestyles. This study will provide insights on how our ancestors’ way of life has left genomics imprint in contemporary foraging community, and how lifestyle changes would alter its biological significance.
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| 23/06/2021 |
£183,909 |
INSTITUTE OF BIOMEDICAL SCIENCES, UNIVERSITY DE SAO PAULO |
Trypanosoma cruzi, the causal agent of Chagas disease, has a complex digenetic life cycle. This organism is well adapted to handle environmental changes, presenting high metabolic flexibility. In this context, amino acids and their metabolism play crucial roles in cell differentiation, maintenance of cell volume and response to different types of stress. This proposal aims to identify the key steps of the amino acid metabolic network which are crucial for T. cruzi to complete its life cycle. With this purpose, we will use the bar-seq CRISPR-Cas9 genome editing strategy to generate mutant knockout cell lines for the coding sequences of 40 enzymes putatively involved in the metabolism of amino acids. Each cell line will be identified by a unique sequence barcode and they will be pooled to allow parallel phenotyping during cell differentiation and infection, both in vitro and in vivo. Relative fitness will be assessed by next-generation DNA sequencing. Identification of the enzymes that are essential for parasite development and infectivity will provide insights on the metabolic strategies T. cruzi evolved to adapt to diverse environments as well as novel targets for target-specific drug design and ligand structure-based screenings in the future.
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| 23/06/2021 |
£274,523 |
UNIVERSITY OF OXFORD |
Typhoid fever remains a significant public health and economic burden in LMICs. The global spread of extensively drug-resistant (XDR) Salmonella Typhi has limited the effectiveness of antimicrobial therapy and threatened lives. Resistance of S. Typhi to azithromycin, the only remaining effective oral drug to treat XDR typhoid, recently emerged in South Asia, posing an immediate threat of untreatable typhoid fever. I aim to investigate the emergence and epidemiology of azithromycin-resistant (AzithR) S. Typhi and determine its impact on typhoid treatment. I will perform genome sequencing of ~500 S. Typhi isolates from the ACT-South Asia Trial conducted in Nepal, India, Bangladesh and Pakistan to investigate the evolutionary and epidemiological dynamics of AzithR S. Typhi. I will conduct laboratory experiments to understand the evolutionary drivers of AzithR S. Typhi and measure the impact of AzithR mutations on bacterial growth dynamics, antimicrobial tolerance, and fitness. Further, I will assess the correlation between clinical responses to azithromycin and in vitro intracellular azithromycin susceptibility of S. Typhi isolates from the above trial. These research investigations are essential to understand the evolutionary and epidemiological landscape of AzithR S. Typhi, as well as clinical responses to azithromycin and appropriate dosages for guiding control measures and clinical practice.
|
| 23/06/2021 |
£819,410 |
UNIVERSITY OF CAPE TOWN |
Neurocysticercosis is caused by the presence of Taenia solium larvae in the brain and is the leading cause of adult-acquired epilepsy worldwide. The central goal of this research program is to determine what events control seizure susceptibility in brain-networks perturbed by neurocysticercosis. We will capitalise on rare access to human brain tissue in Cape Town by using human organotypic brain slice cultures (OBSCs) together with T. solium larvae. In Aim 1 we will determine how cestode larvae perturb neuroinflammatory processes by measuring the dynamics of cytokine release, glial cell activation and cell death. In Aim 2, we will use fast calcium imaging to test the effects of larval products on network excitability. This will be correlated with observations of morphological, electrical and synaptic changes within neuronal networks. We will also determine whether changes in chloride and hydrogen ion homeostasis underlie the development of seizures. In Aim 3 we will use powerful molecular techniques (including single nuclei RNAseq) to elucidate how T. solium larvae modulate gene expression in the human brain. By integrating our observations made studying inflammatory, neuronal and gene networks in the human brain, we expect to uncover novel insights into the cellular and molecular underpinnings of neurocysticercosis.
|
| 23/06/2021 |
£122,496 |
KEMRI-WELLCOME TRUST RESEARCH PROGRAMME |
Medical and nutritional management in acutely-ill undernourished children in developing countries aim to support rapid weight gain. However, such children remain at risk of death and poor catch-up growth post-hospital discharge. Little is known about mechanisms regulating childhood growth after acute illness. I hypothesise that persistent systemic inflammation (SI) is a key determinant of growth post-discharge among undernourished children. SI is associated with reduced linear growth in community cohorts, and is demonstrable at hospital discharge among undernourished children, potentially indicating untreated infections, microbiota dysbiosis, gut-circulation microbial product translocation, or enteric inflammation. My proposed work is nested within the CHAIN cohort that aims to characterise modifiable risks for mortality among acutely-ill children children and investigate its causes. I will examine relationships between growth and markers of SI, blood metabolomic profile, growth mediators, and microbial exposures comparing with well community children through a collaborative network between KEMRI-Wellcome; Kenya, the University of Oxford and the Wellcome Sanger Institute. Better understanding of relationships between SI and post-discharge growth is expected to inform therapeutic strategies to improve recovery.
|
| 23/06/2021 |
£244,713 |
KEMRI-WELLCOME TRUST RESEARCH PROGRAMME |
Medical and nutritional management in acutely-ill undernourished children in developing countries aim to support rapid weight gain. However, such children remain at risk of death and poor catch-up growth post-hospital discharge. Little is known about mechanisms regulating childhood growth after acute illness. I hypothesise that persistent systemic inflammation (SI) is a key determinant of growth post-discharge among undernourished children. SI is associated with reduced linear growth in community cohorts, and is demonstrable at hospital discharge among undernourished children, potentially indicating untreated infections, microbiota dysbiosis, gut-circulation microbial product translocation, or enteric inflammation. My proposed work is nested within the CHAIN cohort that aims to characterise modifiable risks for mortality among acutely-ill children children and investigate its causes. I will examine relationships between growth and markers of SI, blood metabolomic profile, growth mediators, and microbial exposures comparing with well community children through a collaborative network between KEMRI-Wellcome; Kenya, the University of Oxford and the Wellcome Sanger Institute. Better understanding of relationships between SI and post-discharge growth is expected to inform therapeutic strategies to improve recovery.
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| 23/06/2021 |
£54,000 |
WELLCOME SANGER INSTITUTE |
Medical and nutritional management in acutely-ill undernourished children in developing countries aim to support rapid weight gain. However, such children remain at risk of death and poor catch-up growth post-hospital discharge. Little is known about mechanisms regulating childhood growth after acute illness. I hypothesise that persistent systemic inflammation (SI) is a key determinant of growth post-discharge among undernourished children. SI is associated with reduced linear growth in community cohorts, and is demonstrable at hospital discharge among undernourished children, potentially indicating untreated infections, microbiota dysbiosis, gut-circulation microbial product translocation, or enteric inflammation. My proposed work is nested within the CHAIN cohort that aims to characterise modifiable risks for mortality among acutely-ill children children and investigate its causes. I will examine relationships between growth and markers of SI, blood metabolomic profile, growth mediators, and microbial exposures comparing with well community children through a collaborative network between KEMRI-Wellcome; Kenya, the University of Oxford and the Wellcome Sanger Institute. Better understanding of relationships between SI and post-discharge growth is expected to inform therapeutic strategies to improve recovery.
|
| 23/06/2021 |
£194,849 |
STELLENBOSCH UNIVERSITY |
Recent studies in Africa and India (countries with high TB- and HIV-burdens) reported increased frequency of zoonotic tuberculosis (zTB) in humans caused by other members of the Mycobacterium tuberculosis complex (MTBC) like M. orygis, indicating that M. bovis infection may be an inadequate proxy for zTB. Similarly, nontuberculous mycobacteria (NTM) lung disease in people is more frequently reported in Africa because of environmental NTM like M. avium complex. NTM are naturally resistant to various drugs commonly used to treat MTBC infection and are often indistinguishable from MTBC when conventional MTBC "specific" immunological tests are used in humans and animals. Consequently, the management and treatment of infected patients are substantially different and complicated by the absence of appropriate culture-independent tests for the combined detection and differentiation of MTBC and NTM. We hypothesize that zoonotic pathogens like M. orygis and M. avium complex are more abundant in livestock, their environments and nearby wildlife than previously thought, especially in areas with immunocompromised people, leading to potentially high transmission risk interfaces. The goal is to develop culture-independent detection and genotyping tests to enhance zoonotic Mycobacteria spp. detection and differentiation directly from livestock specimens collected from low-resource areas, their environment and near-by wildlife reservoirs.
|
| 18/06/2021 |
£13,029 |
QUEEN MARY UNIVERSITY OF LONDON |
This project will examine some of the many links that exist between reading and domestic healing in the collection of the Museum of the Home. The focus of the project will be the under-utilised collection of books relating to health and the domestic environment, dating from the seventeenth to twentieth centuries. For many, the primary location of their experiences of health and ill health was the home; in this context, the reader was the ‘patient’ and the book took the place of a medical practitioner. How were these texts intended to impact their readers’ domestic practices and their wellbeing – and how did readers interact with these texts? Influenced by Roy Porter’s ‘Doing Medical History from Below’, I will examine the intimate relationships between medical books and their readers, focusing on the ‘patient’s’ experience. Research produced during the Fellowship will inform a gallery redisplay, in addition to providing material for future development of the Rooms through Time galleries. The project will connect a wider audience of museum visitors to these stories through accessible written content as well as the Museum’s public engagement programmes, encouraging understanding of and reflection on a shared history of domestic health.
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| 18/06/2021 |
£14,328 |
UNIVERSITY OF OXFORD |
Through a collaboration with the United Nations Environment Programme (UNEP), this 6-month secondment will bring insights from the fields of environmental justice, medical anthropology, and health geography into UNEP’s implementation plan "Toward a Pollution Free Planet". The point of departure for this collaboration is premised on an understanding of pollution as embedded in wider processes of industrialisation that causes social fragmentation and a diffused disempowerment of the communities it affects. As this represents an underexplored area of work in international policymaking, this secondment will focus on understanding and proposing implementation pathways that can lead to increased participation of communities in initiatives to curb pollution.
The outputs produced through this secondment will be integrated within UNEP’s Pollution and Health unit's work on integrated methodologies and tools. The first half of the secondment will be spent conducting a literature review on pollution and community action in the form of a report. The report will focus on identifying the factors that promote and hinder community participation, resilience, and agency. The second half of the secondment will be spent to produce an indicators framework to be utilized to assess the effectiveness of UNEP’s implementation plan in engaging the public and fostering participation and resilience.
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| 18/06/2021 |
£15,306 |
UNIVERSITY OF YORK |
Socioeconomic inequalities in health are an increasingly central policy concern and accurate measurement is crucial in identifying effective policies to reduce health inequalities. I propose updating and refining previous OECD work examining inequalities in longevity by education in member countries around 2011. Updating the analysis involves using more recent data from national mortality registers linked to administrative data on education. Refining the analysis involves applying appropriate methods to allow for biases due to missing data. This is important since education data are often collected via the workforce, so there may be systematic patterns of missingness relating to non-participation in the workforce, which are associated with education.
The key goal is to devise a robust methodology for routinely calculating educational inequalities in longevity in a time- and labour-effective manner. The project contributes to the OECD mission of promoting wellbeing, and specifically the OECD work package ‘Health inequalities and inclusive growth’ and report ‘Health at a Glance’. It will also help the OECD become the main authority on educational longevity inequalities in member countries.
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| 18/06/2021 |
£6,325 |
UNIVERSITY OF WARWICK |
My project will examine the potential use of blockchain technology in the delivery of public services, particularly in the areas of healthcare and welfare in Britain. A blockchain is a type of database that functions as a digital ledger, a way of recording transactions in a permanent, transparent, and irreversible format. Although blockchain technology has existed for decades, its real-world applications have only recently garnered attention from policy makers and politicians. Amidst booming interest in perhaps the most famous financial blockchain – Bitcoin – my project will look at how this technology could transform the nature and provision of healthcare and welfare services in Britain.
The type of information recorded and secured on blockchains is not restricted to financial transactions. It can relate to patient records, the movement of resources in a supply chain, legal documents, and an endless array of other information. As such, it has potential to revolutionise the way organisations utilise and manage data, eliminating problems like fraud and human error in the management of data. The project will examine these potential applications by interviewing key stakeholders, including academics, computer scientists and senior administrators in the NHS and the DWP.
|
| 18/06/2021 |
£27,439 |
UNIVERSITY OF LEEDS |
The applicant will collaborate with the World Health Organisation (WHO) Disability Unit in the Non-Communicable Disease department and the Mental Health Department, to research and contribute to the next WHO Global Report on Disability and Health. She will conduct a scoping review of the global health of people with an intellectual disability and write case studies, in relation to;
1. Availability and accessibility of health services
2. Consideration of the needs of people with an intellectual disability in emergency planning (eg virus outbreaks)
3. The impact of public health campaigns on people with an intellectual disability and
4. The quality of the data we collect about people with an intellectual disability.
The World Health Assembly resolution May 2021 will set the agenda on health and disability for WHO Member states for the majority of the next decade. The project provides the opportunity to be part of the team researching and writing the Global Report on Disability and Health and developing the recommendations that will have a global influence, while leading on the work about people with an intellectual disability. The team will collaborate on a peer reviewed publication and support the researcher’s networking and integration into WHO.
|
| 18/06/2021 |
£28,686 |
UNIVERSITY OF LEEDS |
This project is aimed at developing an understanding of public health models in relation to interventions designed to address health inequalities faced by autistic adults, who face a heightened risk of mental illness and suicide. I will explore possibilities of creating meaningful dialogue between 'difference-based perspectives' on autism and overlapping forms of neurological difference and existing frameworks that focus on difficulties/or deficits. This will centre on working with AT-Autism to create a body of evidence and a rationale for the creation of a national peer-support scheme for autistic students in higher education, focusing on students in humanities programmes. AT-Autism is developing a mentoring scheme in response to government strategies targeting the radicalisation of autistic young adults in criminal justice settings, and while my project aims to intervene at an earlier stage of policy development, it explores the kinds of evidence are used in assessing risk factors (the risk of experiencing mental health problems while at university) and protective factors. While learning more about policy and relevant legislation, I will provide AT-Autism with my own expertise in language and narrative to encourage recognition of the plurality of possible stories about autism, including those that situate autism as a positive identity.
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| 18/06/2021 |
£11,049 |
INSTITUTE OF DEVELOPMENT STUDIES |
The global covid-19 pandemic has highlighted the scale of violence against women (VAW), and how far we still have to go to prevent VAW and provide quality responses to victims/survivors. Priority setting processes are an essential part of aligning funding with knowledge gaps. However, processes vary globally, are often not inclusive, and often dominated by the interests of funders in the global north.
The Sexual Violence Research Initiative (SVRI) is the largest network for VAW research, providing an essential platform to share research and connect. Engaging with the SVRI’s extensive networks, the key goal of this project is to engage global and regional groups in a discussion about the utility and efficacy of priority setting processes. This will be achieved by creating a space where priority setting processes can be critically examined with an emphasis on decolonising these processes and standardising priority setting methods to improve VAW research moving forwards.
The outcome will be a co-produced set of global principles for research priority setting which embody what has been learnt during the pandemic, reflect the work of regional and global groups and ensure that intersectional voices, including voices from researchers in low and middle income countries, are heard and represented.
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| 18/06/2021 |
£13,029 |
BIRKBECK UNIVERSITY OF LONDON |
This project will catalogue and challenge the marginalisation of voices within mainstream British feminist movements (1). Based at the Feminist Library, this will culminate in an exhibition.
Public exhibitions are frequently sites of erasure and silence (2). British feminist movements similarly contain inequalities of speech (1), but the archive at the Feminist Library hosts one of the most diverse collections of feminist activism and scholarship in the UK. Organising an exhibition focused on marginalised periodicals will enable academic audiences to view feminist resources that are not reproducible in academic journals (3), and will facilitate a public dialogue around the dominant feminist narrative and associated political challenges (1).
Library staff and volunteers will act as a steering group for this project. I will catalogue and analyse archival materials and facilitate steering group discussion and reflections to provide insight into priority areas of marginalisation within British feminism. This will determine the focus of the exhibition.
References
Olufemi L. Feminism, Interrupted: Disrupting power. London: Pluto Press; 2020.
Clover DE. Animating ‘The Blank Page’: Exhibitions as Feminist Community Adult Education. Social Sciences. 2018 Oct;7(10):204.
Thomlinson N. ‘Second-Wave’ Black Feminist Periodicals in Britain. Women: A Cultural Review. 2016 Oct 1;27(4):432–45.
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| 18/06/2021 |
£9,466 |
QUEEN MARY UNIVERSITY OF LONDON |
The aim of this project is to review current debates surrounding regulation of targeted online advertising. The movement to ban targeted or ‘surveillance’ advertising has gained momentum over the last five years, particularly in the wake of the Cambridge Analytica scandal and rising concerns about the impact of the attention economy on mental health and democratic norms. Advocates of banning targeted online advertising cite various social benefits, but such a ban would also be a major intervention that would strongly impact numerous business and digital publishers.
I will write a report in the form of a Parliamentary Office of Science and Technology Note, a 4-page briefing document for members of parliament. It will review the most recent literature surrounding targeted or ‘surveillance’ advertising and interview key stakeholders in academia, industry, government and the third sector. The report will detail the costs and benefits for both society and the economy and will consider how targeted advertising affects public trust in digital technology. I will then explore the practicalities and effectiveness of different levels of regulation in this area and consider these in the context of current government aims to further regulate the digital sphere.
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| 18/06/2021 |
£24,244 |
UNIVERSITY OF CAPE TOWN |
During my secondment with MSF, my project will focus on equity in humanitarian responses to global health emergencies. Humanitarian organisations such as MSF are a critical part of the international response to global health emergencies. Increasingly humanitarian organisations are required to reflect on equity within their work. Questions of equity relate to, amongst others, how MSF works with other actors such as governments, engagement activities with affected communities, provision of health care services, the role of technology and research-related activities. This project has three objectives:
Policy review: I will conduct a review of policies that guides the response of MSF with a specific focus on how equity is operationalised.
Critical review and analysis: I will conduct a review and critical analysis of literature related to equity in humanitarian responses in global health emergencies. This review will summarise normative and empirical accounts, frameworks, and considerations of equity, including research as part of the humanitarian response.
Recommendations: Based on insights gained from objectives 1 and 2, I will develop targeted recommendations regarding equity for relevant stakeholders involved in MSF's work. I will also facilitate interactive sessions with MSF staff about their experiences of equity, which will also inform recommendations.
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| 18/06/2021 |
£43,836 |
UNIVERSITY OF YORK |
Vets regularly experience ethical dilemmas when balancing the needs of animals, their owners and financial constraints. Moral stress, described as a feeling of conflict over what care it is appropriate to provide, may even contribute to the heightened risk of suicide observed in the veterinary profession. Charitable veterinary providers such as PDSA are currently working under extremely challenging conditions, with reduced capacity and increased demand caused by the COVID-19 pandemic.
Whilst ethical discussion groups and the use of ethical decision making tools have been proposed for supporting veterinary decision making, such practices have yet to be evaluated for their effectiveness in veterinary rather than equivalent human medical teams.
I will pilot the use of an ethical decision making tool within a supportive group environment to help PDSA veterinary teams explore their approaches to ethically challenging cases. Through in depth interviews, I will invite veterinary team members to share their experiences of moral stress and evaluate the effectiveness of small group structured ethical discussions.
My research will help PDSA develop strategies for improving veterinary mental health through supported ethical decision making. The research will also help us to better understand the causes and effects of moral stress in veterinary teams.
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| 18/06/2021 |
£33,188 |
UNIVERSITY OF SHEFFIELD |
When people register as blood stem cell donors, they do so to save a stranger’s life. However, on rare occasions, donated tissue does not go on to clinical use, potentially being cryopreserved indefinitely. This presents a socioethical conundrum for registries, who have to make a decision about the future of this tissue, e.g., should it be destroyed, or used in therapeutic research? This secondment fellowship is a collaboration with Anthony Nolan, the world’s first blood stem cell, or bone marrow, registry. The secondment topic, co-produced with Anthony Nolan, is an exploration of this issue, which has become urgent as COVID-19 has increased instances of unanticipated cryopreservation globally.
The secondment fellowship comprises (i) exploration of perspectives of international stem cell donors on the potential futures of cryopreserved tissue beyond the clinic through focus groups with donors, and (ii) generation of critical social science to be disseminated to registries around the world through a report for practitioners. Findings will generate knowledge to inform global practice regarding cryopreservation, and the use of donor stem cells in therapeutic research. The secondment aims to build collaborative relationships with non-academic organisations for future social science research on the global stem cell infrastructure.
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| 18/06/2021 |
£30,636 |
UNIVERSITY COLLEGE LONDON |
Though Black and Minority Ethnic (BME) populations have been significantly overrepresented in COVID-19 mortality statistics, they are vastly underrepresented in NHS management. It is critical to address this lack of diversity amongst decision makers to ensure equitable representation, as current NHS leadership is not adequately representative of the workforce or communities for whom it cares. Principally this project asks: what is the scope and capacity within non-clinical NHS management and NHS decision-making to understand and address BME healthcare worker experience in the face of emerging and changing health care structures, and how can it be improved for the future of equitable health service delivery and diversity in the workforce?
Working with the Nuffield Trust, key project goals are:
Investigate the current understandings and approaches to race and ethnicity within non-clinical London NHS Management teams. This will be achieved through embedded ethnography within 1-3 London NHS Trusts; chosen for diversity of workforce.
Encourage more open dialogue to navigate ethnic and racial concerns when it comes to mitigating COVID-19 and other future health risks. This will be achieved through an open-access, widely available report and associated workshop-toolkit that will be published online and circulated to management teams and stakeholders.
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| 17/06/2021 |
£12,839 |
UNIVERSITY OF SHEFFIELD |
Gestational trophoblastic diseases are rare conditions that span the worlds of reproduction and oncology. A lack of awareness surrounding gestational trophoblastic disease impacts patients, as they attempt to make sense of the condition whilst simultaneously undergoing diagnosis, monitoring and treatment.
For some patients, sense-making involves engagement with visual representations of GTD. These include biomedical diagrams illustrating its genetic causes. Patient accounts of these diagrams can provide alternative perspectives to research on GTD, as visual material can provoke feelings and responses that are not captured by traditional qualitative methods.
This project will involve collaborative work with patients, scientists and artists to reimagine the medical illustrations used to represent GTD and other forms of cancer. The project will provide participants with insight into biomedical explanations of cancerous conditions, and support them to develop creative ways of sharing illness experience.
Activities will comprise an initial creative workshop, ongoing artistic support and dissemination events. Through the workshop and artistic follow-up, patient participants will share experiences and produce their own visual representations of disease. The display and discussion of participants’ creations in an online gallery, and through a live digital event, will allow these to be shared with practitioners and relevant charities. This will enable patients’ stories to be heard in new ways and raise awareness of GTD, as well as informing the fieldwork and analysis conducted for the wider research.
This engagement work will involve continuous evaluation to ensure the activities have been enriching for patient participants, relevant stakeholders, and for the researcher’s skills.
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| 17/06/2021 |
£73,445 |
UNIVERSITY OF LEEDS |
We propose a programme of activities that will communicate project findings to a range of audiences. The programme will impact especially on public awareness and understanding of disability’s interaction with technology and the experiences of disabled users. It is centred around three strands:
Bespoke exhibits at major science festivals, beginning with Sheffield Festival of Mind 2020, then New Scientist Live in October 2023 and subsequently portable to other festivals across 2024.
Feature programme at 2022 Leeds International Film Festival (LIFF) focused on fiction and documentary films that explore disability, embodiment and technology.
Commission of artist Sarah Browne to produce creative moving-image artwork, in conjunction with the LUX Arts Agency, the largest distributor of contemporary art film and video in Europe. The final work will screen at festivals across the UK and Europe and be hosted on the project website.
Each strand will be developed with existing partners (named in the original Collaborative Award application) and disability arts groups and disabled mentors in Leeds, Sheffield and Dundee.
The activities will engage thousands of people. When the programme has finished, we will have communicated our research to audiences with interests ranging from developments in new/future technologies to contemporary art and film. Our interaction with the public will allow for individuals to volunteer, through our website, to participate in the project’s public consultation workshops on the co-design of research outputs across 2022 and 2023. We will feed all event response data into our publications and reports in the final year of the project.
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| 17/06/2021 |
£89,311 |
UNIVERSITY OF LIVERPOOL |
ATtaining EQUity of Access TO Research (At The EQUATOR) will transform research culture to ensure equity of access to research. Initially focussing on women of childbearing age, using activities aligned with MILK and establishing key capacity at the Infectious Diseases Institute (IDI), community members will have input and involvement at all stages of research, from conception through dissemination. Co-creation of resources to enable meaningful two-way dialogue will include posters, video clips, infographics, drama and song in both an urban and rural population. Evaluation of impact, primarily through focus group discussion (FGD) at inception, midpoint and end, will include novel and interactive methods of feedback from community members.
.
At The EQUATOR will achieve this through:
.
A: Institutional Level (Capacity Building)
.
Skills and capacity audit of personnel and projects at IDI at baseline – projects, people, level of understanding of PE & I, barriers
Public engagement training – initially outsourced then co-creation of relevant materials
Social media training
Developing standard operating procedures with guidance on PE & I at all phases of research from conception through dissemination
Establishing a PE & I working group within the IDI Research Department
.
B: Community Level
.
Strengthening the Community Advisory Board (CAB) structures (from ad hoc to regular)
Identification of key community leaders
Mapping community networks and communication channels
Community consultation at grant application and protocol development stages
Identification of key community members for co-creation activities
Community engagement alongside site initiation visit
Regular community meetings during execution of project
Dissemination event
Dialogue to establish ongoing research priorities
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| 17/06/2021 |
£69,000 |
IMPERIAL COLLEGE LONDON |
The ongoing COVID-19 pandemic has changed our world and lives, in many different ways. Restrictions on social contacts and closure of schools have brought with them a significant disruption to children’s daily routines, including exercise patterns and eating habits. The anxiety associated with social isolation, in combination with an increased sedentary lifestyle, has led to serious concerns about the long-term impact of COVID-19 on the global childhood obesity crisis. Our interactive science workshop "You’ve got guts!" will focus on positive messages centred around what keeps us healthy and why our guts play a central role in promoting health.
Our workshop is a stimulating virtual as well as real-life learning experience designed for pupils aged 8-11 in our local community (White City). In collaboration with experts in science communication and professional science animators we will create several animated features conveying key aspects of gut health and healthy diets. The animated features, combined with direct two-way dialogue between pupils and scientists, will help pupils gain a better understanding of the connection between diet, gut health and overall well-being. Workshops will be virtual initially, but, as current lockdown restriction are eased, will be disseminated more widely as part of local science festivals and events in dedicated engagement spaces. Scientists involved in this project will gain valuable training and experience in PE with young audiences. Our PE activities will help develop and deepen links between our Institute and local schools, strengthening our Institution’s reputation and visibility in the local community.
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| 17/06/2021 |
£24,256 |
CENTRO INTERNACIONAL DE ENTRENAMIENTO E INVESTIGACIONES MEDICAS |
The radio drama: "Myths and Realities of Cutaneous Leishmaniasis" will consist of 6 episodes of 10 minutes each in Spanish language and it will be a co-created product of the interaction with the inhabitants of the municipality of Tumaco, particularly with local health workers and patients. The creation and dissemination of the radio drama will be carried out in collaboration with the local community broadcaster: Tumaco Stereo, and through it, the importance of early and timely treatment in the management of cutaneous leishmaniasis (CL) will be promoted in Tumaco, a municipality that is endemic for CL and that is affected by socio- economic exclusion, and an intense armed conflict, which make accessing health education difficult.
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| 10/06/2021 |
£1,924,730 |
KING'S COLLEGE LONDON |
The proposed Centre in Medical Engineering focuses on medical imaging, and is a renewal of our existing Centre. Our vision is to bring together teams from multiple scientific disciplines to identify and solve complex multi-factorial challenges, focusing on the most important clinical and biological issues. By combining expertise in biomedical and clinical research with excellence in underpinning sciences of imaging engineering & physics, computational and mathematical approaches and imaging chemistry, we will deliver impact that improves the understanding, diagnosis and treatment of neuropsychiatric, oncological and cardiovascular diseases. The Centre will have a unique combination of characteristics that allow delivery of this vision. The current critical mass of imaging scientists combines with cutting-edge facilities across multiple imaging modalities, strong industrial links and our location within a major hospital campus to create an exciting, synergistic environment where the most challenging questions can be addressed. In addition to producing world-leading outputs, the Centre infrastructure will accelerate translation to clinical benefit and industrial uptake. The Centre will act as a focus for recruitment of leading international talent and training of the next generation of research leaders, enhancing excellence. We will make a major contribution to public engagement, enhancing the strong current activity. |
| 10/06/2021 |
£2,490,921 |
UNIVERSITY COLLEGE LONDON |
Image-guided Intervention (IGI) has enabled greater surgical precision resulting in reduced tissue trauma, co-morbidity, complications, and hospitalisation time. However, significant limitations arise from the challenging use of IGI systems, and their predominant reliance on preoperative anatomical images. Disrupting existing IGI, we will deliver pathologically, anatomically, and physiologically optimal surgery by combining diagnostic-quality imaging/sensing with ergonomic smart instruments. The Wellcome Trust Centre for Surgical and Interventional Sciences (WTC-SIS) will launch a new phase in which anatomical cues, which have driven interventional therapies for centuries, are augmented by physiological and pathological insight. Three fundamental research themes will link the WTC-SIS interdisciplinary groups: Physiological navigation, focusing on fusing anatomical, physiological and pathological information for real-time guidance/monitoring. Clinician experience, focusing on optimising the clinical team cognitive/ergonomic workload. Precision instrumentation, focusing on designing interventional devices that both sense physiological/pathological information and interact with tissue. WTC-SIS will serve as a hub-and-spoke translational catalyst for indication-specific externally-funded projects across surgical domains. A single unified Centre (hub) will provide all relevant skills and know-how, from scientific expertise to good manufacturing principles. This will drive rapid translation in our clinical satellites (spokes) and industry engagement through the development of a Health Technology Assessment programme. |
| 10/06/2021 |
£5,146,064 |
UNIVERSITY OF DUNDEE |
The vision for the Centre is to help tackle the urgent unmet medical need and lack of drug discovery research for Neglected Tropical Diseases (NTDs) by creating the hub for NTD drug discovery and being the collaborator of choice for academics, Pharma and Product Development Partnerships (PDPs) in the translation of discovery science into drug candidates. The success of this vision will be evidenced by increased integration, efficiency and effectiveness of the discovery science, drug discovery and mode-of-action teams in Dundee, providing: Accelerated delivery of NTD drug candidates for our PDP partners, with an initial focus on visceral leishmaniasis and Chagas' disease. Improved paradigms for carrying out NTD drug discovery, including improved understanding of PKPD relationships and more predictive disease models. Improved methodology to determine drug modes of action and resistance mechanisms. Increased exploitation of novel drug targets through structure based drug discovery, involving collaborators worldwide. Training and support for international scientists in the theory and practice of NTD drug discovery. Increased public engagement and awareness of the impact of, and need for, new medicines for NTDs and a greater understanding of the nature and importance of drug discovery. |
| 07/06/2021 |
£1,096,432 |
IMPERIAL COLLEGE LONDON |
Background: Early-onset type 2 diabetes (diagnosed
Goal: I will decipher heterogeneity of early-onset type 2 diabetes in white and south Asian individuals using epidemiological and genetic approaches.
Proposal:
Determine whether early-onset type 2 diabetes is enriched for sub-phenotypes contributing to higher risk, using analysis of large datasets to examine ethnic differences in presentation and progression by age-at-diagnosis with application of supervised and unsupervised statistical methods.
Determine if the higher risk of early-onset type 2 diabetes in south Asian individuals is driven by excess polygenic risk, by undertaking a cohort study with application of trans-ancestry polygenic scores compared to controls.
Summary: This broad population-level study together with deep genotyping and phenotyping of affected individuals has the potential to produce new insights leading to better surveillance, earlier therapies, and fewer complications.
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| 07/06/2021 |
£574,165 |
UNIVERSITY COLLEGE LONDON |
In Alzheimer’s disease (AD) there is a drive towards earlier clinical trials, before symptoms manifest, prior to significant neuronal loss. However current approaches for identifying those at risk of imminent decline and tracking progression lack sensitivity.
I previously identified a characteristic pattern of early cortical loss in AD. In the current fellowship I will develop sensitive quantitive cortical imaging biomarkers, and improve understanding of early AD-related neurodegeneration and its link to molecular pathology.
First, I will undertake multi-compartmental modelling of multi-shell diffusion MRI to track presymptomatic microstructural breakdown of cortical neurons, across three separate cohorts, and compare with established imaging markers.
Secondly, I will acquire ultra high field (7T) MRI and undertake quantitive multiparameter mapping to characterize extra-neuronal cortical microstructure, including myeloarchitecture and iron deposition, at sub-millimetre resolution.
Thirdly, I will assess associations between tau PET and microstructural imaging.
I will use my expertise in blood-based biomarkers and novel measures of cognitive decline to explore their relationship with cortical microstructure.
Goals:
Assess how microstructural change can be optimally assessed in-vivo.
Determine the nature, timing, and distribution of early cortical breakdown.
Use microstructural cortical imaging to estimate proximity to symptom onset.
Examine how neuronal breakdown is mediated by tau deposition.
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| 07/06/2021 |
£861,960 |
UNIVERSITY OF CAMBRIDGE |
Neural stem cells (NSCs) in the developing embryo brain share transcription programs with glioma stem cells (GSCs) in malignant brain tumours, and both are susceptible to Zika Virus infection. In the developing brain this can result in microcephaly, whereas in brain tumours it could offer insights relevant to oncolytic virus development. However GSC and NSC susceptibility to Zika and other viruses depends on the microenvironment. In particular, microglia progenitors migrating into the embryo brain from the yolk sac are believed to bring virus with them, whereas my preliminary data suggests that mature tumour-associated microglia instead drive a virus resistance phenotype in GSCs. This project seeks to establish the mechanistic basis for the microenvironment regulation of virus susceptibility in normal and malignant progenitors, and to suggest therapeutic strategies for modulation of these.
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| 07/06/2021 |
£379,655 |
UNIVERSITY OF CAMBRIDGE |
Cancers upregulate telomerase in order to lengthen telomeres and therby to propagate their survival and immortality. However, in 10-15% of cancers, telomere length is instead maintained by the alternative lengthening of telomere (ALT) pathway. A breakthrough in understanding this pathway came when ATRX (alpha thalassemia/mental retardation X-linked), a chromatin remodeller with various regulatory roles throughout the genome, was discovered to be mutated or lost in ~90% of ALT cancer cell lines and tumours. An important mechanism of ATRX function is in conjunction with DAXX, the histone 3.3 (H3.3) chaperone, whose mutations are also associated with ALT activation. ATRX and DAXX act together to deposit H3.3 and its binding partner H4 at heterochromatin, such as telomeres, aided by HP1. Deposition of H3.3 helps to maintain telomeres in a canonical state, preventing aberrent secondary DNA structure formation leading to activation of the ALT pathway.
My proposal is to elucidate, by cryo-EM, the structure of HP1-ATRX-DAXX-H3.3-H4 in complex with the nucleosome. This structure would provide functional and mechanistic insights into chromatin remodelling, and histone deposition by this central ALT associated complex. This field is clinically exciting, as targeting the ALT pathway is a promising therapeutic approach for cancer.
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| 07/06/2021 |
£1,673,630 |
UNIVERSITY OF OXFORD |
Dengue causes up to 96 million clinical infections annually. Despite this burden, there are currently no licensed therapeutics. Severe dengue is characterized by shock, organ dysfunction, cytopaenias, and vasculopathy, which occur late in the disease, during viral clearance, driven by an excessive host immune response and hypercytokinaemia. One of the most targeted ways of controlling this excessive inflammation is through interleukin-1 receptor (IL-1R) blockade (anakinra).
My overarching hypothesis is IL-1 mediated pathways drive hyperinflammation and severe disease in dengue. I hypothesize that therapeutic IL-1R blockade in selected patients with dengue will improve clinical outcomes through attenuation of the inflammatory response. The accompanying immunology and transcriptomic analyses aims to reveal any additional pathophysiological pathways involved in severe dengue.
I will test this hypothesis by conducting a phase 2 clinical trial of anakinra in dengue patients with hyperinflammation. I will also perform detailed mechanistic studies, investigating the effect of IL-1R blockade on dengue pathogenesis by assessing kinetics of inflammatory markers, cytokine trajectories, inflammasome and endothelial activation markers, cellular immune responses and antibody studies in trial patients with and without anakinra treatment. I will also investigate immune cell genetic signatures by disease severity and if IL-1R blockade can normalize these signatures over time.
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| 07/06/2021 |
£457,663 |
KING'S COLLEGE LONDON |
Intrauterine infection accounts for at least 40% of cases of spontaneous preterm birth. The most common route of pathogen entry into the uterine cavity is likely to be ascent of vaginal microbes as a result of compromised cervico-vaginal innate immune defences. All mucosal surfaces are protected to some degree by mucus barriers formed by polymeric gel-forming mucin proteins secreted from epithelial goblet cells. Accordingly, research has identified a potential protective role for cervical mucins and mucus barriers in the antimicrobial defence of the pregnant cervix.
This project will address the hypothesis that a compromised mucus barrier function confers an increased risk of infection-related preterm birth. Our key goal will be to investigate the specific role of cervical mucins in mucus barrier integrity and antimicrobial defence using knock out mouse models, as well as exploring cervical mucins from cervical samples (collected in our prematurity clinic) from women at risk of preterm birth. Furthermore, this project will investigate the use of a mucin-like biopolymer, which would mimic a healthy pregnant cervical mucus plug, as a potential preventative therapy for preterm birth using a mouse model of preterm birth.
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| 07/06/2021 |
£594,603 |
UNIVERSITY COLLEGE LONDON |
Background: Impaired social functioning is a core feature of dementia and declines progressively through the disease course, but we do not currently understand the specific causes of this decline and have no effective treatments for social functioning. Social cognitive impairment, particularly impaired theory of mind, is a likely major cause of this decline and, if this is established, it could be a target for future interventions aiming to maintain social functioning.
Key goals:
To test whether theory of mind deficits, or impairment in other social cognitive domains, are associated with current and subsequent level of social behaviour and functioning in Alzheimer’s disease.
To develop novel approaches to the measurement of social behaviour and function in Alzheimer’s disease and establish their reliability and validity.
To examine neuroimaging correlates of theory of mind impairment in Alzheimer's disease.
Methods: I will construct a new observational cohort study of 207 people with mild Alzheimer’s disease and conduct a detailed social cognition test battery. I will assess social functioning and behaviour over 1 year using questionnaires, behavioural observation, and remote digital monitoring. To examine neural correlates of social cognitive decline, I will analyse already-collected structural and functional neuroimaging and social cognition data from my collaborator.
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| 07/06/2021 |
£649,059 |
UNIVERSITY COLLEGE LONDON |
Hippocampal damage impairs episodic memory, but it is unknown precisely why. Research in non-humans suggests that damage to a specific hippocampal subfield (cornu Ammonis 3, CA3) impairs computational processes called pattern separation (the ability to distinguish between similar but distinct memories; PS), and pattern completion (the ability to recall a full memory from partial cues; PC). I have shown that focal bilateral human CA3 pathology causes extensive episodic amnesia alongside reduced functional connectivity between the hippocampus and episodic memory network. Episodic amnesia could arise from disrupted PS/PC during learning and/or retrieval, or, from aberrant interactions between PS/PC and other cognitive processes supported by the hippocampus, critical to episodic re-experiencing (temporal sequencing, visuospatial re-experiencing).
This Fellowship will use functional MRI (fMRI) in a well-characterized cohort of patients to investigate the effects of CA3 pathology on episodic learning and retrieval.
Goals:
To understand how CA3 damage disrupts the normal hippocampal-cortical interactions required for episodic learning and retrieval.
To investigate whether episodic amnesia arises solely from a failure of PS/PC or from disrupted interactions between PS/PC and other processes such as temporal ordering or visuospatial re-experiencing.
To seek mechanistic understandings of how CA3 pathology disrupts episodic memory retrieval across the lifetime using fMRI.
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| 04/06/2021 |
£19,995 |
UNIVERSITY OF OXFORD |
Human colour vision arises when cone cells in the retina absorb light, and estimates of the spectral sensitivities of the cones are fundamental to the field. However, the current, so-called "standard observer" models of cone sensitivities are based on data from participants recruited in London from a narrow demographic. We question whether these pseudo-representative models have biased our understanding of human colour vision, and how to best address the on-going ethnic bias in participant recruitment for colour vision research.
The major aims of this project are first to quantify the recruitment bias in relation to ethnicity in colour vision experiments, then to build an evidence-base of cases in which such bias is problematic, and lastly to raise awareness of the issue towards adoption of better practice and the development of an inclusive biological model.
The two main challenges posed by historical and current research practice are (i) underestimation of the true variability that exists in humanity; and (ii) features of the standard observer model that are unrepresentative of specific populations. Addressing these challenges will improve basic science (e.g. controlling for factors that would otherwise obscure mechanistic understanding of biological processes) and have wider impact in applications of colour science (e.g. through the development of measurement standards that are appropriate for diverse observers).
The completed activity will document current knowledge of ethnic variability in biological colour vision, providing a resource to motivate further consideration of ethnic diversity in recruitment, and will provide a jointly-authored ‘roadmap’ for how best to achieve change.
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| 04/06/2021 |
£19,300 |
UNIVERSITY OF LEEDS |
itDf works with the lived experience of people living with disabilities and aims to integrate disabled individuals, communities and family members, as well as NHS user groups into its research design. The project draws on a variety of disciplinary backgrounds and has adopted a reflexive stance on the methodologies that make the ‘entanglement and risk’ of multi-, inter- and cross-disciplinary work rich and productive. With such a multiplicity of perspectives, voices and values, and with a commitment to disability-informed practice, it is crucial that the project team develop facilitation skills, particularly the macro and micro skills and practices needed to create and maintain inclusion, engagement and participation throughout the project cycle.
At the end of a successfully completed period of D & I funding in 2024, we will have developed a programme of work that will match the project's need for better practice. We will also meet the aims of Wellcome’s new (March 2021) diversity, equity and inclusion strategy, placing people with disabilities as central partners in our research design and practice, In particular, the project team will:
As individuals have developed professional facilitation and mentoring competencies
As a team enhanced creativity and inclusion in project research co-design and produced a culture of continuous improvement, including regular participatory evaluation.
Have communicated the value of these approaches to project partners and colleagues in our respective institutions.
Have created a safe and secure space for people with disabilities to contribute to the project that recognises their difference, working methods and wishes.
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| 31/05/2021 |
£30,000 |
ASSOCIATION OF MEDICAL RESEARCH CHARITIES |
Not available |
| 31/05/2021 |
£39,724 |
HUMAN CELL ATLAS, INCORPORATED |
This year’s Human Cell Atlas General Meeting will convene our community virtually to share updates and insights on new HCA research and initiatives, as well as to highlight the work of the HCA Biological Networks and continue to build on progress from the HCA Biological Network Seminar Series.
Key outcomes of this meeting will include a shared appreciation for recent advances and future needs that will facilitate the construction of an integrated atlas; progress toward strategic roadmaps for different organs, tissues, and systems; and an enhanced understanding of how the Human Cell Atlas will provide a healthy reference for the understanding of disease.
Event Overview
Day 1: Plenary talks and networking opportunities.
Themes: HCA Overview, Computational Advancements and Cross-Cutting Approaches
Day 2: Poster viewings, biological network interactive sessions, and breakout sessions.
Theme: HCA Biological Network updates, and plan to organize to build out roadmaps.
Day 3: Plenary talks, panel discussions and networking opportunities.
Theme: HCA and Disease Impact, and Defining 10-year plan.
A portion of the requested funds will also provide partial support for the 2021 HCA Asia General Meeting, to be held in November or December 2021.
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| 31/05/2021 |
£104,589 |
UNIVERSITY OF OXFORD |
This work will complement the Global Research on AntiMicrobial (GRAM) project estimating the global burden of drug resistant infections (antimicrobial resistance, AMR). The work will establish the best practice in quantifying the burden of AMR through the comparative analysis of selected data sets from the GRAM project and synthetic data generated using mechanistic models. Key goals include comparative estimates of the burden of AMR for selected data sets and evaluations of the appropriateness of different analytical approaches for different types of data and different epidemiological processes. In particular, the work will determine: i) under what circumstances the assumption that resistant infections fully replace sensitive infections with the same species is appropriate for quantifying the burden of AMR; ii) under what circumstances the contrasting assumption that resistant infections add to the burden rather than replacing sensitive infections is appropriate; and iii) under what circumstances the intermediate assumption of partial replacement is appropriate.
|
| 31/05/2021 |
£163,036 |
LANCASTER UNIVERSITY |
In a context of austerity, pandemic and unemployment, 14- to 24-year-olds have above-average levels of anxiety, significant rates of depression and lower life satisfaction than previous cohorts. Building on our model of upstream socioeconomic pathways for health impact, this project examines prospective impact of Universal Basic Income, a system of unconditional cash transfers, on anxiety and depression among 14-24s. It brings together an established, multi-disciplinary team to:
Objective 1) create a ‘risk’ factor for anxiety and depression among 14-24s from existing data
O2) deploy the RSA’s Citizen Engagement Workshops and focus groups with disabled people to advance designs for a ‘transitional UBI’ for 14-17s, an overall scheme aimed specifically at mental health impact, and account for additional needs
O3) use the ‘risk’ factor to model the impact of the cash transfer schemes from 2) on anxiety and depression among 14-24s
O4) design research protocols to measure impacts in different schemes using the examples of ActEarly’s Bradford pilot and the RSA/Scottish Government’s prospective Dunfermline trial
This will lead to a series of publications, an end of project report published by the RSA and a set of impact measurement research materials. We will seek to ‘leverage’ these to secure further funded research.
|
| 31/05/2021 |
£1,982,664 |
THE GRADUATE INSTITUTE OF INTERNATIONAL AND DEVELOPMENT STUDIES |
I-DAIR is a Geneva-based global platform to enable inclusive, impactful, and responsible research into digital health and Artificial Intelligence (AI) for health. I-DAIR’s mission is the transformation of personal and public health through collaborative research and development of digital technologies. This proposal for a grant of GBP 2 million over two years (2021- 2022) to fund the key capabilities necessary for I-DAIR to fulfill its primary functions as an enabler of digital health and as a convener of key stakeholders for digital health. The grant will complement a CHF 7 million (GBP 5.4 million) investment by Fondation Botnar, which has allowed I-DAIR to start building a Project Team and begin a two year incubation phase, with launch scheduled for 2022. By enabling key strategic outcomes, Wellcome’s contribution will allow the Project Team to make the case for I-DAIR at launch as a global catalyst for digital health and artificial intelligence (AI) research and development (R & D), and for democratising the R & D landscape by bringing more attention to networks, needs and opportunities in low-and middle-income countries.
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| 31/05/2021 |
£198,620 |
NATIONAL ACADEMY OF SCIENCES, AMERICA (NAS) |
The G20, as proposed by the Italian G20 Presidency, has mandated a High-Level Independent Panel (HLIP) to recommend actionable solutions for reliable and sustainable financing of the global commons for pandemic prevention, surveillance, preparedness and response. The Panel’s recommendations will be presented to the G20 Finance Ministers and Central Bank Governors Meeting in July. To provide the HLIP with support for logistics, coordination, outreach, and communication/engagement, The National Academy of Medicine (NAM) proposes to establish a joint Secretariat comprised of 4-5 individuals from the NAM and the Wellcome Trust. From February through October 2021, it is expected that the joint Secretariat will support the execution of the independent review by the HLIP. The work of the Secretariat during these eight months will include: 1) meeting logistics and organization; 2) meeting facilitation (agenda setting, conduct, and procedures); 3) outreach and communication with key political and other stakeholders; and, as needed 4) limited research/analytical/writing support for health-related content.
|
| 20/05/2021 |
£427,809 |
WEST SUSSEX COUNTY COUNCIL |
The project will make accessible for research eleven archives from post-war new towns in England, Wales and Ireland. Eight of these archives will be catalogued and all will be safeguarded through conservation and preservation work. The new towns included are: Basildon, Bracknell, Crawley, Cwmbran, Newton Aycliffe, Peterlee, Redditch, Runcorn, Shannon, Stevenage and Warrington.
The archives are held by nine partner organisations brought together through the Association of New Towns Archives and Museums. The Association builds on existing academic partnerships, and this project will develop those further. Key outcomes include not only itemised catalogues and protected collections, but also a collaborative dissemination programme.
This project will provide a substantial increase in the evidence base available for researchers seeking to interrogate the new towns’ legacy. The project is particularly timely in the context of the current public health emergency. New towns have much to contribute to current policy making in urban planning and public health including: new homes to reduce overcrowding; generous public green space; amenities within 15 minutes of the home; and supporting walking and cycling. There is renewed interest in many aspects of new town design as plans are made for social recovery in the aftermath of Covid-19.
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| 20/05/2021 |
£180,137 |
UNIVERSITY OF SUSSEX |
Mass-Observation (M-O) has been recording everyday life in Britain since 1937. Since the start of the Covid-19 crisis, we have collected over 8500 pieces of narrative life writing, ranging in format from open-questionnaire responses and day diaries to diaries kept for several months by self-selecting volunteers of all ages from around the UK. This unique set of large-scale qualitative data offers extensive research value and potential to contextualise quantitative data generated throughout the pandemic.
This project will open up the extensive collections of qualitative data relating to the impact of Covid-19 on the mental and physical health and social welfare of volunteer writers around the UK. We will build a tool for discovery and exploration that allows researchers to interrogate these collections.
A database will comprise metadata on the writers and writing that enables researchers across disciplines to interrogate the content of the data, thereby contributing to our understanding of the social and personal impact on UK health and wellbeing during the Covid-19 pandemic. The tool is designed to open up access to the texts that have been submitted, allowing researchers to select relevant materials and export the data into their own choice of research tools for analysis.
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| 20/05/2021 |
£230,958 |
NATIONAL LIBRARY OF SCOTLAND |
This pilot project will preserve and provide research access to 10,000 websites relating to health information (and misinformation), and will use this collection to enable more health research on the UK Web Archive.
Our project brings together four co-applicant institutions, and a network of other organisations and researchers, to tackle one of the most pressing research issues of our time: how can the story of changing online health information be captured and understood?
During the Covid-19 pandemic, online health advice, data and scientific evidence have been contested, revised, used and mis-used with global consequences – but the digital record of this activity is fragile and hard to access.
We will:
Curate a new research-ready collection of websites within the UKWA, with the theme of Health Information and Misinformation, ensuring a wide representation of diverse and otherwise under-collected sources.
Use this collection as a test-bed to explore options for metadata, computational analysis, ethics and rights issues.
Build a research network across disciplines including use cases, involving researchers in the process of building, evaluating and using collections.
Produce a project report with recommendations for future work and advocacy for change to make web archives more representative, inclusive and open for health research.
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| 20/05/2021 |
£113,611 |
UNIVERSITY OF LEEDS |
Leeds Animation Workshop (LAW) is a not-for-profit cooperative company established in 1978 and run by women. It produces and distributes animated films on social, health and educational issues, with international distribution. Subjects include childcare, violence against women, bereavement, child protection, parenting and relationships, gender and equal opportunities, bullying and homelessness. LAW has created films for audiences with learning difficulties and provides training in basic animation for adults and young people.
The LAW archive is a unique survival. It is the only complete archive of a collective independent filmmaking organisation. The archive is key to understanding the production of public information films and provides a counterpoint to ‘establishment’ films of the period. This is an essential national and international resource for exploring intersections between feminist activism, creative practice, and public health information.
The project will:
Secure the archive in a publicly accessible repository, appraised, organised and repackaged to archival standards.
Create an online catalogue with detailed index points to enable network mapping and exploration.
Showcase interdisciplinary research opportunities, and create new research networks through the University of Leeds and beyond.
Embed the archive in research led teaching and lifelong learning, including online delivery.
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| 20/05/2021 |
£493,456 |
UNIVERSITY OF CAMBRIDGE |
This two-year, collaborative project will open up to health researchers worldwide 187 medieval manuscripts containing medical recipes across Cambridge collections, and the currently inaccessible corpus of approximately 8000 Latin and Middle English medical recipes that they contain.
A combined programme of manuscript digitisation, cataloguing and conservation will provide multiple points of entry. Researchers will see recipes in their original form: through high-resolution images viewable via the Cambridge Digital Library (CUDL), and medium-resolution images available for free download and reuse via CUDL and International Image Interoperability Framework (IIIF) manifests.
Fully searchable XML descriptions of the manuscripts’ contents, physical characteristics, and histories will be published alongside, revealing the intellectual and material contexts in which these texts were circulated and received. Adhering to interoperable TEI guidelines, these descriptions will facilitate cross-collection discovery, building strong links with comparable manuscripts in Oxford and Manchester.
Hyperdiplomatic transcriptions, created using Transkribus, will provide a level of detail unmatched by existing finding aids, enabling keyword searching and granular, computational analysis of the recipes. The project will empower other organisations to undertake similar work with their collections by creating a robust and extensible methodology, and disseminating it through a website, workshops and symposium for researchers, curators and libraries.
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| 20/05/2021 |
£308,990 |
GREATER MANCHESTER COALITION OF DISABLED PEOPLE |
The GMCDP archive collection reveals the changing perspectives, language and attitudes towards disabled people that have occurred over recent decades. It highlights changes in medical practices, discussions and debates around bio-ethics and end of life issues, campaigns for independent living, the self-organisation of disabled people, development of disability culture, and the significant impact of wider health determinants (education, income/poverty levels, employment, housing etc). The GMCDP Archive is the largest, most comprehensive archive of the lives and experience of disabled people and the activism in England (JT Assessment)
The project will:
Work with Archives+ to catalogue and classify the collection.
Make the catalogue available online.
Establish a viable and sustainable system for viewing the collection (providing physical access to research material).
Make parts of the collection available digitally online (e.g. seminal papers).
Ensure that all openly available material is presented for viewing in a range of accessible formats and that there is an on-going system in place to transcribe new and/or restricted material. A significant challenge, but essential element of the project.
Share our learning on making collections fully accessible by developing guidance and toolkits, delivering workshops and training to other collection holders.
Connect with relevant institutions to promote the resource.
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| 20/05/2021 |
£281,758 |
UNIVERSITY OF BRISTOL |
The Welfare State International archive spans five decades and provides an unparalleled record of pioneering participatory arts practice for health and wellbeing a generation ahead of its time. This project will make available this uniquely detailed history of the evolution of community arts for wellbeing, and provide evidence and inspiration for future research and practice.
We are responding to demand from a broad spectrum of social science, health and arts researchers, and practitioners, to enable exploration of WSI's innovative methodologies. Through community engagement and co-creation, WSI gave the marginalised a voice and empowered communities. They evolved from radical travelling performers, by way of intensely researched place-based and co-produced performances, to become embedded community practitioners and celebrants. Their internationally acclaimed work shifted the parameters of arts practice and policy in the UK and beyond, kindling the arts for wellbeing movement and emerging practices in social prescribing.
A comprehensive archive catalogue will be produced and published online, alongside selected, co-curated digitised material responding to key research themes, increasing the resource’s usability in uncertain times. Repackaging will ensure long-term survival alongside remedial conservation for stabilisation where necessary. Audiovisual items will be preserved and digitised for access. Dissemination activities will create additional research impact.
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| 11/05/2021 |
£98,426 |
LANCASTER UNIVERSITY |
Healthcare as an industry is one of the most environmentally destructive on earth in almost every respect (e.g. energy use, harmful gas emissions, and physical waste). The enormous environmental toll of delivering healthcare is fundamentally at odds with healthcare's goal of improving health and wellbeing. Indeed, it is the drive to achieve healthcare excellence with world class medical safety and effective treatments that is ultimately so resource intensive and polluting. This project aims to address the dilemma of how to ethically make medical decisions that adequately account for patients and the environment. In particular, I am interested in how we can ethically make trade offs between what is owed to individuals, collective groups, and future generations. For example, what might be best for the treatment of an individual may harm the environment and be detrimental to collective society or future generations. What is the best course of action? I use these three groups as lenses to examine three case studies of areas of environmental concern in medicine: the environmental cost of medical treatments; medical waste production; and the environmental benefits of remote treatment. My findings aim to inform this cutting edge area of applied ethics, healthcare policy and practice.
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| 11/05/2021 |
£127,173 |
UNIVERSITY COLLEGE LONDON |
With 22.1% of global conflict-affected populations afflicted by mental disorders, Mental Health and Psychosocial Support (MHPSS) has become an increasingly important set of interventions (Charlson et al., 2019). However, care has remained removed from broader socio-political and historical context. This is despite that the psychosocial" is conceptualised as one’s psychological development within, and in interaction with, the social environment (Glass, 2000). In conflict-affected contexts where social environments become strained, structural issues of reconstruction are typically managed by "peacebuilding" actors. In other words, MHPSS and peacebuilding remain siloed, ignoring that peace and mental health are intrinsically linked. Furthermore, interventions remain top-down and externally driven.
Accordingly, this research builds atop interdisciplinary critiques of both fields and asks, "can community-based critical psychology approaches effectively integrate and improve MHPSS and peacebuilding practice in conflict-affected areas?". Focusing on fieldwork with conflict-affected youth in Bogotá, Colombia, this research will take a Participatory Action Research approach in collaboration with local partners and communities, whereby Critical Community Psychology theories will be applied for the development of integrated "psychosocial peacebuilding" approaches. Through the introduction of these theoretical and methodological innovations, a "skeleton" of a model can be developed to be "fleshed out" and implemented in other conflict-affected contexts.
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| 11/05/2021 |
£107,696 |
UNIVERSITY OF OXFORD |
Since 2012, the UK’s ‘hostile environment’ immigration regime has sought to precaritise non-citizens’ lives, and thereby encourage their voluntary departure. In recognition of this explicitly violent objective, empirical legal scholars have increasingly sought to elucidate migrants’ experiences of adversity in the UK with attention to the legal structures and practices that comprise this regime. This research will seek to expand this focus to return practices. Previous research on return has overwhelmingly focused on deportation – which comprises a minority of returns from the UK – and neglected voluntary return, despite its statistical and conceptual significance to the hostile environment regime. As voluntary return also affects far more women than deportation, the practice carries additional importance for scholars of gender and migration. Through ethnographic and narrative accounts of South Asian women’s lived experiences of ‘voluntary return’ from the UK to Punjab, this research will foreground voluntary return’s impacts for women’s health, safety, wellbeing and relationships, and consider whether these experiences might be conceptualised as ‘gendered harms’. These findings will develop understandings of migrant women's autonomy, dignity and bodily integrity, and states' obligations to non-citizens under a political and legal system that sharply differentiates their rights from those of citizens.
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| 11/05/2021 |
£95,026 |
UNIVERSITY COLLEGE LONDON |
Following the lapse of the Contagious Diseases Acts in the late nineteenth century - legislation that allowed for the routine inspection of prostitutes in order to reduce the rates of STDs - rising rates of venereal disease created, by the outbreak of war in 1914, an atmosphere of widespread sex panic that associated the disease with moral infection, particularly in metropolitan locales. My research proposes that the venereal disease epidemic of the early twentieth century was a significant medical and cultural event of particular concern to literary modernists in and around the city, including Joyce, Woolf, Eliot and Pound, and Lawrence, and activated a nexus of interrelated concerns such as anxieties surrounding birth control, prostitution, and non-procreative intercourse. This project will demonstrate how the eugenic language of social hygiene influenced modernist aesthetic strategies and suggest that literary modernism itself contributed to emerging ideas of sexual health by reflecting contemporary fears of illness and contamination. In doing so, it will deepen our understandings of the place of the literary in the production of medical knowledge at this time, and examine the crucial role of cultural forms in the dissemination and transmission of public health discourse in the early twentieth century.
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| 11/05/2021 |
£99,326 |
UNIVERSITY OF HUDDERSFIELD |
Advanced nursing practice has been of tremendous value to British healthcare. The government, NHS managers and patients alike have placed high expectations on Advanced Nurse Practitioners (ANPs), and researchers have concluded that ANPs have risen to the challenge. However, it is ironic that while ANPs have been deployed across varying sectors of British healthcare, neither the government nor the NMC - nursing's regulatory body - has placed legal parameters around the role's boundary of practice. There is no doubt that professional boundaries in healthcare have shifted. Before the 1990s, nurses had been innovatively expanding their practice boundaries in response to service needs. Consequently, the ANP role evolved under changing healthcare needs. It could be interpreted that British medical history does not understand advanced practice. Therefore this study will draw on the example of the USA and interpret such evidence to be applicable to the British context. Nursing historiography currently lacks any historical analysis of the implementation of Advanced Nurse Practitioners, their role and advance practice's evolution. This thesis will correct this oversight and be the first to write a holistic historical analysis of advanced practice's scope of practice.
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| 11/05/2021 |
£95,373 |
UNIVERSITY COLLEGE LONDON |
This work responds to a growing volume of research on the wellbeing of sexual migrants. Little attention has been paid to defining migration in this literature, which is often understood in a purely spatial sense. In this project, I claim that sexual migrants – whether from the UK or abroad – traverse temporal, as well as spatial, boundaries. This, I claim, has important implications for sexual wellbeing and risk. Through ethnographic research in a London sexual health clinic, including two sets of 15 semi-structured interviews with service users and ten interviews with clinic staff, I seek to uncover the extent to which abrupt shifts between timelines, such as coming out of the closet, transitioning, or moving to radically new environments such as halls of residence or retirement homes, contribute to sexual risk. This research will problematise racist and imperialist geographies of risk that locate risk in faraway lands, while also bringing to light corrective measures that will improve patient experiences and health outcomes of temporal migrants, from wherever they originate. These measures include a recalibration of eligibility criteria for targeted risk reduction interventions and an identification of further training needs for sexual health staff working with temporal migrants.
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| 11/05/2021 |
£106,241 |
UNIVERSITY OF HULL |
This project proposes a new critical study of English hospice architecture, aimed at making evidence-based recommendations for inclusive hospice design. Although 40 million people need palliative care worldwide annually, relatively little research has examined the settings in which palliative care is administered or attempted to understand how patients, visitors and staff experience them. The widespread tendency in contemporary hospice architecture to make palliative care settings resemble domestic residences is rarely interrogated, despite potential problems surrounding the home’s complexity and the question of whose home is being imitated. A better understanding of hospice architecture is needed to establish how to design hospices inclusively for individuals from all socio-economic and cultural backgrounds, especially given documented disadvantage in access for some groups.
This project will employ an interdisciplinary methodology, examining English palliative care facilities through site visits and analysis of primary documents, and exploring how individuals experience these environments through ethnographic field work, including observation, interviews and focus groups.
This study will provide a novel examination of English hospice architecture, highlighting the voices of the users of palliative care settings. Findings will be synthesised into recommendations for policy makers on how to address the issue of domestic design inclusively in palliative care settings.
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| 11/05/2021 |
£110,278 |
UNIVERSITY OF EDINBURGH |
Mental health activists and service-users have long argued for research and interventions to take into consideration structural determinants of mental distress such as violence and inequality. Yet, current scholarship on high rates of mental distress amongst women in Pakistan focus on proximal social determinants (factors pertaining to individuals and families).
This project challenges public health investigations that places responsibility of poor mental health of women in the region on family conflict, thereby misplacing causal accountability and missing the opportunity for large-scale transformation and social change. Taking poor mental health amongst women in northern Pakistan as a case study, this project examines how structural determinants such as gender inequality, poverty, and impact of development interventions, shape women’s mental health in northern Pakistan. The proposed research will comprise of in-depth interviews, participant observation and archival research in Gilgit Baltistan, where high rates of suicides/attempted suicides have been recorded.
The project draws on critical perspectives from the fields of global mental health, international development, and gender studies. It aims to provide evidence and insights to researchers, mental health service providers, advocates, and policymakers in delivering health and gender justice through informed interventions and policies in Pakistan, and more broadly, South Asia.
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| 11/05/2021 |
£89,482 |
BIRKBECK UNIVERSITY OF LONDON |
This practice-led project, from a disabled artist-researcher, investigates humour as a form of activism within the UK Disability Arts Movement. Focusing on the under-researched National Disability Arts Collection and Archives, it will document the emergence and uses of critical or polemical humour between 1976 and 2010. This archival research, supported by conversations with the movement’s artists, will combine object-orientated creative practice and sensory enthnography with historiographical research.
Art history has neglected these artists, who created institutions essential to UK arts today. Overlooked by disability studies too, their transgressive humour critically engaged with changing ideas of disability. For the medical humanities, the research will create new knowledge of how disabled people have driven and understood changing ideas of disability. For critical medical humanities, this project will offer a new paradigm of disability arts research, specifically addressing the significance of the disabled artist-subject as researcher.
At a time when the experience of disability in the UK is increasingly individualised, understanding this humour’s agency, collectivity and its effectiveness in disability activism is urgent. This study will inform arts policy, re-position disability activism within art history, and inform critical understanding of how ideas of disability are influenced and understood by disabled people.
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| 11/05/2021 |
£87,362 |
BIRKBECK UNIVERSITY OF LONDON |
This project will be the first comprehensive history of the Beaumont Society, a UK based trans support network. It will focus on the ways that members of the Society conceptualised their sense of self, both within the organisation and in relation to other trans and cis gender people and cultures. This research will be much more than a history of the society itself but will make significant strides in historicising trans identities and experiences in the UK, exploring the ways trans people negotiated the medical and health discourse that have historically legitimised trans identity, alongside other ways of understanding gender crossing in their everyday lives. These perspectives will in addition allow for reconsideration of wider themes of belonging and selfhood and the changing nature of social movements from the 1960s to the early years of the internet. Using a combination of archival research and oral history the project will be organised thematically, examining trans subjectivities through the everyday including domestic life, work, clubs and leisure, and other countercultural and political movements. The relationship of trans identities and experience to shifting gender norms will be a cross cutting theme.
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| 11/05/2021 |
£131,210 |
UNIVERSITY OF ST ANDREWS |
My PhD research aims to deepen anthropological understandings of health, illness and disease in contexts where the Guarani-Mbya people, rodents and microorganisms become entangled through leptospirosis within the Jaragua´ Indigenous Land – a small territory surrounded by the city of Sa~o Paulo, Brazil’s largest metropolis. My project will be based on the ethnographic study of multispecies relations entangling indigenous people, Leptospira spp bacteria, governmental agencies of disease and rodent control, and health professionals. The project will focus on the examination of Guarani-Mbya perceptions of and practices around rodent-borne infection so as to unsettle the colonial vestiges of epidemiological reasoning that continues to inform understandings of zoonosis. This investigation of human-rodent relations will be path-breaking for Amerindian Studies, as, for the most part, these have focused on animal-human relations primarily in contexts of hunting and pet-keeping. The ethnographic data produced by the project will also be useful for reconceptualizing and developing rodent-management strategies and community-led programmes in other Amerindian contexts, contributing to critically expanding the One Health initiative towards an ethnographic-based, decolonized, community-led, and multispecies approach. [zoonosis, Amerindian Studies, rats, Guarani-Mbya, Brazil]
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| 11/05/2021 |
£133,183 |
UNIVERSITY OF EDINBURGH |
Transnational medical practice is a common phenomenon in contemporary Tibetan medicine, especially among exile practitioners in India and Nepal. Both in the form of medical tours abroad or local treatments of foreign patients and via telemedicine, doctors provide transnational medical care. However, as a result of the deterritorialization of practice and practitioners or new phenomena like telemedicine and innovations in medical treatment options, varying degrees of changes in contrast to national treatment paradigms occur that raise questions about the efficacy or benefit for patients. This research seeks to explore and analyse transnational Tibetan medical practice and asks to what extent this trend transforms essential principles, perceptions, and representations of Tibetan medicine. The aim is to determine and question tendencies towards a modern or global Tibetan medicine, following Wujastyk and Smith's categories of modern and global Ayurveda. Using the methods of participant observation and semi-structured interviews with Tibetan medical doctors and patients, I will conduct a 13 months long multi-sited ethnographic fieldwork in India, Nepal, and Europe. Ultimately, the research will help to understand the challenges to and possibilities for globalised medical practice, contributing to the growing anthropological interest in global health.
Keywords: Tibetan medicine, transnational medical practice, therapeutic travel, telemedicine
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| 11/05/2021 |
£86,903 |
UNIVERSITY OF KENT |
Mediterranean red coral has long been treasured around the world and is currently under threat from intensive fishing, oil drilling and rising sea temperatures caused by climate change. This project will explore the value placed on Mediterranean red coral, Corallium rubrum, a natural material sourced and prized in medieval and Renaissance Italy but also a culturally significant foreign import to Protestant England c.1600-1750. While coral is highly visible in early modern English sources, the historical importance of coral to English beliefs about physical and mental health is yet to be analysed. Drawing on a wealth of documentary evidence, material and visual culture, held in The National Archives, V & A, British Museum, Wellcome Collection, Science Museum and National Portrait Gallery, I will examine how coral was used as a medicinal ingredient, contributed to a domestic armoury against natural and supernatural threats, and was also a luxury commodity, perceived to be a material imbued with particular values, properties and powers in English society. Once considered to be a limitless natural treasure of the seas, the ecological threat to red coral in the Mediterranean makes understanding our long history of engagement with this precious species all the more critical at this time.
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| 11/05/2021 |
£171,260 |
UNIVERSITY OF OXFORD |
My dissertation seeks to argue that the modern Western Scientific advancement was largely predicated on the supply of South Asian bones from India to Britain during the legal creation of the British Raj in 1858. In doing so, it attempts to link the trade of bones and bodies to what I call the ‘Red Industry’—a full-fledged socio-economic establishment employing numerous labourers, specialized in different units, which thereby assumed a pivotal place in the network of imperial capitalism, propelled by profit. Besides leading to the emergence of ancillary industries, wherein bones are seen as potentially esoteric, aesthetic and even agricultural resources, I argue that the ‘Red market’ also projected itself as indispensable with regards to the contributions in various socio-medical fields: forensic anthropology, phrenological works, osteo-archaeological discoveries and leading studies on Osteoporosis. Focusing primarily on the local perceptions of the dead, and the surrounding inter and intra-caste polemics on dissection, the work essentially seeks to bridge the long-standing gap between the trade economy and the overarching historical debates predominantly concerning bio-ethics and public health, while interacting with law, labour, society and medicine throughout the mid-nineteenth to the late twentieth centuries—the era of decolonization.
Keywords:
British Raj, South Asia, Public Health, Medicine
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| 11/05/2021 |
£94,754 |
GOLDSMITHS, UNIVERSITY OF LONDON |
Meaningful dreams, visions and coincidences are a remarkably common feature of the dying process. While patients and families report their profound spiritual significance, mainstream clinical literature explains them in materialist terms. This project asks how health professionals respond to such events on the ground, whether they reflect this materialist approach or if there are examples of healthworkers engaging in more ontologically and epistemologically open ways. The research will explore how philosophical responses influence the day-to-day practices of care. It will also ask whether variation in interpretations of such events runs along existing lines of social or cultural difference among both healthworkers and patients. I will take a methodologically interdisciplinary approach combining an ethnography of a hospice in-patient unit (utilising my experience as a palliative care nurse) with narrative interviews of staff who have responded to deathbed experiences. Drawing on feminist care theory, science and technology studies and the medical humanities this study will explore the significance of responses to deathbed phenomena for both clinical knowledge practices and patient care.
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| 11/05/2021 |
£83,492 |
UNIVERSITY OF THE WESTERN CAPE |
The project aims to explore the various social and political constructions of lay care work during the Covid-19 pandemic and the early stages of the HIV/AIDs epidemic in Cape Town. It will analyse the tensions and possibilities that arise when informal, self-organised and localised care work done by ordinary people interacts with the formal health system, considering how this represents a potential for social change in the health system and broader society. Analysis will draw on Feminist care theory and De Certeau's concept of tactics and strategies, situating the project in a broader critique of the ways in which the dominant neoliberal and capitalist order produces a crisis of care that marginalises care work and stifles possibility for meaningful collaborations between the formal health system and ordinary people doing this work. Research will involve archival and document-based data such as meeting recordings, media pieces, policy documents, academic and NGO reports, and documentary films regarding lay care work and community-based care during Covid-19 and the early stages of the HIV/AIDS epidemic (90s-early 2000s). It will also draw on in-depth interviews with participants who were actively involved in and/or able to reflect on the provision of place-based, lay care during both cases.
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| 05/05/2021 |
£300,000 |
UNIVERSITY OF OXFORD |
A major challenge in establishing novel therapeutics for neurological diseases is the assessment of tissue health. The inaccessibility of the brain for biopsy has motivated the development of novel technologies, with diffusion Magnetic Resonance Imaging (MRI) emerging as one of the most promising techniques to non-invasively assess brain tissue. Diffusion MRI generates images sensitive to the microscopic motions of water within and around cells. It has demonstrated considerable potential to identify novel biomarkers in a number of neurological diseases.
Despite this promise, conventional diffusion MRI methods have failed to access certain key brain regions. In these regions, rapid signal-decay (short-T2) leads to low-quality images with the appearance of ‘black holes’. I propose to establish an imaging platform that enables us to assess tissue health in these previously inaccessible regions. I will achieve this using a little-known but powerful technique, ‘steady-state diffusion’.
Building on a framework I have recently developed, I will:
Transform steady-state diffusion images into those with clear biological interpretation.
Enable in vivo use by overcoming its extreme motion-sensitivity.
Reduce examination times by integrating the estimation of signal dependencies.
Utilising this platform, I will investigate the substantia nigra, a black hole brain region of critical importance in Parkinson’s disease.
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| 05/05/2021 |
£300,000 |
THE FRANCIS CRICK INSTITUTE |
Intrinsically disordered proteins/domains (IDPs/IDRs) are highly flexible and lack a defined secondary or tertiary structure. Their highly reactive and versatile interaction surface contains diverse small linear motifs that enable IDP/IDRs to act as key regulatory protein interaction and signalling hubs. In addition, a new set of small proteins have recently emerged by the identification of thousands of microproteins or smORF-encoded peptides (sPEPs) from which a few validated sPEPs play crucial regulatory roles via protein-protein interactions and add a new regulatory dimension to multiple cellular processes. Due to the size of sPEPs and high flexibility of IDPs, conventional tagging, biochemical and cell biological approaches are not suitable for the study of these type of proteins. I will overcome this by implementing a pipeline to achieve the orthogonal site-specific incorporation of minimally invasive non-canonical amino acids in IDPs and sPEPs. With this approach I aim to study the protein-protein interaction networks, localization and function of IDPs and sPEPs involved in innate immune processes such as the antiviral response or neutrophil defense mechanisms against pathogen invasion.
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| 05/05/2021 |
£300,000 |
KING'S COLLEGE LONDON |
The function of the cerebral cortex relies on the cellular balance between excitatory (pyramidal cells) and inhibitory neurons (interneurons), which is disrupted in disorders such as autism or schizophrenia. The emergence of cortical function relies on spontaneous synchronous activity among large groups of pyramidal cells and interneurons, which later desynchronize for efficient information processing. Prior to this shift in network activity, interneuron numbers are adjusted through activity-dependent programmed cell death mechanisms. The contribution of interneuron programmed cell death to the change in network dynamics and the identity of the cell types participating in these events remain unclear. I will address these questions by combining in vivo longitudinal functional imaging of the postnatal somatosensory cortex with cell type identification via multiplex in situ RNA localization. This strategy will allow correlating the identity of one neuron with its activity pattern and participation in network dynamics during early postnatal development. I will perform complementary experiments in mouse models engineered to contain abnormal numbers of cortical interneurons, thereby assessing the importance of neuronal numbers for­ cortical function. This project addresses the fundamental question of how neuronal diversity and numbers contribute to the emergence of functional circuits during physiological and pathological brain wiring.
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| 05/05/2021 |
£300,000 |
UNIVERSITY OF OXFORD |
Generalisation is central to intelligent behaviour. Recent work has shown the classic dichotomy of hippocampal function, relational memory and spatial cognition, can be unified through the language of generalisation. Here the structure of the task (spatial navigation, transitive inference etc) is learned and abstracted in order to be reused when entering new environments. Animals (and hippocampus) do more than just space and memory. They display complex behaviours that are reused and arbitrarily combined in novel situations. This raises the exciting possibility that animals learn the structure of behaviours and generalise them to new situations (e.g. the steps to baking a cake are reusable for making cookies). The common role of generalisation and abstraction would unify representations of behavioural (reinforcement) learning with spatial map-like learning.
My research will build detailed theories and precise computational models to find a formalism with a common language for representations of reinforcement learning and space. Though much of the reinforcement learning literature has focused on more intuitive notions of reward and value to find in neural data, my models will predict that neurons additionally represent the structure of the behavioural tasks. I will look for this neural signature in data from both old and ongoing experiments.
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| 05/05/2021 |
£300,000 |
KING'S COLLEGE LONDON |
This project investigates the genetic basis of psychiatric disorders and neurological diseases with three key goals.
First, to gain insight into the molecular mechanisms underlying genetic associations with these outcomes through the integration of genome-wide association study (GWAS) summary statistics with a range of newly released functional genomic annotations. These include variant-level annotations such as the effect of genetic variation on gene expression, methylation and chromosome structure within relevant tissues and cell types, as well as gene-level annotations such as expression profiles across tissues, cell types and developmental stages.
Second, functionally informed polygenic scores, such as imputed and observed gene expression risk scores, will be stratified by enriched functional genomic annotations and used for clustering patients into aetiological subtypes, which will then be characterised using sociodemographic and clinical variables.
Lastly, this study will evaluate the utility of machine learning models containing functionally informed polygenic scores and cluster membership information for prediction of diagnosis, prognosis and treatment response. I will use data from a range of ancestral populations to improve the accuracy of genetic predictors in all populations. Together this project can inform novel drug development, identify clinical subgroups, and promote personalised medicine through improved prediction of clinically relevant outcomes.
|
| 05/05/2021 |
£300,000 |
UNIVERSITY OF EDINBURGH |
The kinetochore is a molecular structure that segregates chromosomes by connecting them to spindle microtubules. In the first meiotic division the kinetochores of duplicated sister-chromatids mono-orient to the same spindle pole, allowing the segregation of the paternal and maternal chromosomes. In human oocytes, meiotic chromosome segregation is highly error-prone, often resulting in chromosomal abnormalities. This worsens with advanced age, leading to miscarriages or trisomies such as Down syndrome, especially in older women. My project aims to define the molecular adaptations to kinetochores that allow mono-orientation in meiosis and understand how these might be defective in human oocytes. I will develop Xenopus laevis oocyte cytoplasmic extracts as a system in which to assemble meiotic kinetochores in vitro and use biochemical analysis to determine their molecular components. Using cell biological assays in oocytes, I will determine how these components work together to mono-orient meiosis-I kinetochores. Furthermore, I will use patient donated surplus human oocytes obtained from IVF clinics to investigate how deficiency in mono-orientation contributes to age-related chromosomal abnormalities.
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| 05/05/2021 |
£300,000 |
UNIVERSITY OF OXFORD |
Human and animals make decisions to harvest the most valuable rewards. This process requires a precise valuation of choice options and appropriate action selection. Despite the fact that many brain regions have been implicated in different aspects of value computation and decision making, the roles of the claustrum, a region with extensive brain-wide connectivity, in value-based decisions have remained unknown. This fellowship combines circuit, behavioural and computational tools to determine the role of the claustrum in value-based decisions.
I will train mice on a value-based decision-making paradigm. First, I will assess the importance of claustral neural activity in choice behaviour by combining viral injection strategies and three-photon microscopy. Then, I will create a biologically realistic spiking neural network and simulate the effect of claustrum on multiple upstream regions. By using Neuropixels systems and optogenetics, I will delineate how long-range inputs from the claustrum contribute to the value signal in frontal regions by recording spiking activity while silencing claustral cells. These results will provide fundamental insights into the neural circuitry of decision-making.
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| 05/05/2021 |
£300,000 |
UNIVERSITY OF CAMBRIDGE |
Epigenetic lesions occur at the early stages of cancer development, and have important roles in tumour initiation and progression. However, our understanding of how cancer cells acquire, propagate and select such aberrant epigenetic states remains very limited.
Therefore, I propose to define the mechanisms by which initiating epigenetic defects drive tumour evolution in Acute Myeloid Leukemia (AML), a deadly bone marrow cancer with no effective treatment.
I hypothesize that initiating genetic defects in the DNA methylation machinery (TET2 mutations) catalyse epigenetic diversity. The resulting epiclones might acquire properties that increase cellular fitness, predisposing cells to undergo transformation and generating a substrate for selection. Using state-of-the-art single cell DNA methylation and transcriptomic technologies coupled with lineage tracing, I will quantify stably propagated epigenetic diversity in TET2 deficient cells (Aim1), and identify selective advantage of high-fitness epiclones upon cell-extrinsic pressures (Aim2). I will then characterize putative driver epimutations in longitudinal AML patient samples and demonstrate their functional role promoting leukaemic transformation using locus-specific epigenomic editing tools (dCas9-DNMT3A; Aim3).
This research will shed light into the fundamental molecular mechanisms driving epigenetic diversification and selection of cancer cells, with the potential to bring an entirely new dimension to cancer treatment by intercepting tumour evolution.
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| 05/05/2021 |
£300,000 |
UNIVERSITY OF OXFORD |
This project aims to advance our understanding of how the human brain evolved to support our unique cognitive skills. Using multimodal neuroimaging, I will investigate the structure-function coupling in the human brain and relate it to species differences in brain organization across the primate lineage. I will focus on the temporal lobe as a model system given its vital role in higher cognitive functions and because it underwent strong reorganization during evolution. To characterize individual patterns of brain organization optimally, I will use a gradient-based approach, where manifold identification techniques are employed to model spatial trends of variance in the data. MRI-based gradient analyses will be complemented and validated by using microstructural information from the BigBrain-Project and from gene expression data. Lastly, I will compare human temporal lobe organization to that of non-human primates to assess how divergent principles of brain organization relate to uniquely human brain function.
In sum, the present project will explore temporal lobe architecture by (1) studying human macro- and microstructural brain architecture in a gradient-based approach (2) relating structural and functional features in a unified framework to account for patterns of organization at the individual subject-level (3) comparing these relationships to those in non-human primates.
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| 05/05/2021 |
£300,000 |
UNIVERSITY OF MANCHESTER |
Commensal microorganisms protect their hosts from pathogens, denying space and resources to would-be invaders. To bypass this host protection, many human pathogens deploy a needle-like apparatus—the Type 6 Secretion System (T6SS)—to inject lethal toxins into commensal cells, thereby establishing infection. Bacterial resistance to T6SS attacks is therefore expected to be a crucial predictor of pathogen proliferation and consequent disease severity. However, it remains unknown when, and how, bacteria evolve the capacity to resist T6SS attacks, hampering efforts to predict or leverage this host protection.
My project will address this knowledge gap by characterising the emergence of T6SS resistance in Escherichia coli. Combining in vitro and in silico approaches, I will first determine the specificity, fitness costs, and genetic bases of evolved resistance, against diverse toxins deployed by Acinetobacter baylyi, a well-studied T6SS attacker species. Next, I will examine how the evolution of T6SS resistance is affected by attacker toxin arsenal and attacker counter-adaptation, to explain why attackers typically deploy multiple toxins in nature. My ultimate goal is to provide a systematic understanding of how commensal bacteria resist toxin-mediated attacks. In the longer term, this may offer applications for the design of invasion-resistant bacterial communities, and improved biotherapeutics.
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| 05/05/2021 |
£300,000 |
BABRAHAM INSTITUTE |
Memory B cells (MBCs) are central to co-ordinated immune responses required to resolve viral infections and mediate protection following pathogen clearance or vaccination. I propose that a newly described subset of atypical MBCs (defined by expression of CD11c and T-bet) preferentially reside within peripheral tissues, where they can differentiate in-situ to provide rapid and localised protection against pathogenic threats. This project will investigate the mechanistic basis for CD11c+T-bet+MBC differentiation following immunisation, testing the hypothesis that Th1 skewed T follicular helper cells (Tfh) regulate the divergence of CD11c+T-bet+MBCs from classical memory responses and their migration to non-lymphoid tissues. CD11c+T-bet+MBC induction will be characterised alongside subsets of Tfh subsets in vaccinated humans and mice, with fate-mapping systems and interventional mouse models used to dissect: (1) the tissue homing capacity of CD11c+T-bet+MBCs; (2) their contribution to establishing protective immunity; and (3) the involvement of CD4-derived signals to CD11c+T-bet+MBC differentiation. These will be complemented by state-of-the-art imaging technologies to visualise the spatial dynamics of CD11c+T-bet+MBCs and Tfh within germinal centre responses following immunisation. Together, these data will reveal whether Th1 polarised Tfh seed populations of CD11c+T-bet+MBCs in tissues to establish local protection against infection. Findings may facilitate tailored development of strategies to enhance immunity.
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| 05/05/2021 |
£300,000 |
UNIVERSITY OF OXFORD |
The Drosophila brain provides a unique opportunity to study the neural mechanisms underlying navigation. Recent work has revealed much about the fly brain’s ring-shaped ‘compass’ region. Within it, a single ‘compass needle’ of activity represents the fly’s heading. When the fly is pursuing a specific heading goal, it locomotes in a straight line, often holding the sun at a specific arbitrary angle (e.g., 90°), which holds the 'needle' stationary. If the fly is pushed off course, the circuitry downstream of the compass kicks in to reorient the fly toward its goal, moving the sun back to 90° and the ‘needle’ back to its original state. How does the brain initialise a specific angular goal (e.g., holding the sun at 90°)? We hypothesise that an asymmetry in a specific brain region (called the asymmetrical body) provides a coordinate system for writing new spatial goals into working memory. This asymmetry may be used to initialise a new spatial goal with respect to a landmark at an arbitrary angle. I will i) use computational modelling to explore the predictions of this hypothesis, ii) use calcium imaging to test these predictions, and iii) use specific genetic manipulations to perturb this process.
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| 05/05/2021 |
£300,000 |
UNIVERSITY OF OXFORD |
Ventricular arrhythmia is the leading cause of death in diabetes, but its mechanisms remain poorly understood, leading to suboptimal therapy. I propose an interdisciplinary project to address this unmet need, combining multiscale human cardiac simulations and experimental studies. I will use my recent computational model of a human myocyte ToR-ORd, which was extensively validated for arrhythmia research, disease representation, and drug assessment.
Goal 1) To build a computational model of a single diabetic myocyte and use it to elucidate how distinct aspects of diabetic remodelling contribute to arrhythmia, also investigating the role of glucose level disturbance.
Goal 2) To demonstrate how remodelling of cardiac sympathetic signalling at the myocyte level affects diabetic arrhythmia vulnerability using simulations informed by newly collected FRET imaging data.
Goal 3) To integrate the single-cell results into 3D models of ventricles based on patient-specific clinical imaging data, investigating the diabetic remodelling of cardiac conduction properties.
Goal 4) To produce a computational tool to search for new drugs with promising antiarrhythmic effects in diabetes and to assess existing therapies, suggesting their optimisation.
In summary, the project is likely to impact future diabetic therapy and to bring new insights into the so-far poorly understood area of diabetic arrhythmogenesis.
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| 05/05/2021 |
£300,000 |
UNIVERSITY OF GLASGOW |
NK cells are innate lymphocytes with crucial roles against viruses and tumours. There is growing evidence that NK cells display immune memory, however many key open questions remain. While memory NK cells where shown in several models and proved to be protective in adoptive transfer experiments, the mechanisms behind these phenomena remain unclear. Answering such questions could reshape our understanding of immune memory and provide new strategies against infectious disease and cancer. Using state-of-the-art scRNA-seq, 3D imaging and precision mouse models, I plan to study NK cell memory following influenza infection. I aim to decipher 1) which subpopulations of NK cells acquire memory, 2) where memory NK cells are located within the lung architecture and which cells (adaptive, innate or stromal) they interacting with, and 3) how memory NK cells act in concert with other memory cells in secondary immunity in immunosufficient hosts. With my background in NK cells and innate memory and the excellent array of sponsors with complementary expertise in influenza, chemokines, computational analysis and 3D imaging, this project provides the ideal platform for novel findings in the field of NK cell memory, expansion of my skillset in cutting-edge techniques, and optimally enables my transition to independence.
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| 05/05/2021 |
£300,000 |
UNIVERSITY OF BRISTOL |
Sub-Saharan Africa (SSA) has the highest HIV burden in the world and will be the region most affected by climate change, with the largest projected decrease in rainfall and limited resources to deal with the consequences. Global warming will lead to more droughts and decreased food yields, resulting in increased food insecurity. Emerging evidence suggests food insecurity could lead to increased HIV transmission risk and sub-optimal HIV treatment outcomes, due to such factors as women resorting to selling sex for survival, access to HIV treatment being interrupted, and decreased HIV treatment absorption in the absence of food.
This project will:
- involve epidemiological analyses (regression, systematic reviews, meta-analyses) on large HIV datasets from SSA to improve the evidence base for the effect of drought and food insecurity on HIV treatment outcomes, HIV incidence and sexual risk behaviours in SSA.
- use mathematical modelling to simulate the existing impact of drought and food insecurity on HIV transmission and morbidity in several countries in Eastern and Southern Africa.
- model the potential effect of global warming in these countries on increasing the impact of drought and food insecurity on HIV transmission and morbidity, as well as the impact of potential interventions.
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| 05/05/2021 |
£300,000 |
UNIVERSITY OF OXFORD |
Polycomb group proteins are chromatin regulators which are essential for mammalian development and are often dysregulated in diseases including cancer. Polycomb proteins make up two distinct complexes, Polycomb Repressive Complex 1 and 2 (PRC1/2). In mammals these complexes have expanded and evolved into a complex interconnected system making it challenging to disentangle the core principles through which they function. I will utilize Salpingoeca rosetta, a choanoflagellate, to dissect a more "ancestral-like" Polycomb system and through a comparative approach unravel the basic core principles through which animal PRCs operate. Firstly, I will interrogate the composition (Aim1) and dissect the biochemical properties and enzymatic activities of S. rosetta (Sr)PRCs (Aim2) to reveal the conserved properties of animals PRCs. I will then utilize genome-wide mapping approaches to address the function of SrPRCs and, using mutants for PRC components, test whether their activities are coupled in the genome (Aim3). Together, these discoveries will provide essential new insight into the principles through which animal PRCs act and will shed light on how they become perturbed in disease. This in turn will inform new avenues for targeted therapeutic intervention in diseases where alternations to PRC function are pathogenic.
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| 05/05/2021 |
£300,000 |
KING'S COLLEGE LONDON |
Stress-related psychopathology (e.g. depression and anxiety) affects one in eight children in the UK. It is therefore crucial to identify modifiable protective factors that can promote mental health in young people. Physical activity is a promising target for the prevention of depression and anxiety. However, the extent to which it can reduce the burden of mental disorders in young people is not known. This is due to the breadth of environmental, social, and genetic factors that could confound the relationship between physical activity and psychopathology. Furthermore, it is unclear whether physical activity can promote resilience to psychopathology in children who are at higher risk by virtue of genetic liability or adversity.
I will apply cutting-edge causal inference methods, such as G-methods, Mendelian randomisation, and twin designs, to test whether physical activity can promote resilience against the development of stress-related psychopathology, using data from large population-based cohorts of children from the UK, Netherlands, Norway, and Finland. Triangulating evidence from multiple analytical approaches will allow me to strengthen causal inferences from observational data and minimise potential biases associated with each method. In turn, the findings will indicate whether interventions targeting physical activity are likely to hold promise to prevent stress-related psychopathology.
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| 05/05/2021 |
£300,000 |
UNIVERSITY OF CAMBRIDGE |
Obesity and associated comorbidities are significant unresolved global health problems. Despite intense research and various social policies, most of the available non-invasive treatments are ineffective in the long term, and the best therapeutic option remains highly mutilating bariatric surgery. Thus, the unmet need is to identify novel, long-term safe treatments. The activation of the brown adipose tissue (BAT), an energy-dissipating organ, is a promising strategy to treat obesity if the challenges of accumulating enough BAT mass and optimised activity are resolved. Since obese people do not have enough BAT, it is crucial to identify at which step of the differentiation and/or activation the BAT of obese patients fails, and whether we can pharmacologically bypass these functional bottlenecks. Recently, Vidal-Puig's lab has optimised a unique differentiation protocol that recapitulates step-by-step the developmental path of human BAT from stem cells. I aim to use this tool to decipher the signals regulating the process and provide an accurate stage-by-stage molecular map of human brown adipogenesis. These data will help to infer novel pharmacologically targetable molecules to improve differentiation and activation of BAT in obese patients and provide essential information for its analysis and classification in patients based on its maturation and functional stage.
|
| 05/05/2021 |
£300,000 |
IMPERIAL COLLEGE LONDON |
Dizziness is common in older adults and is strongly associated with more frequent falls. Nonetheless, treating this condition represents a significant challenge as clinicians are often unable to identify a physical cause (and, thus, dizziness is ‘unexplained’). Pilot work implies that unexplained dizziness may stem from attempts to consciously process balance. However, a causal relationship has not been established. Further, the specific mechanisms through which conscious processing influences dizziness remain unknown. My goals are to (i) investigate whether conscious balance processing is causally associated with symptoms of unexplained dizziness, and (ii) identify the neuro-cognitive mechanism/s that likely underpin such a relationship.
I will conduct a programme of research to test the hypothesis that conscious balance processing influences dizziness through a hypersensitivity to sensory input, in that even minor fluctuations within ‘normal’ bounds are perceived as unsteadiness. I will measure symptoms of dizziness and assess sensory processing during baseline balance conditions, as well as during experimental manipulations that either promote or prevent conscious balance processing. Data will be compared between older adults with unexplained dizziness and age-matched controls. This work will advance our understanding of how neuro-cognitive factors contribute to dizziness, informing the development of novel therapies that target these mechanisms.
|
| 30/04/2021 |
£20,000 |
NEUROMATCH ACADEMY, INC |
Not available |
| 30/04/2021 |
£7,247,952 |
WORLD HEALTH ORGANIZATION, SWITZERLAND |
The O2 Taskforce is coordinating access to emergency oxygen for COVID-19 patients in LMICs. Since the start of the pandemic, affordable, sustainable access to oxygen has been a growing challenge LMICs. COVID-19 has put huge pressure on health systems, with hospitals running out of oxygen, has resulted in preventable deaths and huge burden on families of hospitalized patients. Oxygen is an essential medicine, and despite being vital for the effective treatment of hospitalized COVID-19 patients, access in LMICs is limited due to cost, infrastructure and logistical barriers. The O2 Taskforce has identified an immediate need of approx. US$ 90 million over the next 1 – 2 months, with a US$1.6 billion need estimated for LMICs over the next 12 months to support.
The proposal will secure funding ($10 million) for acute oxygen COVID-19 needs in LMICs as identified by the O2 Taskforce. The funds will support countries to access oxygen and to unlock available resources to build more sustainable, resilient oxygen systems. Activities may include technical assistance for implementation of oxygen services, investments for market interventions and for additional country assessments/development of country funding proposals. This investment is intended to accelerate and amplify the impact of follow on scale-up funding. |
| 30/04/2021 |
£39,956 |
UNIVERSITY OF LEIDEN |
Not available |
| 30/04/2021 |
£116,653 |
NHS CONFEDERATION |
Execute UK assigned tasks and responsibilities within the Joint Action to a high standard, establishing the UK as a valued and trusted partner.
Gather a body of evidence of NHS and UK expertise on data processing in the health sector to contribute to the development of the European Health Data Space.
Regularly convene and consult a wide range of UK stakeholders to ensure that UK health data interests across the sector are fully understood and represented.
Maintain regular updates and briefings on the scope and objectives of the development of the European Health Data Space, to maximise UK preparedness.
Identify and pursue opportunities to progress UK interests in the health sector, and on digital policy development more broadly.
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| 30/04/2021 |
£115,255 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
Snakebite has recently been recognised as a Neglected Tropical Disease, In addition to the limited availability of high quality antivenoms, one of the major challenges to improving outcomes is that there is currently no established mechanism for a) determining the key evidence gaps, b) coordinating the necessary research and evidence generation and c) providing appropriate scientific and technical advice to governments and Ministries of Health to inform appropriate policy development.
This application seeks to undertake the initial work necessary for planning how these public health and policy issues could be addressed in sub-Saharan Africa. It will comprise two main phases:
a) a wide-ranging scoping review and mapping of critical issues and priorities
b) exploration of the best approaches and structures to address the issues identified in phase 1 and development of a clear strategy and plan to implement a solution
The overarching aim is: To undertake the preliminary work necessary to identify the barriers to evidence-based decision making at national and regional level for snakebite in Africa and to inform the optimal design of a major research and policy initiative that will overcome these barriers.
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| 30/04/2021 |
£199,522 |
UNIVERSITY OF OXFORD |
This award will support a series of interactions between academics from diverse backgrounds with a shared interest in mapping, analyzing and critically unpacking decolonization debates in global health research. Decolonization discussions and activism have become far more prominent over the last year, bringing both opportunities for positive transformation (through disruption, change and renewed interest in global power inequities) as well as challenges (including the ‘trending’ of the decolonization agenda leading to – at worst – the ‘colonization’ of the arena itself). Now, as much as ever, decolonization discussions and debates need to be critically examined. We will organize a set of exchanges and activities to: 1 Unpack and reflect upon the term ‘global health research’ using a decolonization lens; 2 Examine how tacit, or embedded, forms of knowledge from Africa are drawn upon and feature in global health research; 3 Imagine what a decolonized or African-centred, and ethical, research initiative in global health might look like; and 4 Share our learning, advocate for change, and identify an African home for future work. We will incorporate a covid-19 research lens, but only in recognition that covid-19 will shine a light upon or amplify far longer and deeper policies and processes.
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| 30/04/2021 |
£190,026 |
UNIVERSITY OF STRATHCLYDE |
This programme of exchange and networking will:
i. Energise the Medical Humanities research ecosystem in South Africa as it evolves.
ii. Embed the research environment at the CSHHH Glasgow, and its current partners, in this process.
iii. Seed a cohort of early-career scholars in the Medical Humanities with experience of research, training and teaching collectively in both South Africa and the UK.
Context
Since 2018 members of the CSHHH Glasgow and the University of Johannesburg have worked together in the Medical Humanities. The Wellcome Trust and both universities invested in these activities. Following the success of this co-working, partners from the University of the Witwatersrand and the University of Cape Town joined the collaboration. The core objective is to connect the four institutions in order to jointly conduct research, training and teaching so that Medical Humanities research ecosystems continue to grow together in both countries.
Activities
The focus is on seeding those ecosystems through investment in the researchers of the future and fresh collaboration across the countries and institutions. The programme will enable;
1. Four Masters students and one Ph.D. candidate to be co-supervised by the PIs.
2. Enhanced networking and communications capacity, including new online resources and platforms.
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| 30/04/2021 |
£201,902 |
UNIVERSITY OF BIRMINGHAM |
Neuroscience and genetics have failed to deliver new treatments for mental disorders. It has been suggested by the NIMH that progress in biomedical approaches has been hampered by our conceptualization and taxonomy of psychiatric disorders and psychopathology. A renewed emphasis on experiential components and first-person perspectives is required to address this problem. Historically, phenomenology, as a branch of philosophy, has provided this methodology and knowledge to the mental health sciences. However, phenomenological psychopathology remains somewhat fossilized in the humanities and social sciences of the mid-20th century. This co-led international award will (1) renew phenomenological psychopathology with the recent contributions of analytic philosophy of mind, hermeneutics, structuralist/post-structuralist philosophy, history, literature, values-based practice, developmental psychology and service user research; and (2) reinvigorate phenomenology for mental health as the philosophical science of subjectivity and first-person experience.
We will develop international scholars from across disciplines and career stages to develop their research leadership and management activities and to engage in Award activities including international exchange fellowships small grants and, knowledge exchange events. The award will commence the reconstruction of phenomenological psychopathology for the 21st century as a democratic discipline with a historicized and inclusive account of the experience of the mental disorder developed.
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| 30/04/2021 |
£201,912 |
UNIVERSITY COLLEGE LONDON |
This collaboration between Brazil, Mexico and the UK brings together environmental, indigenous, biosocial, multispecies, gender and theoretical expertise in Medical Anthropology, to extend interdisciplinary engagement concerning how the Anthropocene epoch impacts on human health. Supported by a post-doctoral researcher in each of the collaborating centres, we will develop Medical Anthropology in four areas: i) indigenous experience and coloniality of the Anthropocene, ii) gender, reproduction and environmental justice, iii) multispecies ethnography and human-animal health, iv) COVID-19 and public understanding of the Anthropocene. From this research and in conjunction with open access publisher UCL Press, we will develop a tri-lingual digital resource for teaching and public reference.
Our collaboration will begin online with bi-monthly meetings followed in February 2022 by a three day virtual cross-disciplinary seminar with invited expertise in science, geography, politics and history. We will work collaboratively to examine how these disciplines can inform Medical Anthropology of the Anthropocene and to identify articulations with policy and practice as these impact on human and environmental wellbeing. In November 2022 we will hold a face-to-face workshop in Mexico to develop dissemination and publications including the digital teaching resource and a multilingual special edition of a Latin American Medical Anthropology journal.
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| 30/04/2021 |
£201,781 |
UNIVERSITY OF BRISTOL |
Building on a developing track record of collaboration between Bristol, Kyoto and Yonsei, BRIDGES:BKY aims to address shared bioethical challenges, through sharing learning and expertise, to benefit postgraduate and early career researchers (PGR/ECRs). Our four challenge areas are: (1) ageing and end-of-life care; (2) clinical ethics support; (3) reproduction and genomics; and (4) theories and approaches in bioethics. These are shared (indeed, global) challenges, which invite new research, and in which the partners have complementary research interests. Guided by these challenges, BRIDGES:BKY will share learning and expertise, including on different methodological approaches to research in these areas. BRIDGES:BKY will leverage our existing links and partnerships to deliver new opportunities to PGR/ECR participants, drawn from across the partner institutions (and beyond), to participate in, and benefit from training workshops, conferences and a (virtual) visiting researcher scheme. Supported by teleconferencing and a dedicated website, activities will be virtual, with some in-person elements (where appropriate). All partners will host and contribute to these activities, through which PGR/ECR participants will develop their knowledge and skills, and their - and the partners’ - future collaborative research endeavours will be shaped.
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| 30/04/2021 |
£492,566 |
UNIVERSITY OF CAMBRIDGE |
Control of the COVID-19 pandemic depends on the development and equitable roll-out of vaccines that remain effective over time. But the evolution of SARS-CoV-2 variants that exhibit variable degrees of immune evasion, and other characteristics including greater transmissibility and/or lethality, threaten to undermine our ability to control COVID-19. It is widely accepted that vaccines will need to be altered over time as the virus mutates. Effective vaccine re-development is dependent upon the availability of global viral sequence data, but there is a lack of sequence data for much of the world, including low, middle and high-income countries. The COVID-19 Genomics UK Consortium (COG-UK) (including the Wellcome Sanger Institute) will leverage its expertise to develop a comprehensive global learning programme on SARS-CoV-2 genome sequencing (COG-GLOBAL). This will be achieved by working with experienced on-line educators. Specific aims include the development of an open access, online modular global learning programme on SARS-CoV-2 sequencing and analysis, allowing users to follow pathways of learning according to professional expertise (laboratory scientist, clinical practitioner, data scientist & epidemiologist, bioinformatician or policy maker); and the development of train-the-trainer courses in collaboration with the Wellcome Connecting Science Advanced Courses, Wellcome Africa and Asia Programmes, and other contributors.
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| 30/04/2021 |
£463,888 |
WELLCOME TRUST SANGER INSTITUTE |
Control of the COVID-19 pandemic depends on the development and equitable roll-out of vaccines that remain effective over time. But the evolution of SARS-CoV-2 variants that exhibit variable degrees of immune evasion, and other characteristics including greater transmissibility and/or lethality, threaten to undermine our ability to control COVID-19. It is widely accepted that vaccines will need to be altered over time as the virus mutates. Effective vaccine re-development is dependent upon the availability of global viral sequence data, but there is a lack of sequence data for much of the world, including low, middle and high-income countries. The COVID-19 Genomics UK Consortium (COG-UK) (including the Wellcome Sanger Institute) will leverage its expertise to develop a comprehensive global learning programme on SARS-CoV-2 genome sequencing (COG-GLOBAL). This will be achieved by working with experienced on-line educators. Specific aims include the development of an open access, online modular global learning programme on SARS-CoV-2 sequencing and analysis, allowing users to follow pathways of learning according to professional expertise (laboratory scientist, clinical practitioner, data scientist & epidemiologist, bioinformatician or policy maker); and the development of train-the-trainer courses in collaboration with the Wellcome Connecting Science Advanced Courses, Wellcome Africa and Asia Programmes, and other contributors.
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| 30/04/2021 |
£85,186 |
PARIS PEACE FORUM |
The Paris Peace Forum will host a series of discussions to maintain the partnership developed by ACT-A (Access to COVID-19 Tools Accelerator) and the governance of global health at the top of the political agenda and further deliver concrete solutions while contributing to the construction of an overall governance framework in the sector. The proposal includes hosting discussions taking place in the framework of a pilot, year-long partnership between the Forum and Wellcome Trust. These discussions would mobilize stakeholders of the Forum’s community and beyond. The Forum would naturally seek Wellcome’s guidance and advice on the scope, topics, invitees, and outputs of these discussions. Stakeholders would be invited to participate in each discussion based on their institutional focus and expertise and on the basis of their capacity to contribute to and implement the desired outcomes. With the support provided by the Wellcome Trust, the Forum could convene two roundtables in 2021, to provide for sufficient time for preparation, eventually for follow-up actions in between and potentially to leverage to key moments in the annual Forum cycle: the Spring meetings of the Paris Peace Forum (May 2021) and the fourth edition of the annual event (11-13 November, 2021).
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| 30/04/2021 |
£1,122,000 |
CAMPAIGN FOR SCIENCE AND ENGINEERING |
See attached document.
|
| 30/04/2021 |
£331,006 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
A highly effective vaccine against yellow fever (YF) is available and part of the Expanded Program on Immunisation in YF endemic countries. Following a change in WHO guidance in 2014, YF vaccination is now restricted to a single dose given in infancy and expected to provide life-long protection. Recent data have highlighted that this schedule might be insufficient as low antibody titres have been documented in infants who received a primary dose at the age of 9 months. A booster dose of the vaccine might be required in order to ensure long-term protection. Data to support future decisions regarding the ideal timing of a potential booster dose and its subsequent immunogenicity are now urgently required.
Our Aim is to assess if a YF booster dose is required for children who received a single dose of YF vaccination in infancy and if so, at what age this booster dose might be most effective to administer.
We will enrol three well characterised cohorts of children aged between 15 months and 8 years of age with available data on primary immune response to YF vaccination to determine ideal timing for a booster and examine underlying innate and cellular immune responses related to sero-protection.
|
| 30/04/2021 |
£2,965,791 |
MICROPHARM LIMITED |
The project will be directed by MicroPharm and will include contributions by scientists at the Liverpool School of Tropical Medicine. It is in direct response to the WHO's stated aim of reducing the mortality and morbidity of snake envenoming.
The aim of the project is to re-establish supplies of Fav-Afrique in its current format as an equine F(ab’)2 based antivenom suitable for the treatment of Category 1 venomous African snakes. Sanofi-Pasteur will continue to supply large pools of plasma from horses immunised with venoms from Echis, Bitis, Naja or Dendroaspis species respectively. The manufacturing procedures will be modernised and simplified to increase yield and decrease cost. Initial supplies will be available for clinical use in Africa by 2023.
|
| 30/04/2021 |
£59,260 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
LSTM is submitting an application for salary supplements in connection with two roles at MLW:
Director of MLW
Deputy Director
Total Number of Current Applications in progress for LMICSS from LSTM for all programmes: 1
Total Number of Current Applications in process for LMICSS to be held at MLW: 1 (comprising 2 nominees)
|
| 30/04/2021 |
£34,237 |
UNIVERSITY COLLEGE LONDON |
UCL currently has one (this) application in progress, to be held at UCL as the administering organisation
|
| 30/04/2021 |
£59,222 |
ANACOR PHARMACEUTICALS INC. |
There is significant need for new treatments for Chagas disease. The disease is caused by the parasite Trypanosoma cruzi, and the disease can be spread by insect vectors, blood transfusions and from infected mothers to their newborn children. Between 10 and 20 million people, mostly in Central and South America are infected with the parasite and the disease results in over 10,000 annual deaths. Chagas disease kills more people in Latin America than any other parasitic disease, including malaria. Increasing numbers of cases are also being documented outside the normal high transmission areas, including in the U.S. and Europe. Although in use for more than four decades, the two drugs available to treat Chagas--benznidazole and nifurtimox-- require a long course of therapy (60-90 days), have serious safety concerns (20-30% side effects result in treatment discontinuation), fail to cure in a significant number of patients (a result of natural resistance of some isolates to current drugs), and are contraindicated in pregnancy. Thus, there is a critical need for new drugs that address these significant shortcomings of existing therapeutics. Oxaboroles—pioneered by Anacor Pharmaceuticals--have emerged in preliminary studies as a class that can potentially fill this important need. The Wellcome Trust is funding a dedicated drug discovery effort at Anacor, partnered with the disease expertise in the laboratory of Professor Rick Tarleton of the University of Georgia. The objective of the project is to deliver a new drug candidate ready to enter clinical trials by 2016. |
| 20/04/2021 |
£1,341,438 |
UNIVERSITY COLLEGE LONDON |
Effective adaptive immunity is dependent on T-cell development in the thymus. The thymus undergoes age-related involution, leading to reduced T-cell output. This is suggested to compromise T-cell immunity and increase risk of disease severity in the elderly. However, it was unknown whether enhancing thymic function would ameliorate the immune defects observed in the elderly.
Transcriptional assessment of thymic epithelial cells (TECs) through development facilitated the generation of genetically altered mouse models in which thymic involution was prevented or reversed. Both models restored normal peripheral T cell populations, and, critically, enhanced the survival of aging hosts when challenged with Toxoplasma gondii. Therefore, TEC-mediated restoration of thymic function improves immunity with age.
Based on these findings, I propose to identify progenitor-successor relationships within adult TECs that maintain the adult thymus and identify age-associated alterations in these populations that could contribute to thymic atrophy. Moreover, I will investigate the mechanisms by which restored thymus function improves immunity in aged mice. Collectively, my proposal will provide an important understanding of how TECs shape immune responses in the elderly, and inform TEC-mediated approaches of thymic regeneration to aid prevention of the degeneration of T-cell immunity that accompanies aging.
|
| 20/04/2021 |
£1,376,391 |
KING'S COLLEGE LONDON |
Why are all brains different from each other and where does this variability come from? A plethora of animal experiments demonstrate the importance of environmental and genetic influence in creating behavioural variation. A third factor named stochastic developmental processes is less established. Despite recent advancements, a systematic review of variation in brain wiring, its origins, and behavioural consequences is still lacking.
My main research goal is to understand the contributions of genetic, stochastic, and environmental factors to variation in brain wiring and behavioural individuality. Recently, I have shown that stochastic, non-heritable developmental processes can result in individually variable wiring diagrams that are associated with individual behavioural characteristics. This system provides a tractable genetic and neuronal model for individuality.
Based on this work, I hypothesize that (1) stochastic developmental processes are a general neuronal property affecting synaptic distributions, wiring and behaviour, and (2) that stochastic wiring differences affect several behaviours ranging from visual guided responses to circadian activity patterns. Within this framework, I aim to answer two key questions on the origins of individuality:1. Is circuit variability a general nervous system property and what are its origins? 2. Does circuit variability contribute to other visual and non-visual behavioural paradigms?
|
| 20/04/2021 |
£1,343,501 |
UNIVERSITY COLLEGE LONDON |
Robustness mechanisms are ubiquitous in biological systems where they act to ensure a stable outcome despite intrinsic (genetic) and extrinsic (environmental) variabilities. However, the underlying mechanisms are often unclear. In my proposed research, I will investigate the mechanistic basis of how systems deal with change in the context of cell migration during development, immune responses, and cancer invasion. Cell migration models I will use for my study include: the posterior lateral line primordium (pLLP) migration in development and macrophage recruitment during wound immune response in zebrafish, and invasion of cultured cancer cells.
The main goals of the proposed original project are: (1) Characterizing the molecular mechanisms and network architectural designs that enable robust adaptation during cell migration in a multicellular organism, (2) Analysing the requirement of regulated membrane trafficking switching during chemotactic adaptation, and (3) Quantitatively defining the role of dynamic buffering in breast cancer spreading.
To achieve these goals, an interdisciplinary approach will be taken, combining live imaging, genetics, biochemistry and phosphoproteomics. I will generate datasets bridging molecular, cellular, and tissue scales to obtain a systems level understanding of adaptive responses. This work will have broad implications for understanding chemotactic adaptation in development, physiology and disease.
|
| 20/04/2021 |
£1,578,744 |
UNIVERSITY OF CAMBRIDGE |
In order to survive, animals need to avoid predators and skillfully navigate the environment. These behaviors critically depend on the sense of vision. In mammals, two distinct systems process visual information: the evolutionarily ancient superior colliculus and the modern visual cortex. We will define their relative functions in two natural behaviors essential for survival: (1)innate defensive responses and (2)spatial navigation.
1)We will study the visual cortex's role in controlling innate defensive behaviors triggered by the superior colliculus. We will focus on the mouse postrhinal-cortex (POR), capitalizing on my discovery that the superior colliculus has, through POR, a dedicated cortical space from which it receives direct excitatory feedback.(Beltramo,Science,2020). We will test the hypothesis that POR, relaying contextual information about the estimated threatening nature of visual stimuli, controls collicular function's plasticity. By silencing distinct cortico-collicular projections, we will determine how the visual cortex shapes the flexibility of colliculus-mediated innate behaviors.
2)We will investigate the contributions of the two visual pathways in spatial navigation, studying how visual input is transformed into the spatial maps found in the entorhinal/hippocampal formation. Perturbing the activity of distinct visual streams, we will establish how the superior colliculus and visual cortex influence the internal maps that guide navigation.
|
| 20/04/2021 |
£1,350,129 |
UNIVERSITY OF CAMBRIDGE |
Pregnancy complications affect as many as one in four pregnancies, yet there remains a critical gap in our knowledge of their underlying aetiologies. As the maternal-foetal interface, the placenta is essential for healthy pregnancy, with poor function being strongly associated with pregnancy complications. However, there is little mechanistic understanding of the molecular events regulating placental development. My research programme will investigate mechanisms of epigenetic programming and gene regulation in early placental trophoblast and reveal how these underpin the development of a functional placenta. Specifically, I will test the hypothesis that epigenetic programming in placental trophoblast is critical for (1) setting up the gene regulatory landscapes in placental cell types and (2) directing appropriate differentiation during placentation. I will apply cutting-edge ultra-low input sequencing methodologies to characterise gene expression, epigenetic marks, transcription factor binding and 3D chromatin folding in multipotent trophoblast cells in mouse embryos. Using single-cell sequencing and histopathology, placental genomic regulation and function will be evaluated in knockout mouse models for epigenetic modifiers, including several histone and DNA methyltransferases. This research will be fundamental to our understanding of placental development and provide novel insights into how errors in epigenetic programming can lead to compromised placental function in pregnancy.
|
| 20/04/2021 |
£1,029,715 |
UNIVERSITY OF SHEFFIELD |
Cell division in epithelial sheets is crucial for tissue renewal, yet unchecked division leads to tissue dysplasia and ultimately cancer. The aim of this project is to discover how cell division is regulated in normal epithelial tissue and how it is perturbed by oncogenic mutations to disrupt tissue integrity. In previous work, I showed how activation of an oncogene, Ras, directly impacts cell division by controlling the shape, contractility and mechanics of single mitotic cells. I now ask how this finding plays out in a complex tissue environment. To do this, I will employ a multi-disciplinary approach, combining imaging and quantitative cell biology with biophysical techniques to study cell division mechanics in normal epithelial monolayers and Ras-mutant pancreatic cancer tumoroids. I will ask how the actin cytoskeleton is regulated during epithelial cell division to permit dynamic cell shape changes while maintaining cell-cell adhesion and preserving barrier function. I will determine how k-Ras activation perturbs this, identifying key mechanistic links between Ras/ERK-dependent transcription and morphological phenotypes. Finally, I will address how these Ras-induced changes to cell division alter the growth and organization of 3D tissue structures in pancreatic cancer.
|
| 20/04/2021 |
£1,036,024 |
UNIVERSITY OF YORK |
Several pathogens, such as African trypanosomes or malaria parasites, undergo antigenic variation in order to evade the host immune response. A key feature for successful antigenic variation is the ability to express a single antigen at a time, in other words monogenic-expression. Trypanosomes express a single variant-surface-glycoprotein (VSG) from thousands of possible genes, a fine example of extreme biology.
Single gene choice remains one of the biggest mysteries of eukaryotic gene expression and the machinery responsible remained elusive in every organism. I recently identified a protein complex that sustains VSG-monogenic expression and is responsible for the spatial integration of the single active-VSG with an RNA-processing centre. I will study the function of this novel protein complex, identify other relevant factors and use VSGs as a model-system to study how nuclear compartments can be organised to enhance gene expression. To pursue these questions, I will apply a wide range of genetic and biochemical approaches that include proximity labelling coupled with mass-spectrometry, next-generation-sequencing, CryoEM, super-resolution and live microscopy.
The mechanistic understanding of how monogenic-expression is initiated and maintained is of great value as it is critical for sustaining infections by trypanosomes, as well as several other pathogens that undergo antigenic variation.
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| 20/04/2021 |
£1,056,320 |
UNIVERSITY OF OXFORD |
A novel energy conserving mechanism, myosin super relaxation (SRX) has recently been discovered in cardiac muscle. SRX is a structural state of myosin, where myosin heads are folded away from actin, preventing force producing actomyosin interactions and contraction.
Little is known about the key regulatory systems that govern the formation of myosin SRX in cardiac biology. It is evident that phosphorylation of key sarcomeric proteins play an important role, but the cellular signalling that underlies these changes is poorly defined.
I aim to define these cellular signalling pathways and how they control sarcomeric protein phosphorylation. I will define how far reaching myosin SRX destabilisation is as a disease causing mechanism. To do this I will employ CRISPR/Cas-9 technologies to develop stem cell models of hypertrophic cardiomyopathy, HCM, a debilitating genetic condition that affects 1 in 500 people. I will augment these human stem cell models with human and murine tissue samples to define SRX abundance and regulation in acquired cardiovascular conditions including atrial fibrillation, heart failure, hypertension, myocardial infarction, and ageing.
In doing so I will define sub-sets of disease pathomechanisms in inherited and acquired cardiomyopathies to allow precision targeting of therapeutics, which will bring significant benefit to patients.
|
| 20/04/2021 |
£917,024 |
UNIVERSITY OF OXFORD |
Changing diets could lead to substantial benefits both in terms of health and environmental impact, with the urgent need to change food consumption being increasingly recognised. Drawing on evidence from interventions targeting unhealthy diets could accelerate progress towards more sustainable diets by quickly narrowing down the choice of interventions to improve food selections. However, we need to ascertain whether key differences between healthier vs. more sustainable foods (including social norms, preferences and knowledge) impact on intervention effectiveness, and/or contribute to inequalities in responsiveness to these interventions.
This programme of work will examine differences in the impact of interventions targeting (a) healthier vs. less healthy foods and (b) more vs. less sustainable foods, and whether impact differs by socioeconomic position (SEP). It will identify key moderators and mediators of the impact of interventions, and the extent to which these contribute to any differential impact by intervention target or SEP.
The programme comprises (1) a conceptual review; (2) experimental studies; (3) field studies in worksite cafeterias and in stores; (4) secondary analyses of purchasing data (e.g. from supermarkets). Identifying the moderators and mediators of dietary interventions will help prioritise the most promising interventions for sustainable and equitable diets.
|
| 20/04/2021 |
£580,111 |
BABRAHAM INSTITUTE |
The protein tyrosine phosphatases (PTPs) are important regulators of cell behaviour and function with kinases to control phosphotyrosine levels. Phosphatases are often seen as an off-switch in signalling, however several PTPs promote downstream signalling. The PTPs are known to be regulated by reactive oxygen species (ROS), which function as second messengers in numerous processes such as growth factor signalling and wound healing by targeting protein cysteine residues. After discovering direct substrates for a receptor-type PTP, we now find that its interactions with these proteins are surprisingly redox-sensitive. I hypothesise that PTPs function as redox-switchable scaffolds, promoting protein complex formation in response to ROS in cells. I will combine biochemistry, cell biology and optogenetic approaches with quantitative mass spectrometry to test this hypothesis. To this end, I will define the molecular details of a PTP redox complex, the signalling pathways that promote cellular PTP oxidation and the sufficiency of PTP oxidation to trigger cell signalling events. The results will shed light on a new signalling mechanism and could yield alternative approaches to therapeutically target the PTPs in numerous disease settings.
|
| 20/04/2021 |
£589,779 |
UNIVERSITY OF YORK |
Bacteria are highly adaptable and can rapidly exchange genes in response to environmental pressures. Gene transfer agents (GTAs) are an understudied mechanism of genetic exchange that package the entire bacterial genome into bacteriophage-like particles. Indeed, phenomenally high frequencies of GTA gene transfer have been reported in the natural environment. Indiscriminate transfer of genes could clearly have a major impact on bacterial evolution, fitness and antimicrobial resistance. Over the past decade, several pleiotropic regulators have been shown to indirectly influence GTA production and I recently discovered the missing link, GafA, that couples GTA production to host regulatory pathways. GafA homologues were found in numerous species and those homologues I tested also enhanced GTA production in their respective hosts. In this proposal I aim to define the mechanism of action for GafA in the model GTA host, including its interaction with the enigmatic RNA polymerase Omega subunit, and to explore the impact of GafA/GTAs in wider range of bacterial species. I will also study the relationship between GTA production and adaptive immunity to bacteriophage infection. Understanding the role and prevalence of GTAs is essential to assess their impact on issues such as AMR and novel interventions to slow its spread.
|
| 20/04/2021 |
£1,069,515 |
UNIVERSITY OF CAMBRIDGE |
Whipworms infect hundreds of millions of people causing trichuriasis, a major neglected disease. Whipworms are large metazoan parasites that inhabit a multi-intracellular niche within their host caecal epithelia, where they manipulate mucosal physiology and inflammation through interactions with the intestinal epithelial cells and stem cell niche. These interactions enable chronic infections where whipworms are tolerated for years; but at a mechanistic level, how they operate is not understood. My research aims to define these interactions and bring a mechanistic understanding to how they underpin whipworm invasion, colonisation and persistence in their mucosal niche. This work will build upon a novel model I developed using caecal organoids (termed caecaloids), the first to reproduce whipworm infections in vitro, to address two fundamental aims. First, to determine how whipworms invade and colonise intestinal epithelia using imaging and transcriptomic analyses of infected caecaloids. Second, to define how whipworms impact stem cell niche remodelling to promote their persistence using microscopy, FACS and transcriptomics of infected caecaloids and chronically-infected mice. This research will transform our understanding of the whipworm mucosal niche potentially yielding new targets for anti-parasitic therapies, and provide novel insights into how the intestinal epithelia repairs damage with relevant application toward intestinal inflammatory diseases.
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| 20/04/2021 |
£106,648 |
WELLCOME SANGER INSTITUTE |
Whipworms infect hundreds of millions of people causing trichuriasis, a major neglected disease. Whipworms are large metazoan parasites that inhabit a multi-intracellular niche within their host caecal epithelia, where they manipulate mucosal physiology and inflammation through interactions with the intestinal epithelial cells and stem cell niche. These interactions enable chronic infections where whipworms are tolerated for years; but at a mechanistic level, how they operate is not understood. My research aims to define these interactions and bring a mechanistic understanding to how they underpin whipworm invasion, colonisation and persistence in their mucosal niche. This work will build upon a novel model I developed using caecal organoids (termed caecaloids), the first to reproduce whipworm infections in vitro, to address two fundamental aims. First, to determine how whipworms invade and colonise intestinal epithelia using imaging and transcriptomic analyses of infected caecaloids. Second, to define how whipworms impact stem cell niche remodelling to promote their persistence using microscopy, FACS and transcriptomics of infected caecaloids and chronically-infected mice. This research will transform our understanding of the whipworm mucosal niche potentially yielding new targets for anti-parasitic therapies, and provide novel insights into how the intestinal epithelia repairs damage with relevant application toward intestinal inflammatory diseases.
|
| 20/04/2021 |
£691,880 |
UNIVERSITY OF GLASGOW |
The activity of viral entry machinery is tightly regulated to ensure successful infection. We have discovered that the hepatitis C virus entry glycoproteins, E1 and E2 (E1E2), possess a hitherto unrecognised regulatory mechanism that controls virus entry and neutralising antibody (nAb) resistance. This is dependent on disorder and dynamics in the peptide tail of E2. We call this the entropic safety catch.
This is important for three reasons: i) it is a significant advance in our understanding of the molecular mechanics of E1E2 ii) rational immunogen design remains hampered by a poor functional understanding of E1E2; our discovery may inform ongoing HCV vaccinology iii) it establishes that viruses can harness structural disorder to regulate virus entry, nAb resistance and protein-protein interactions.
We will ask how the entropic safety catch functions during infection; examining its adaptive tuning in response to emergent nAbs, and investigating its evolutionary origins. We will use biophysical and structural analysis to determine the molecular basis that allows the safety catch to control entry. This work will uncover fundamental mechanisms by which dynamics and disorder govern protein function. This will be relevant to HCV, and likely other important pathogens, having implications throughout the viral proteome and beyond.
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| 13/04/2021 |
£1,660,717 |
UNIVERSITY OF CAMBRIDGE |
Transmissible cancers are malignant somatic cell lineages that spread between individuals by the allogeneic transfer of living cancer cells. These cancers, whose three known instances in mammals affect dogs and Tasmanian devils, provide a unique perspective on cancer evolution and host interaction. I will investigate this by deeply sequencing whole genomes from 1100 tumours selected from across each cancer’s range, together with matched bulk RNA sequencing and targeted single-cell RNA sequencing. Time-resolved phylogenetic trees for each clone will be annotated with mutation and gene expression data, and the source and consequence of mutation explored. Host cell contribution to the tumour microenvironment, and its variation across hundreds of tumours, will be assessed using allelic and cell-type deconvolution. Combining genetic, microenvironment composition and clinical data, I will explain how the immunological interface between allogeneic cancer and host varies between individuals, and how this interaction controls the outcome of disease. The inherent heterogeneity and short lifespans of most cancers may obscure their underlying biological patterns. By capturing variation in hundreds of clonally derived tumours inhabiting different hosts, I seek to deeply probe the mutational, evolutionary and immunological principles of cancer.
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| 13/04/2021 |
£1,422,364 |
WELLCOME TRUST SANGER INSTITUTE |
Transmissible cancers are malignant somatic cell lineages that spread between individuals by the allogeneic transfer of living cancer cells. These cancers, whose three known instances in mammals affect dogs and Tasmanian devils, provide a unique perspective on cancer evolution and host interaction. I will investigate this by deeply sequencing whole genomes from 1100 tumours selected from across each cancer’s range, together with matched bulk RNA sequencing and targeted single-cell RNA sequencing. Time-resolved phylogenetic trees for each clone will be annotated with mutation and gene expression data, and the source and consequence of mutation explored. Host cell contribution to the tumour microenvironment, and its variation across hundreds of tumours, will be assessed using allelic and cell-type deconvolution. Combining genetic, microenvironment composition and clinical data, I will explain how the immunological interface between allogeneic cancer and host varies between individuals, and how this interaction controls the outcome of disease. The inherent heterogeneity and short lifespans of most cancers may obscure their underlying biological patterns. By capturing variation in hundreds of clonally derived tumours inhabiting different hosts, I seek to deeply probe the mutational, evolutionary and immunological principles of cancer.
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| 13/04/2021 |
£2,023,433 |
THE FRANCIS CRICK INSTITUTE |
How epigenetic pathways regulate development and disease remains a major question in human biology. A remarkable paradigm for understanding epigenetic mechanisms is X-chromosome inactivation, the silencing of one X chromosome in females (XX) that equalises X-dosage with males (XY). X-inactivation in eutherian (placental) mammals is mediated by the non-coding RNA (ncRNA) Xist. How Xist silences the X chromosome, and how expression of Xist is regulated, remain poorly understood. Marsupials diverged from eutherian (placental) mammals 160 million years ago, and exhibit distinctive developmental features that make them ideal for studying development and disease. Using our colony of opossums, we identified RSX and XSR, the marsupial equivalents of Xist and Tsix, providing a comparative system for understanding RNA-mediated chromatin remodelling. In this proposal, we will deploy the opossum model system to identify deeply conserved epigenetic mechanisms regulating mammalian X-inactivation and X-chromosome reactivation, and to elucidate how they interface with global epigenomic changes in the early embryo and germline. Our datasets will shed light on the evolution of mammalian lineage specification, pluripotency, imprinting and germline development. We will apply genome editing to marsupials for the first time, accelerating discovery in other research fields, including cancer biology, neurobiology and infectious disease.
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| 13/04/2021 |
£2,141,297 |
UNIVERSITY OF LEEDS |
Immune receptor turnover and subcellular localisation are regulated by attachment of ubiquitin, which controls receptor internalisation and endosomal-lysosomal degradation. Receptor ubiquitylation is fine-tuned by ubiquitin-processing enzymes, ligands and adaptor proteins, which regulate immune signalling output in a spatio-temporal manner. We identified a new signalling complex called BRISC, which is a deubiquitylase (DUB) and required for recycling of interferon and Toll-like receptors (TLRs). BRISC partners with adaptor proteins SHMT2 and EPS15 to regulate interferon and TLR signalling, although the role for each adaptor is unclear.
My laboratory uncovered a fascinating molecular mechanism by which vitamin B6 regulates BRISC activity, thus revealing a new example of metabolic control of immune signalling. Here, we aim to uncover how BRISC activity is controlled and directed to immune receptors. Using an integrated structural biology approach we aim to understand how BRISC partners with new adaptor proteins to perform its functions. Using BRISC-selective chemical probes in cell-based assays we aim to ascertain BRISC’s role in elevated inflammation in normal and disease conditions. These new tool compounds represent an exciting opportunity to better understand BRISC activity, receptor degradation and immune signalling functions, and how DUBs can be exploited as therapeutic targets for autoimmune diseases.
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| 13/04/2021 |
£1,378,334 |
UNIVERSITY OF LIVERPOOL |
Severe brain swelling leads to death in cerebral malaria (CM) but detection requires MRI. Almost no children with CM have access to MRI, therefore an alternative is required to identify patients for intervention. Optical coherence tomography (OCT) can detect raised intracranial pressure and ischaemic injury by imaging the optic nerve head, and retina respectively. We aim to study OCT as a method to identify patients at risk of death from brain swelling and disability from ischaemia; and to develop a low-cost OCT device with integrated AI image analysis.
We will conduct a controlled cohort study of 120 children with CM in Malawi to compare OCT to MRI in detecting severe brain swelling. We will follow them for a year with neuro-developmental assessments to investigate retinal OCT in predicting neurological deficits; and correlate retinal and cerebral atrophy. We will also assess OCT in quantifying raised intracranial pressure in non-malarial coma, and retinal haemorrhages for predicting worsening of brain swelling in CM.
We will use fibreoptic and micro-electromechanical advances to develop handheld OCT design and make a low-cost, robust device suitable for malaria-endemic settings. We will develop AI techniques to automatically segment and quantify optic nerve head swelling and intraretinal hyper-reflectivity (ischaemia).
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| 13/04/2021 |
£1,671,997 |
UNIVERSITY OF LIVERPOOL |
Invasive non-typhoidal Salmonella disease (iNTS) has emerged as a major killer in sub-Saharan Africa, responsible for ~500,000 deaths since 20091. The disease primarily affects people who are immunocompromised by HIV, malaria, anaemia or malnourishment2, and has a high case-fatality-rate (14.5%1).
In Africa, iNTS is caused by one clade of S.Typhimurium and two clades of S.Enteritidis3–5. Despite many decades of research on gene function and infection biology of Salmonella, the pathoadaptive mutations that have driven the emergence of African clades are unknown. Such knowledge is vital to decipher iNTS pathogenesis and develop control strategies in the future.
To address this knowledge gap, I will decipher the mechanisms that African and gastroenteritis-associated Salmonella employ to survive and replicate within a core niche, human phagocytic cells. I will achieve this using our powerful combination of comparative genomics and transcriptomics, plus new innovations in experimental evolution and genome-wide, high-throughput fitness assays.
By understanding the molecular basis of the intra-macrophage lifestyle, I will determine whether these neglected African-Salmonella pathovariants have used common or divergent approaches to combat the antibacterial properties of human cells.
My Research Question is:
How do African Salmonella pathovariants survive and replicate so effectively in human macrophages?
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| 13/04/2021 |
£1,871,095 |
UNIVERSITY COLLEGE LONDON |
The tight regulation of mitochondrial transport and anchoring in brain cells is essential for providing ATP at the correct spatial location to power neural function and computation, and for providing calcium buffering at sites of calcium entry or release. Using a multidisciplinary approach, combining imaging, biochemistry, electrophysiology and mouse transgenics we will determine the molecular and cellular mechanisms by which the cytoskeleton coordinates mitochondrial transport, localisation and remodelling in neurons and glial cells. The influence of this regulation on the development and maintenance of neuronal connectivity, function, plasticity and pathology will then be determined in vitro and in vivo. The main objectives are to define (i) the role of Miro proteins as central coordinators of the activity-dependent transport, positioning and remodelling of mitochondria through the microtubule, actin and septin cytoskeletons; (ii) how mitochondrial position and calcium buffering in neurons and glia impacts the formation, maintenance and plasticity of synapses; and (iii) the mechanisms by which disrupted mitochondrial dynamics lead to neuronal pathology and neurodegeneration. Our proposal will provide unique insight into how mitochondrial networks in neurons and astrocytes contribute to regulating the operation and plasticity of synapses and how their disruption leads to neuronal pathology in brain diseases.
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| 13/04/2021 |
£2,760,782 |
UNIVERSITY OF EDINBURGH |
All living systems – cells or organisms – operate in and must adapt to constantly changing environments. RNA transcription, processing and assembly with protein complexes form the core of the gene expression system, but many key features remain unclear. At times, very substantial changes take place; for example, in response to sudden environmental changes, following infection or during developmental progression. To address unresolved questions in RNA biology, we developed biochemical techniques to identify key, relevant RNA-protein, RNA-RNA and protein-protein interactions. These will be improved and applied in the proposed work, supported by bioinformatics. RNA systems are highly conserved in evolution, so techniques developed in yeast can be adapted for human cells and applied to understand disease. RNA biology in a cellular context is subject to dynamic changes. Kinetic analyses will therefore be applied, particularly during changes in cell state.
Specific topics:
1: How is the nascent RNA linked to transcription termination and RNA processing
2: How does RNA metabolism respond to environmental stress?
3: How is host RNA metabolism remodelled during Coronavirus infection?
4: What are the roles of ncRNAs in neuronal development?
The insights generated, and the experimental and bioinformatics techniques developed, will underpin future work by many groups.
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| 13/04/2021 |
£2,500,000 |
UNIVERSITY OF EDINBURGH |
The character of a cell is determined during differentiation by selective gene activation and silencing. In addition to high level decisions about which genes are on or off, it is now clear that levels of transcription in each differentiated cell must be precisely calibrated. This proposal seeks a comprehensive understanding of two proteins, SALL4 and MeCP2, that optimise transcription programmes in order to stabilise cellular states. Despite very different biological outputs, SALL4 and MeCP2 share striking similarities. Both are DNA binding proteins that recognise short, frequent DNA sequence motifs; both interact with histone deacetylase-containing corepressor complexes to modulate expression of many genes; and both are of proven biological and biomedical importance. Our intention is to study these proteins in parallel using a molecular genetic approach in order to elucidate fundamental mechanisms that consolidate cell identity before and after differentiation. To explore the generality of this form of transcriptional control, we will screen for novel transcription modulators that also interpret regionally variable genomic features by sensing short DNA sequence motifs. Our findings will have implications for regenerative medicine and reveal the molecular basis of diseases caused by deficiency of these and similar proteins, including Rett syndrome, Okihiro syndrome and cancer.
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| 13/04/2021 |
£2,904,144 |
UNIVERSITY OF OXFORD |
Substandard and falsified (SF) antimicrobials are a massive but underappreciated global health challenge in great need of innovative research to inform interventions. We will build on our collective pioneering research, to construct an innovative, multidisciplinary research hub that will improve understanding and inform global policy and action. Leading specialists investigating illegal wildlife trade, forensic genomics and chemistry, social network analysis and modelling, will work together to answer two main aims:
1. How can innovative forensic tools be used to identify sources and trade routes?
How can novel genomic (‘pharmabiome’), chemical and isotopic analysis with social network techniques be used to characterise the epidemiology of SF antimicrobials to inform policy and action to improve our global pharmaceutical supply quality? We will conduct high-throughput sequencing and novel chemical analysis of falsified and genuine antimicrobials to determine their comparative pharmabiome/chemical spectra, followed by social network analysis of origins and trade routes.
2. What are the public health impacts of SF antimicrobials?
What are the modelled impacts of SF antimicrobials on patient outcome, global public health, especially engendering antimicrobial resistance and how can these be minimised? Using a One Health approach, which pathogen-antimicrobial pairs are at greatest risk of SF antimicrobials?
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| 13/04/2021 |
£1,151,174 |
MRC LABORATORY OF MOLECULAR BIOLOGY |
Our cytosol could provide ample resources for invasive bacteria, yet is maintained in a remarkably sterile state. We recently discovered that cells deposit polyvalent protein arrays at bacterial surfaces to convert cytosol-invading bacteria into anti-bacterial signalling platforms. The deposition of M1-linked ubiquitin chains by the E3 ubiquitin ligase LUBAC recruits and activates IKK complexes, resulting in NF-kB signalling, while the deposition of guanylate-binding proteins (GBPs) recruits and is required for the LPS-dependent activation of Caspase-4, resulting in pyroptotic cell death and the release of IL-18. Here, we will explore this novel principle of cell-autonomous immunity to better understand cytosolic anti-bacterial defence.
We will therefore investigate
The origin and function of ubiquitin-dependent signalling platforms, with special emphasis on the ubiquitylation of bacterial lipopolysaccharide (LPS) by the E3 ubiquitin ligase RNF213, which represents the unprecedented ubiquitylation of a non-proteinaceous substrate
The origin and function of the GBP-dependent signalling platform, specifically its assembly mechanism and how it promotes activation of caspase-4 and other downstream effectors.
|
| 13/04/2021 |
£2,444,805 |
UNIVERSITY OF CAMBRIDGE |
Children with Still's disease, the paradigm of autoinflammation-cum-autoimmunity, are predisposed to developing a cytokine storm with excessive activation of T lymphocytes upon viral infection. Loss-of-function of FAMIN is the sole known cause for monogenic Still's disease. We de-orphaned FAMIN as an unprecedented purine nucleoside enzyme that combines ADA-, PNP- and MTAP-like activities with adenosine phosphorolysis – challenging fundamental principles of purine metabolism. Dendritic cells with absent FAMIN activity prime for excess antigen-specific cytotoxicity, IFNgamma secretion, and T cell expansion, resulting in exaggerated virus-specific T cell responses and immunopathology. Enhanced priming is already manifest with hypomorphic FAMIN-I254V, for which ~6.3% of mankind is homozygous, and which predisposes for Crohn's disease and leprosy. Here we will address FAMIN biology from virtually atomic to organismal resolution: We will explore how FAMIN operates in a cell, and how it controls energy metabolism, ascertaining redox and pH homeostasis. We will investigate how FAMIN in dendritic cells potently restrains T cell priming, and whether the FAMIN-coordinated biochemical mechanisms are involved in often fatal virus-induced cytokine release syndromes. This work will reveal an ancient biochemical mechanism that potently controls adaptive immune activation at a very fundamental level, providing insight into immunity to pathogens, autoinflammation and autoimmunity.
|
| 13/04/2021 |
£1,088,447 |
UNIVERSITY OF DUNDEE |
Protein phosphorylation regulates protein function in a switch-like manner. Although each phosphorylation site only exists in two states (on/off), the frequency of switching between these states can vary dramatically. Individual molecules that flash on and off rapidly can possess unique signalling properties, but these are difficult to study because dynamic information remains hidden from current analytical methods. We will use heavy-[18O2]-ATP and mass spectrometry to quantify, for the first time, the rate that individual substrates are phosphorylated and dephosphorylated over time. We will measure this globally and characterise different complexes during mitosis that rely on phosphorylation-dephosphorylation cycles to function correctly (BUBc/RepoMan/Centralspindlin/COMA). We will study how these cycles control signal-switching and protein binding-release events, which we predict are needed to order mitotic progression, generate gradients of activity and/or assemble protein complexes. These concepts will be tested with purified components, mathematical modelling and quantitative microscopy. Although we use mitosis as a model system, this work has far-reaching implications. If binary phosphorylation events generate more complex outputs by varying their on/off rates, then any pathway could use this property to transmit information differently. It is therefore crucial to investigate this phenomenon because these rates could be modulated to drive both signalling and disease.
|
| 13/04/2021 |
£2,337,836 |
UNIVERSITY OF LEICESTER |
Eukaryotic gene regulation depends upon a plethora of multi-protein complexes that both control the organisation of chromatin and establish specific patterns of post-translational modifications of histone tails. These histone marks are key to the processes of gene regulation. Deciphering the roles and mechanisms of the complexes that regulate chromatin is one of greatest challenges in understanding how genome activity is controlled.
We aim to understand the roles and mechanism of action of a family of essential, non-redundant histone deacetylase complexes that control chromatin accessibility across the genome. These HDAC complexes share a common catalytic engine, but contain very different accessory proteins and have diverse oligomeric states. Although these are essential complexes, conserved from nematodes to man, we have only a very limited understanding of their mechanism of action.
We will take two approaches to determine the mechanisms through which these complexes engage with their chromatin substrates and to understand how this determines their biological function.
We will use structural techniques to determine the architectures of three exemplar complexes in complex with chromatin. We will use genomic and proteomic techniques to explore how these structures mediate their distinct biological activities.
|
| 13/04/2021 |
£1,564,396 |
IMPERIAL COLLEGE LONDON |
The TPL-2/ABIN-2/NF-kappaB1 p105 complex is essential for transmitting Toll-like receptor (TLR) signals, turning on inflammatory responses via TPL-2 kinase activation of ERK1/2 and p38alpha MAP kinases. This proposal will investigate the roles in innate immunity of the newly discovered functions of the TPL-2 complex in stimulating phagosome maturation in macrophages independently of MAP kinase activation.
1) TPL-2 and ABIN-2 regulation of phagosome function in professional phagocytes.
Mechanisms of TPL-2 and ABIN-2 regulation of phagosome maturation in mouse and human macrophages will be established.
Roles of TPL-2 and ABIN-2 regulation of phagosome function in mouse neutrophils and dendritic cells will be investigated.
2) TPL-2 and ABIN-2 regulation of innate immune responses to pathogenic bacteria.
Roles of TPL-2 and ABIN-2 regulation of phagosome function in mouse immune responses to Staphylococcus aureus will be determined.
3) TPL-2 induction of phagosome maturation in inflammatory bowel disease (IBD).
The human MAP3K8 gene encoding TPL-2 is linked genetically to the development of IBD, an auto-inflammatory disease that involves an abnormal mucosal immune response to intestinal bacteria. The role of TPL-2 regulation of phagosome function in gut inflammation will be investigated, using human monocyte-derived macrophages from IBD patients/control individuals, and the Citrobacter rodentium mouse model of colitis.
|
| 13/04/2021 |
£1,182,524 |
MRC LABORATORY OF MOLECULAR BIOLOGY |
To sustain life, cells must first duplicate their genome and then segregate both copies into two daughter cells at division. This requires regulation. In eukaryotes, the timing of DNA replication, segregation and cytokinesis are coordinated by a cell cycle clock, which marks time through the rise and sudden fall in the activity of a conserved set of CDK-Cyclins. Interestingly, the archaeon Sulfolobus acidocaldarius possesses a cell division cycle like ours, with distinct phases of DNA replication and cell division separated by gap phases, while lacking obvious homologues of CDK-Cyclins. Since Sulfolobus and eukaryotes are thought to share a common ancestor ( > 1,000,000,000 years ago), and use similar machinery to fire origins and to complete cell abscission, this suggests that cell cycle regulation predates eukaryotes and the evolution of CDK-Cyclins. Building on our recent discoveries, in this proposal we aim to test this hypothesis by studying the role and regulation of proteasome-mediated protein degradation in resetting the Sulfolobus cell cycle. Through this work we expect to identify core common regulatory principles of cell cycle control and to identify cell cycle control machinery that has been conserved from archaea to eukaryotes - shedding new light on the origins of the eukaryotic cell cycle.
|
| 13/04/2021 |
£2,864,125 |
UNIVERSITY COLLEGE LONDON |
Higher cognitive functions by which we learn to understand our environment and behave flexibly within it rely on the construction, from sequential experience, of a coherent representation of our situation (aka an internal ‘model’ or ‘cognitive map’). I aim to understand the neural basis of his process via precise mathematical models that directly link low-level neuronal mechanisms to behaviour in prediction, planning, generalisation and memory. This project involves convergent computational and experimental work in mice and humans at the neuronal, systems and behavioural levels, using methods ranging from multi-photon imaging in mice, through virtual reality and neural-level electrophysiology in mice and epilepsy patients, to functional brain imaging in healthy volunteers. Three streams of work address the integration of sensory information and actions into a common representation, how representations of states structured by transitions allow path integration and prediction for planning, and how such representations interface with encoding and retrieval during memory. Success will provide a quantitative understanding of how neural activity in medial temporal, retrosplenial and medial prefrontal brain areas support these complex cognitive functions, and a starting point for relating cognitive symptoms to dysfunction of this neural system in conditions such as posttraumatic stress disorder, schizophrenia and Alzheimers disease.
|
| 13/04/2021 |
£3,118,574 |
UNIVERSITY OF OXFORD |
Rehabilitation after brain damage such as stroke depends in part on the brain’s ability to reorganise. It is therefore critical that we understand how brain plasticity after injury happens, and how it can be influenced.
Clinical gains with rehabilitative training should depend not only on gains made during practice but also on offline consolidation, particularly during sleep. Therefore, if we can identify modifiable processes of consolidation, and amplify those to boost consolidation, that would be predicted to improve outcomes.
Using rodent models to understand the mechanisms of offline consolidation, we will identify (1) modifiable electrophysiological signals (reactivation, slow waves, or sleep spindles) that occur with consolidation and (2) imaging read-outs of plasticity, including myelin plasticity, associated with successful consolidation. These will be taken forward into human studies to develop non-invasive closed-loop devices to manipulate functional processes of consolidation during sleep after stroke. This will pave the way for future trials to test whether low-cost interventions that boost consolidation and plasticity can deliver lasting clinical improvements.
|
| 13/04/2021 |
£1,854,976 |
BABRAHAM INSTITUTE |
Microglia are the main immunological cell of the brain. These residential cells possess both immunological and neurodevelopmental functions, and have pathological roles during age- and injury-associated dementia. We recently characterised a new addition to the neuroimmunological landscape: transiently-resident brain CD4 T cells. Brain T cells are required to trigger the post-natal differentiation of foetal microglia, licensing their neurodevelopmental functions. Much remains unknown about potential further interactions between brain CD4 T cells and microglia. We have adapted cutting-edge technology to enable the parallel study of brain CD4 T cells and microglia. First, will use an adapted flow-based ProCode approach to unravel the molecular control over CD4 T cell entry to the brain and acquisition of the residential phenotype. Second, we have developed a novel genetic tool for competitive chimeric analysis, allowing us to study microglia niche-sensing and the role of interaction with CD4 T cells on microgliosis. Third, we will single cell lineage tracing to dissect the clonal evolution of microglia, and the influence of CD4 T cell interaction on microglial clonal dominance during ageing and following traumatic brain injury. The results will generate new insight into neuroimmune inter-cellular dynamics, and will validate new tools with broad applicability to biomedical sciences.
|
| 13/04/2021 |
£2,030,820 |
KING'S COLLEGE LONDON |
We wish to define the key interferon (IFN)-stimulated gene (ISG) effectors for three pathogenic human viruses – HIV-1, SARS-CoV-2 and influenza virus – and understand the molecular basis for antiviral function. Specific ISGs will be identified in unbiased gene silencing (siRNA/ CRISPRi) screens, some of which we have developed. For HIV-1, we will initially focus on the antiviral mechanisms and post-transcriptional regulation of post-entry inhibitors we have identified, human-TRIM5alpha and MX2, including the central roles played by ubiquitination and phosphorylation. Our discovery that NCOA7 suppresses endocytic virus infection (e.g., SARS-CoV-2) provides the opportunity to study how the endolysosomal system can be dysregulated, potentially through altering vacuolar-ATPase activity. New screens for ISGs targeting SARS-CoV-2 or influenza virus will be undertaken using wild-type viruses as well as engineered strains carrying disruptions in candidate IFN- or ISG-antagonists. We will explore the molecular mechanisms and regulatory pathways used by the most potent ISGs using multiple complementary experimental approaches, including proteomic and approved drug screens, and determine how these viruses escape or survive ISG action. By understanding the ISG effectors that can control these viruses, we will gain fresh insights into viral replication strategies, disease processes and host immunity, and inform future antiviral therapeutic development.
|
| 13/04/2021 |
£1,604,303 |
UNIVERSITY OF OXFORD |
The theme of the proposed research is our understanding of the replication and assembly of Influenza virus, from a structural imaging perspective. The transcription and replication of the influenza virus genome occurs in the nucleus and the structure of the isolated polymerase reveals at a molecular level key steps in transcription and replication. The genome of Influenza virus is composed of 8 RNA segments each bound to the viral RNA polymerase and multiple copies of N protein to form ribonucleoprotein complexes (vRNPs). Newly replicated vRNPs are transported out of the nucleus, where they are trafficked to the cell membrane and assemble to form new viruses budding out from the cell membrane. How the production and assembly of RNPs is coordinated in the nucleus and the details of how the vRNPs are transported out of the nucleus to the cell membrane is unknown.
By integrating structural, biochemical and cellular imaging, I aim to understand with atomic-level detail, vRNP production, nuclear export and viral assembly. This will be done using crystallography and single particle cryo-EM, combined with high resolution cellular EM and X-ray tomography, correlated with cryo- fluorescence imaging of infected cells to understand these key stages in the viral cycle.
|
| 13/04/2021 |
£663,703 |
UNIVERSITY COLLEGE LONDON |
Mental health problems are a leading cause of ill-health, with 1 billion experiencing mental health or substance use disorders worldwide. In the UK, anxiety and depression contributed 8% of the years lived with disability in 2017 and are associated with the second largest costs to society after dementia. This morbidity is accompanied by substantial suicide mortality, which rose by 10.8% in 2018, with even faster rises amongst young people.
Socio-economic disadvantage is strongly associated with mental ill-health. Austerity and immigration policies (i.e. systemic "shocks") implemented in the UK since 2010 may have increased mental health problems, particularly in disadvantaged populations, including people from ethnic minority backgrounds and may have been further exacerbated by the COVID-19 pandemic. However, causal evidence is missing.
Data typically available to evaluate such issues are observational (without random allocation) and population-wide (without controls), biasing straightforward estimation of causal effects. To advance causal inference of systemic shocks (policies, COVID-19) on population health outcomes, we will develop a generalisable statistical framework to overcome biases inherent to observational data. We will then apply this to evaluate the cumulative long-term causal impact of these shocks on mental health outcomes using longitudinal and spatial data, with particular focus on ethnic inequalities.
|
| 13/04/2021 |
£3,100,312 |
QUEEN'S UNIVERSITY BELFAST |
The following will extend our previous successful trials on impact of vision care on children's education and adult productivity:
CLEVER (Cognitive Level Enhancement through Vision Exams and Refraction): The first randomized trial to assess impact of eye care delivery (near and distance spectacles) on reducing rates of cognitive decline with aging, enrolling 874 participants > = 60 years in Hyderabad, India.
Piloting and delivery of STABLE (Slashing Two-wheeled Accidents By Leveraging Eyecare): The first randomized trial on the impact of vision care (distance spectacles) on traffic safety in a lower-middle income country (Vietnam), involving 875 young myopic motorcycle users.
Piloting and delivery of THRIFT (Transforming Households with Refraction and Innovative Financial Technology): A randomized trial on the impact of free reading glasses to support use of smartphone banking apps in Bangladesh among 400 elderly recipients of government Old Age Allowance payments.
ZEAL (Zimbabwe Eyecare And Learning) formative research on hyperopia and educational outcomes in Zimbabwe: . This work involving 2000 school-aged children in order to prepare for an eventual randomized trial will assess a novel, low cost vision test we have designed to screen for hyperopia, while examining the impact of uncorrected hyperopia on children’s current reading levels.
|
| 13/04/2021 |
£1,963,217 |
UNIVERSITY OF CAMBRIDGE |
In cells from every domain of life, RNA acts to communicate hereditary information, to regulate gene expression, and to support network control. Therefore, the fates of diverse RNA molecules, their biogenesis and lifetime, play a critical role in determining complex cellular behaviour. We propose to investigate the processes that govern RNA fate in bacteria. We hypothesise that defined ribonucleoprotein complexes act in key steps of cellular control, including co-transcriptional ribonucleoprotein folding and surveillance of transcripts during translation. We will test this experimentally and will also seek to understand how such complexes might be linked to sensing and responding to cellular status, including metabolic remodelling.
To this end, we will study the structure and function of key RNA-processing complexes in model bacterial species. Our targets include both stable protein-RNA complexes, which will be isolated and examined by high-resolution structural and functional analysis, and more transient assemblies, which will need to be investigated inside the cells to capture their information-rich physiological states. Our work will help to elaborate rules that define the lifetime and biological impact of RNA and its contribution to complex cellular phenotypes, including infectious virulence and antibiotic resistance of various bacterial species.
|
| 13/04/2021 |
£2,035,864 |
UNIVERSITY OF OXFORD |
This research project aims to define the key roles of newly defined T cell subsets, and how they integrate signals between innate and adaptive immune responses to optimise host defence. Recent work on immune responses in human tissues has revealed the complex landscape of immunity and emphasised the role of poorly-defined unconventional T cell subsets. In the past 5 years my lab has defined some of these roles including 3 main findings - a striking sensitivity to innate cues, relevant for initiation of protective responses to viruses, a wide palette of functions including a role for barrier repair, and the ability to co-ordinate adaptive responses following experimental vaccination. In this application I aim to take these findings much further, harnessing a set of novel tools and aiming: 1) To define the mechanisms underpinning the link between MAIT cells (as a paradigm for innate-like T cells) and vaccine responsiveness; 2) To understand the mechanisms by which such cells may impact on outcomes of severe viral infection. Overall this work is highly relevant to major health challenges such as SARS-CoV-2, influenza, viral hepatitis and microbial infection - and to the vaccines needed to combat these challenges.
|
| 04/04/2021 |
£7,645,274 |
UNIVERSITY OF EDINBURGH |
ECAT-I (Edinburgh Clinical Academic Track – Inclusive) will build on the research excellence and mentorship developed during the successful ECAT Wellcome Clinical PhD programmes.
Our key aims are to recruit and retain healthcare professionals from diverse backgrounds, to foster research that is inclusive, innovative and imaginative and to support a positive research culture. We will extend the scope of the programme to include our world-leading expertise in social science, health data science and informatics and provide trainees with new opportunities for international collaboration. We propose to:
Provide excellent doctoral training and post-doctoral support to an inclusive and diverse cadre of researchers across a range of healthcare professions, from hospital and community-based clinicians to allied healthcare professionals.
Build a positive research culture in and around our ECAT trainees promoting creativity, inclusivity and integrity.
Support trainees through the challenges of maintaining research momentum post-PhD and continue to take a highly pro-active and targeted mentorship approach, promoting clinical academic career progression of ECAT lecturers to Career Development Fellowships or substantive academic posts.
Extend our scientific ambition and align it to the research needs of diverse health professions building capacity in social science, data science and informatics and fostering international partnerships.
|
| 04/04/2021 |
£7,454,880 |
UNIVERSITY OF MANCHESTER |
Our programme will deliver excellent doctoral training for all healthcare professions. We are building a comprehensive inter-disciplinary programme across biomedical discovery and experimental medicine, reaching into our leading skills in physical sciences, engineering and computational/data science.
We have fully refreshed our partnership across the Universities of Leeds, Manchester, Newcastle and Sheffield; seven out of eight new directors are new. We have forged fresh partnership with the Alan Turing Institute, integrated our comprehensive ties with industry, and deepened our links to the Francis Crick Institute. We have coalesced features that define our best research culture and developed a thoughtful approach to equality, diversity and inclusion to ensure we capture talent, regardless of background or profession. The training will be valuable to fellows, supervisors and directors alike and set best-practice that will permeate our partner organisations. We are particularly proud of a new initiative with the Nuffield Foundation/STEM Learning to host 16-19 year olds as part of widening participation in higher education and scientific research.
This programme is important to us. We need a research-intensive workforce trained to the highest standards equipped to innovate for a surrounding population with some of the greatest health needs and reduced life expectancy in the UK.
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| 04/04/2021 |
£7,390,835 |
UNIVERSITY OF LEICESTER |
Leicestershire’s social and demographic features, including the highest proportion of non-white residents (55%) in the UK, provide a unique and important opportunity to address key health issues across an ethnically and culturally diverse population, recently amplified by the pandemic.
We will capitalise on our strong track record of supporting clinical academics, with a focus on nurses, midwifes and allied health professionals, to grow the multidisciplinary research base in the inclusive management of long term conditions across healthcare systems and academic partners. Projects will focus on research-practice gaps in our areas of our research expertise to holistically improve patient care. Integration of basic scientists, social scientists, clinical academics, clinicians and data scientists to develop collaborative and strategic research programmes, combined with an outstanding training environment will provide an intellectually stimulating, methodologically rigorous and supportive environment for PhD fellows.
We will establish a sustainable integrated framework for healthcare professional academic career pathways to build capacity in clinical research leadership and create an inclusive research culture. Formal evaluation will ensure sustainability and best practice sharing. The long term goal is to increase the visibility and breadth of healthcare professional researchers and to transform holistic patient clinical care addressing health inequalities.
|
| 04/04/2021 |
£7,247,676 |
UNIVERSITY OF NOTTINGHAM |
This unique partnership between four Midlands-based universities (and regional NHS Trusts) builds an innovative multidisciplinary doctoral training centre for healthcare professionals focussing on Mental Health & Neurosciences (MH & N), which will foster a progressive and dynamic inclusive research culture to support and develop 25 outstanding PhD scholars.
Our holistic approach ensures that scholars’ needs are central to a supervisory system, supporting their research skills and career development, while ensuring wellbeing and quality of life. Every multidisciplinary cohort will have multiple opportunities to meet professionally and socially for peer support and companionship during their PhD.
Scholars can choose to research a ‘theme’ representing the lifespan (children, young people and perinatal MH; common MH; severe MH; dementia; and physical health comorbidity with MH), using specific bio-psycho-social ‘approaches’. Profession-specific mentors will ensure scholars remain connected to their primary professional groups. Scholars will leave our programme as well-rounded clinical-academics with high-levels of MH & N research acumen, and enhanced communication and leadership skills.
Ultimately, we aim to:
(1) develop the next generation of multidisciplinary clinical academics in MH & N
(2) conduct and disseminate world-leading research
(3) create and sustain an ambitious Midlands-based, internationally connected, compassionate clinical-academic ecosystem, collaborating to address the key contemporary mental health challenges.
|
| 04/04/2021 |
£9,285,942 |
UNIVERSITY OF LIVERPOOL |
This programme will deliver high quality, bespoke doctoral training for 20 clinical scientists across multiple scientific disciplines to address health priorities in the Global South. Through careful selection, high quality supervision and training, and access to excellent facilities in both the UK and globally, we will develop a cohort of trainees highly skilled at implementing research in Low and Middle Income Countries (LMICs).
Building on 13 years of successful PhD programme delivery for medical doctors and, more recently, veterinarians, we will broaden the programme to include clinical specialties for which we have established supervisory capacity and research excellence. We will provide new avenues in Global Health training opportunities for midwifes, with expansion to other clinical professions as demand and support develops. The programme will be supported by strong doctoral training frameworks in place at University of Liverpool & Liverpool School of Tropical Medicine. Equality, diversity and inclusivity will be embedded at all points of the programme consistent with the practice of the two institutions.
Success will be measured by progression of fellows into academic positions and Fellowships during and after completion of clinical training and their subsequent emergence as independent research leaders addressing health priorities in LMICs.
|
| 04/04/2021 |
£8,724,456 |
QUEEN MARY UNIVERSITY OF LONDON |
This doctoral programme for Primary Care Clinicians aims to increase research capacity across contemporary primary care to create future research leaders who will develop innovative and evidence based practice and policy to improve population health and support the NHS. Five clinical PhDs per year for five years (in total approximately 18 GPs and 7 other primary health care clinicians) will be hosted across 10 NIHR School for Primary Care (SPCR) members, building on our successful previous Wellcome PhD programme. The NIHR SPCR represents the leading departments of academic primary care in England and provides extraordinary critical mass enabling a broad and inclusive supervisory pool, access to databases, international expertise and bespoke training. Doctoral students will have supervisors across two consortium members and will join 45 NIHR SPCR doctoral students appointed from 2021-2026 to form a supportive cohort of peers who have the opportunity for regular contact at training meetings and our very successful Annual Trainees Event. Equality and diversity are core values underpinning the Programme which promotes the development of networking and collaboration, builds strong and experienced research groups and provides a rich, supportive research environment for doctoral students to develop into successful clinical academics and future research leaders.
|
| 04/04/2021 |
£8,323,636 |
QUEEN MARY UNIVERSITY OF LONDON |
Underrepresentation of patient groups and diseases in research is both a cause and a consequence of health inequality. People may be underserved by healthcare and underrepresented in research due to 1) social inequalities related to demographic and protected characteristics, 2) marginalisation related to socioeconomic, lifestyle or legal factors, or 3) health status e.g. mental health, or rare diseases. Disease mechanisms, phenotyping and novel therapeutics are often studied in homogeneous populations with chronic underrepresention of certain groups. If studies fail to include these groups, outputs will be less accurate, relevant or effective in underrepresented populations, thereby exacerbating health inequalities.
To tackle these problems and redress these inequalities we will support fellows’ individual and specific training needs so that they are more able to manage career transitions and have the confidence to apply their imagination to bold research with populations and in diseases that will benefit the most from their efforts. This DTP will:
Recruit the best and most motivated fellows from a diverse range of applicants into a progressive research culture environment.
Conduct world-class research with underrepresented populations supported by specific training
Tackle barriers to Academic Transitions:
(optional) Pre-Doctoral Training Phase
Bespoke Career Development Programme
Post-Doctoral Support Phase
|
| 04/04/2021 |
£8,568,661 |
UNIVERSITY OF GLASGOW |
This Programme will address the substantial challenges posed by increasing multimorbidity. Hosted in the Scottish societal context, where multimorbidity is a significant health concern, but examining globally relevant problems, it will create a generation of innovative world-class researchers empowered to find ways to prevent multimorbidity, discover pathways tractable to novel intervention, and optimise management. We will achieve this through PhD projects designed to build synergistic, multidisciplinary collaborations across participating institutions, promoting new thinking on this complex topic.
Fellows will be recruited from a range of clinical/health professional backgrounds and experience the mentorship/skills training and support that will enable them to become future research leaders and make transformative contributions to multimorbidity and its clinical management internationally. We will promote intellectual curiosity, scientific rigour, peer learning, research integrity, translation into practice, public engagement and the principles of equality and diversity while imparting cutting-edge analytical skills. Underpinned by the track-records and resources of the Universities of Glasgow, Edinburgh, Dundee, and St Andrews, we will offer exceptional opportunities for clinical research across the translational spectrum from examining aetiology and mechanisms, through data science and epidemiology, to applied clinical research in a unique collaborative training environment, promoting development of a critical mass of multimorbidity researchers.
|
| 04/04/2021 |
£7,679,110 |
UNIVERSITY OF CAMBRIDGE |
The aim of the programme is to train the next generation of healthcare professional researchers and future research leaders, addressing challenges to health. The Universities of Cambridge and East Anglia in partnership with the Wellcome Sanger Institute will offer healthcare professionals of outstanding calibre unrivalled opportunities for research training spanning basic science, translational medicine, interdisciplinary and applied health research in an environment which represents the largest concentration of biomedical research in Europe. We will offer pre-doctoral research placements and training as part of our drive to widen participation and support fellows to make informed choices of research and supervisor. Strong, ongoing, mentorship is central to our programme and we will actively foster a vibrant, positive and inclusive research culture. During their PhDs, in addition to acquisition of research skills, making significant discoveries and achieving a doctorate, we will empower fellows with bespoke training & development and support supervisors and mentors, to ensure a successful research experience. Postdoctorally, we will guide fellows, tailored to their individual progress, to make the transition into higher research fellowships and clinical pathways, enabling ongoing training with continuance of research momentum.
|
| 04/04/2021 |
£7,096,279 |
UNIVERSITY OF BRISTOL |
Building on our Wellcome-funded Clinical Academic Training Programme (GW4-CAT) that uniquely supports Medical, Dental and Veterinary professionals; we will deliver a scheme that combines world class PhD training with exit to mentored post-doctoral positions with protected research time, open to all health professions (GW4-CAT-HP). Capitalising on the world class facilities and absolute commitment of the universities of Bath, Bristol, Cardiff and Exeter (Great Western 4 - GW4), and our partner NHS Boards and Trusts and Vet School, our objectives for GW4-CAT-HP are to:
Recruit talented Fellows from diverse disciplines and clinical specialties, supporting them to make bold choices by accessing the wide range of world-class cutting-edge research environments across GW4 where they will be stretched intellectually and practically.
Foster a positive and inclusive research culture, through robust equality, diversity and inclusion (EDI) practice and enabling the highest standards of research integrity through support and formal training.
Ensure, through bespoke and structured long-term support and mentoring, that all our Fellows secure externally funded post-doctoral support and linked clinical academic posts provided in partnership with our NHS Trusts, Boards and Vet School, to achieve research independence and retain excellent researchers in clinical academia.
|
| 04/04/2021 |
£11,877,508 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
Our goal is to implement a transformative global health research programme that nurtures a new generation of diverse researchers addressing existing and emerging health challenges in Africa, by working across professional and research disciplines, with equity as a core value. Our partnership between five UK universities (UKIs) and six leading African research organisations is well-placed to provide the facilities, skills, mentorship and networks they need to become future leaders in equitable global health research. Our consortium includes world leaders in our proposed research themes, including infectious diseases; maternal, child and adolescent health; non-communicable diseases; and mental health. The UKIs will support matched PhD students from our African partner organisations to create a blended south-north cohort, providing a networked community of Fellows with transcultural experience, and a diverse learning and research environment.
Fellows will conduct their research at one of our African partner organisations. Each fellow will have two co-supervisors (one based in Africa), and will have access to online courses and educational activities at the UKIs, research support activities run by our partner organisations, and a mentorship programme. We will establish a Digital Global Health Academy to provide researcher development, and to foster an enabling and equitable research culture.
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| 04/04/2021 |
£7,831,772 |
KING'S COLLEGE LONDON |
We will train the next generation of clinical academics in mental health research in a richly interdisciplinary training environment. The programme will include doctors, nurses, clinical psychologists and allied healthcare practitioners who will take training fellowships across a diverse range of topics relevant to mental health science. For mental health science to flourish we need to encourage clinicians both from within and outside disciplines traditionally involved in mental health, and to encourage collaboration with non-clinical academics with technical and scientific skills often absent from traditional PhD programmes in mental health. Supervisory teams will always combine clinical and non-clinical academics. Three programmes of research will be available, representing emerging opportunities in mental health science: (1) translational neuroscience, (2) digital mental health and (3) social science and policy. Fellows will be trained in key topics to equip them to negotiate their future careers with an emphasis on generating impactful research. The training will enhance a culture which values diversity and inclusion, open and reproducible science and the critical importance of patient and public voices in research.
|
| 31/03/2021 |
£9,960 |
AFRICAN POPULATION & HEALTH RESEARCH CENTRE, KENYA |
Critical to realizing APHRC’s vision of transforming lives in Africa through research is public engagement with research and health concepts. We are submitting this Development Grant to facilitate the preparation of the Transformation pilot grant for which the team has been invited to apply. During the development, a mix of senior and junior staff from APHRC will work with expert consultants and engage stakeholders in the area of Global Heating and its impact on Health to develop the plan for fellowship support and training program for The Global Heating and Health Public Engagement Programme (G2H-PEP). The pilot of this Leadership Transformation Programme will produce a cohort of fellows who will have an extended network of contacts working on public engagement, and will have gained leadership skills and tools to ensure their wellbeing and resilience while developing as leaders in a living system. The overall objective of the program will be to produce a network of public engagement fellows interested in global heating and its health impacts. The co-design process will ensure that the pilot cohort goes through a relevant training program and receives the support necessary for meaningful engagement with the public.
|
| 31/03/2021 |
£10,000 |
DALBERG GLOBAL DEVELOPMENT ADVISORS LIMITED |
This proposal is to help develop an initial proof of concept of the Transformation Programme pilot for public engagement leaders. We propose working for ~4 weeks to help refine and build out what this proof of concept would look like - specifically as it relates to the flow, curriculum and approach of the pilot programme.
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| 31/03/2021 |
£139,270 |
BRUEGEL |
A high-level panel, led by co-chairs Tharman Shanmugaratnam, Lawrence H. Summers and Ngozi Okonjo-Iweala, has been mandated by the Italian presidency of the G20 to propose reforms and other measures that will lead to more reliable and sustainable financing of pandemic prevention, preparedness, and response. To support the deliberations and decision-making of the panel, Bruegel and CGD will establish a team to lead the analysis and content development of the proposals. The work of the project team and the panel is aimed at eliciting concrete and cooperative action by the G20 finance ministers. The team will develop an outline for the final report of the panel for discussion and feedback with the co-Chairs. Furthermore, the team will carry out three background analyses that will enable the informed discussion and brainstorming among panel members and the development of financing proposals: i/ landscaping current financing and issues, existing asks and proposals, ii/ landscaping current financing and issues, existing asks and proposals and iii/ governance, organization, and incentives. Reflecting the panel’s views as well as the teams’ own analyses, a draft and then final report will be developed building on the initial outline and the background analyses and consultations.
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| 31/03/2021 |
£166,200 |
ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE |
Snakebite is a strategic priority for RSTMH given its high levels of death and disability. Although there has been an increase in research funding recently, there is still an unmet need to encourage junior researchers to undertake a career in snakebite research. The RSTMH Small Grants Programme is a unique grant funding programme open to early career researchers from anywhere in the world that aims to fill a gap in the research career pathway. RSTMH grants are for up to £5,000 to those early in their careers (e.g. researchers, healthcare professionals, NGO workers, health economists, social scientists) who are working in a field relevant to tropical medicine or global health. These grants typically represent the first time someone has received funding in their own name and helps develop their research and management skills.
In 2020, Wellcome piloted a partnership with RSMTH to fund 10 grants in snakebite research. With Wellcome funding, RSTMH awarded grants to African, Asian, South American and European nationals across various snakebite research areas. Following on from the success of the pilot, RSTMH is seeking funding for a 3-year partnership with Wellcome to fund 10 projects per year and up to 30 in total in snakebite research.
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| 31/03/2021 |
£46,492 |
SOCIAL GOOD FUND |
Climate change presents a unique and urgent threat to planetary health. Compounded by the COVID19 pandemic, we face a very real risk of losing 50 years of global development, exacerbating health, economic, and social inequities.
COP26 will provide a special opportunity for global leaders to set a course for a healthy and green recovery.
Informed voices from across the globe are crucial in driving decision makers to deliver ambitious climate action. Health workers are among society's most trusted and respected professionals, and the health case for climate action is powerful, offering millions of lives saved through reduced non-communicable diseases, health resilience, and adaptation, and fully offsetting the costs of mitigation through health cost savings.
Wellcome Trust funding will enable the Global Climate Health Alliance (GCHA) to amplify the voices of medical and other health professionals globally, including those in low and middle income countries (LMIC) which have been underrepresented in the international climate conversation, on the massive health opportunities of climate action.
We will build capacity, link new voices to media advocacy opportunities, and disseminate Wellcome coalition asks through our global networks, thereby influencing climate action at the national and international level in the run up to COP.
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| 31/03/2021 |
£49,936 |
STOPAIDS |
Action for Global Health (AfGH) and Students for Global Health (SfGH) in partnership aim to increase our respective health networks' (reaching more than 50 organisations), and members' (in 34 student branches) contribution to a shared climate and health agenda through capacity building, mobilising, and increasing collaboration between key stakeholders (our members, partners and other actors) and supporting synthesised advocacy and campaign events in the lead up to COP26. In particular we will focus on increasing access to engagement with youth, global south and NMIC stakeholders on the intersection of health and climate.
We will partner to work with the 'Climate Change Coalition' to activate and engage cross sectoral partners including global south, LMIC and youth organisations around a shared policy agenda and build support for sustainable health and climate change strategies leading up to G7 and COP26. We will actively participate in the climate coalition and build our and other actors' resources to activate and mobilise support for health and climate. We will draw on the breadth and strength of our members collective experience and expertise to actively engage with and broaden understanding of the intersection between health and climate.
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| 31/03/2021 |
£16,000 |
OPEN RESEARCH CENTRAL |
The open access movement has demonstrated that "openness" is a benefit to the creation, dissemination, and reuse of knowledge. Through a variety of policies and initiatives, there is renewed momentum for sharing research outputs as part of a more connected and collaborative open research ecosystem. However, there remains a need for consensus around how best to deliver a research dissemination system that maximises the benefits for both science and society, and the researchers upon which such a system depends.
Open Research Central (ORC) is a not-for-profit organization that aims to change the paradigm for primary research dissemination by bringing together key representatives across the scholarly ecosystem to define standards, build a movement to expand adoption of these standards, encourage the community to provide researchers with services that meet these standards and promote these standards.
To build further momentum and adoption globally of open research publishing approaches, the ORC Board wish to secure resource for 18 months to underpin more significant fund raising efforts to enable ORC to deliver on its mission, to develop and start to put into place a sustainability plan, and to support the Board in the day-to-day running and management of ORC.
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| 31/03/2021 |
£146,002 |
CENTER FOR GLOBAL DEVELOPMENT |
A new high-level panel, led by co-chairs Tharman Shanmugaratnam and Lawrence H. Summers, has been mandated by the Italian presidency of the G20 to propose reforms and other measures that will lead to more reliable and sustainable financing of pandemic prevention, preparedness, and response. To support the panel's deliberations and decision-making, CGD and Bruegel propose establishing a team to lead the analysis and content development of the proposals, with logistical, outreach, engagement, and coordination support from a secretariat at Wellcome and the US National Academies of Medicine. The team will develop a short scoping note on the economic rationale behind prioritizing public investment in prevention, preparedness, and response, an outline of the final report for discussion and feedback from the co-chairs, background analyses (on landscaping current financing and issues, existing asks and proposals; setting a financing goal and assessing its value for money; and governance, organization, and incentives), a long list of 10-15 proposals for governance reform and/or new or existing financing sources and mechanisms (with pros and cons for the panel's consideration), and a final report reflecting the panel’s views and the teams’ own analyses.
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| 31/03/2021 |
£236,035 |
UTAH FILM CENTER |
"THE ARM RACE: HOW WE CONQUERED COVID" (working title) is a documentary film that will be the dispositive chronicle of the global race to research, develop, manufacture and distribute COVID-19 vaccines in the most enormous coordinated effort ever undertaken. In this unprecedented moment in history, the film will celebrate the herculean efforts of the scientific, research and immunization community during a complex time of mistrust, vaccine hesitancy, and misinformation - when trust in science itself has come under fire.
The stories track development of vaccines, (including research built on previous work fighting outbreaks including Ebola and HIV/AIDS,) and how public health agencies from hospitals to the WHO are responding to the crisis. Our narrative goes beyond the lab, delving into the complexities of underserved populations, equitable access and inclusion. We see opportunities in additional content, leveraging existing assets, foregrounding the making of the film and our collaboration with the global public health community. This project will spark interest in science’s potential to solve global health challenges by documenting the largest public health effort in human history, while also offering insights into our successes and failures to help prepare the next generation to better respond to future pandemics.
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| 31/03/2021 |
£910,964 |
P1VITAL PRODUCTS LTD |
Intensive care unit (ICU) staff face repeated exposure to traumatic work-related events and have reported high levels of posttraumatic symptoms during the pandemic. Novel, scalable and preventative interventions are required.
We are developing a "cognitive vaccine" approach for ICU staff against one key symptom – intrusive memories of traumatic events. These are unwanted, distressing and disrupt functioning.
Our novel, brief gameplay intervention is repeatable, flexible, non-stigmatising, scalable, and driven by mental health science.
This digital intervention is guided by an initial session of psychologist support, then self-administered; delivered same day or months post-trauma, suitable for repeated trauma exposure, fits with busy lives of ICU staff, without discussing trauma detail.
Part 1 uses a Bayesian design to optimise and co-develop procedures with ICU professionals and move at speed under pandemic conditions, allowing limited rollout (guided-version) in these unprecedented times.
Part 2 uses a pragmatic RCT (three arms: guided/non-guided/attention-control) testing clinical effectiveness and acceptability to inform clinical practice. If the non-guided intervention is effective (i.e. no psychologist support) it will accelerate the speed of rollout.
Meanwhile through global mental health workshops with stakeholder communities we seek to understand the views of various communities worldwide regarding implementation of this novel intervention form.
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| 31/03/2021 |
£150,000 |
SAVE THE CHILDREN |
In the 2020 Spending Review HMG signaled its intent to renege on a manifesto commitment and cut ODA form 0.7 to 0.5% of GNI (on top of the budget cut that happened automatically due to economic contraction). To do this, HMG wishes to repeal the relevant in coming months.
Work to sustain the Government’s support for ODA is already delivering results with an increasingly credible threat of a government rebellion and sustained media interest. However, increasingly our political intel says we may be at risk of winning the vote and losing the argument. Put simply, ‘hard whipping’ of a rebellion, combined with some horse-trading between different groups, might be enough to carry a vote but it won’t stop the debate flaring back up. This grant would allow us to scale the emergency effort around the legislation while also creating a more enabling environment for the longer team:
by bolstering our public affairs capability in Qs 1/ 2,
by expanding our local organising effort to an additional ten constituencies from Q1-4 and
by expanding our comms plans from Q1-4.
A key part of this partnership would be Wellcome’s inclusion in regular political updates, intel and learning sessions.
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| 31/03/2021 |
£79,188 |
UNIVERSITY OF TORONTO |
Checklists are simple tools that are often used to promote safety in clinical applications, because they can easily be integrated into a clinical workflow deployment without the need for extensive training or additional technology. Currently, machine learning in health focuses on large, complex deep neural networks. In comparison with deep neural networks, checklists are far easier to use, understand, and scrutinize. In practice, checklists are difficult to develop, and the vast majority of real-world checklists are hand-crafted by panels of experts.
Given the widespread integration of electronic health data over the past decade, our goal is to learn checklists from data for clinical tasks. The main application of our method, in partnership with Dr. Leo Celi at Beth Israel Deaconess Medical Center (BIDMC) in Boston, is to predict mortality in patients eligible for Continuous Renal Replacement Therapy (CRRT).
A generated checklist for CRRT is clinically desirable in the intensive care unit as a mechanism to trigger a multidisciplinary discussion with the patient’s family, to consider the value of the treatment weighed against the physical burden and cost. Thus we include operational considerations such as number of items in the checklist, the false negative/positive rate tradeoff, and fairness across protected groups.
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| 31/03/2021 |
£1,464,291 |
DRUGS FOR NEGLECTED DISEASES INITIATIVE |
Through the rapid establishment of a translational pathway, DNDi and its partners aim at providing the next generation of candidate medicines for SARS-CoV-2 clinical trials as well as integrating back-translations to validate the most appropriate preclinical models. The project is planned to run from September 2020-December 2021, with a total budget of 1.97M GBP, split into three pillars of activities composed of short and medium- term deliverables:
Pillar 1 : Selection of the best combination of repurposed antiviral drugs to include into the 3rd arm of the ANTICOV clinical trial and the next back-ups
Pillar 2 : Support candidate progression through an integrated pharmacometrics package involving both Physiologically-Based Pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) modelling approaches
Pillar 3 : Development of a translational platform and performance of a comparative analysis of selected drugs/combinations (including those from Pillar 1) to better understand and refine the screening cascade with best translational value; definition of a Target Candidate Profile (TCP) for SARS-CoV-2 mild infection
This project will cement a collaborative partnership in the SARS-CoV-2 translational space that will pave the way to future longer-term discovery projects and preparedness for additional future threats.
Key words: COVID-19 / Drug re-purposing / Translational drug development pathway
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| 31/03/2021 |
£303,984 |
MILKEN INSTITUTE |
In partnership with the Wellcome Trust, the Milken Institute's FasterCures and the Financial Innovations Lab program will examine ways to engage, accelerate or modify existing models or design new models that can support the development and commercialization of new antibiotics. The project will look to thoroughly vet the barriers and incentives for implementing a more sustainable system, focusing on identifying fund models and financing mechanisms that are applicable across disease areas and markets. The Lab will utilize the Milken Institute’s network and expertise to thoroughly vet funding models to ensure they are operational and provide a platform towards implementation.
Using the Lab’s signature model, the project will: 1) complete independent research and stakeholder interviews on the nuances of the issue area to complete a landscape analyses; 2) host a moderated, in-person roundtable with interdisciplinary leaders, including non-governmental organizations, researchers, policymakers, investors, financial institutions, academics, and industry experts to generate market-based solutions, and 3) produce a summary report on the findings of the roundtable, including policy recommendations and models for financial incentives. By leveraging a diverse pool of knowledge, the Lab will develop solutions to help fund and expedite new, innovative ways of funding new antibiotic development and commercialization.
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| 31/03/2021 |
£3,446,620 |
MASSACHUSETTS INSTITUTE OF TECHNOLOGY |
The goal of this proposal is to develop, implement, and evaluate machine learning algorithms for trustworthy clinical AI. The proposed technology aims to support a wide range of healthcare
applications, including diagnostics, treatment personalization, and prediction of treatment outcomes. These applications utilize diverse sources of data, including clinical notes, images, and test results. Rather than designing a disease/application-specific AI algorithm, we are interested in developing a capacity that can be readily embedded into existing AI models to improve their transparency and ability to incorporate human feedback as well as strengthen their data privacy guarantees. The Jameel Clinic team has deployed AI tools in many clinical areas. These tools would be our testing ground for measuring the effectiveness and flexibility of the proposed platform.
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| 31/03/2021 |
£340,531 |
UNIVERSITY OF OXFORD |
By bringing GOARN Research and ISARIC partners together in the LMIC setting during COVID-19 we hope to strengthen the clinical, social science and operational research response.
Aim: to support the roll out of the ISARIC WHO natural history protocol (known as the Clinical Characterisation Protocol - CCP) across LMICs:
Overarching goals:
Support the roll out/uptake of the CCP across 5 countries per region, where feasible* (across four ISARIC regions of S America, Africa, S Asia & SE Asia).
Support the set up and running of local dynamic clinical data dashboards in at least 10 sites per ISARIC region
Share the aggregate data with WHO to assist with providing a global picture on the incidence and presentation of moderate to severe cases across a representation of the LMICs to inform clinical management and public health planning and control.
Support the establishment of follow up modules and programmes for discharged hospitalised cases in 5 sites per region to evaluate longer term health impacts of COVID-19 on individual, health services and society to inform prevention and care planning.
*Brazil are in an intense first wave and reaching out to another 4 S. American countries would be challenging at the time of writing.
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| 31/03/2021 |
£1,335,301 |
NATIONAL UNIVERSITY OF SINGAPORE |
Drug-resistant infections (DRIs) have recently been recognised as a major challenge by the G20 and the UN General Assembly, with a disproportionate impact on the people of Asia. Potential solutions will require multidisciplinary and multi-country collaboration in order to successfully address in terms of innovative discoveries, implementation of policies and roll-out and evaluation of the best evidence based clinical practices.
The current model of clinical research in low and middle-income countries (LMICs) is to fund individual clinical trials on an ad-hoc basis, with each trial requiring significant investment in research infrastructure and skills development in addition to the trial-specific costs. This model is inefficient scientifically, developmentally, and financially.
In response to the challenge of AMR, Wellcome plans to set up a pilot clinical trial network (CTN) in SEA. The CTN will significantly increase the quality and efficiency of clinical trials in the region, resulting in an improved understanding of DRI, improved treatment of those infections and an increase in the supply of new drugs to fight AMR. The support hub for this clinical trial network will be based in Singapore.
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| 23/03/2021 |
£54,887 |
UNIVERSITY OF MANCHESTER |
This activity will establish Salford's Ordsall Hall (OH), a free-to-access heritage property, as a dynamic site for developing public healthcare knowledge and engagement for its 35,000 annual users. It will also offer a case study of how other UK heritage organisations can encourage positive health outcomes for their users by making public healthcare a focal point of public and learning programmes.
OH's 2.5 acres of organically-managed gardens will become a site for cultivating and analysing plant species that were widely used in early modern sleep-care routines, from soporific tonics to foodstuffs. A series of workshops with OH's users will involve them in planting and cultivation, and in remaking experiments based on historical sleep recipes. The PI's team will use their digital microscopy expertise to reveal the material qualities of individual plants, which will enrich the research project. The workshops will generate material for learning resources, vlogs, and recipe cards for OH's users, in which Salford schools feature strongly (c.40 schools). This activity supports the Personal, Social and Health Education (PSHE) learning objectives now mandatory in UK primary and secondary schools, which emphasise the importance of, and connections between 'sufficient sleep' and 'time spent outdoors' for physical and mental health. The project will encourage positive health outcomes for OH's users by juxtaposing historic sleep-care practices with current healthcare concerns about sleep quality. Project outcomes will be scaled through the project website, and through strategic webinars with the Museums Association, GEM (Group for Education and Museums), and the Historic Houses Association.
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| 23/03/2021 |
£27,709 |
UNIVERSITY OF READING |
The prevalence of self-harm in the UK has nearly tripled over the last decade (BMJ 2019). However, studies of self-harm have focussed on its biomedical causes to the exclusion of social and cultural factors. This project facilitates new ways of discussing self-harm through artistic practice.
In collaboration with ArtLab (the outreach arm of University of Reading art department) and The AnDY (Anxiety and Depression in Young People) Clinic, the completed project will have delivered a series of creative workshops for people with a history of self harm, their loved ones, and service providers. I will have accumulated artwork and qualitative feedback from these workshops which helps me to understand how my research relates to (and differs from) modern narratives about self-harm. As ‘co-researchers’, participants will explore and express their ideas about representations of self-harm and generate a greater understanding of one another’s perspectives.
These insights will be disseminated as a dynamic online exhibition of (anonymised) artwork and feedback from the workshops, made freely available to mental health charities and NHS trusts as a resource for promoting discussion about the socio-cultural aspects of self-harm. I’ll also discuss the project and the exhibition at local arts, science and heritage events such as the Being Human festival, encouraging greater openness about mental ill health. Additionally, my findings will be incorporated into a scholarly monograph on the topic of self-wounding in early modern England, specifically as part of an ‘epilogue’ which considers how historic experiences of self-wounding relate to modern self-harm.
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| 23/03/2021 |
£81,762 |
UNIVERSITY COLLEGE LONDON |
Dementia is common in Parkinson’s, being six times more likely in Parkinson’s patients than in the general population. Despite this, those working in the Parkinson’s community avoid using the word or having discussions about dementia due to worries about adverse responses from patients. While a difficult conversation, new tools are needed to create awareness and open dialogue, so that we can better help patients and involve them in research and treatment targeted at dementia in Parkinson’s.
As a clinician investigating mechanisms of dementia in Parkinson’s, I struggle to navigate these difficult topics with patients, and the wider public. Dementia can feel like a new trauma for patients who have just become accustomed to living with Parkinson’s. However, I need to talk about cognitive decline in Parkinson’s to engage patients in the research. In clinic, early conversations about Parkinson’s dementia can help patients gain access to appropriate support, prepare for the future, and benefit from treatments to slow progression of dementia in Parkinson’s.
Therefore this project will:
Identify roots and triggers of discomfort linked with the concept of dementia within the Parkinson’s community
Co-produce information resources to support dialogue and awareness including: (i) a clinical tool to enable discussion of dementia between professionals and people with Parkinson’s, (ii) a hub of accessible, non-threatening information for people with Parkinson’s to learn about their risks
Embed toolkits in Parkinson’s UK’s resource packages and run a campaign to raise awareness of the risk of dementia and the toolkits.
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| 23/03/2021 |
£99,680 |
KING'S COLLEGE LONDON |
Building on existing community engagement activities, each month for two years, we will run ‘PRECISE-DYAD open days’ to connect with study participants, their families and community members. The aim of this project is to dedicate time for interactive learning and discussions about pregnancy and mother and child health. These open days will take place in the communities where the participants live or at the health centre where the study takes place (The Gambia= 3, Kenya= 2). The choice of location will optimize participation by selecting centrally located/convenient locations.
The PRECISE-DYAD open days will be delivered as follow:
A variety of interactive activities including storytelling, plays and interactive games on topics related to pregnancy, mental health, brain function and nutrition. These activities will be led by the PRECISE-DYAD health care workers following appropriate training programs.
Printed material highlighting interesting PRECISE-DYAD study data relating to the community will be shared at the open days. A team member will provide an overview of the study data and encourage further conversation on topics of interest to the attendees.
Thank-you ceremony and tokens of appreciation will be provided to participants. These will be conducted at the end of ‘PRECISE-DYAD open days’ and will include wraps to carry children and polaroid pictures of the woman and her child, if present.
A video will be recorded by a local professional team to showcase community perceptions of maternal and child health.
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| 23/03/2021 |
£40,757 |
UNIVERSITY COLLEGE LONDON |
Our knowledge of Latin America’s past is predominantly based on colonial and governmental sources, side-lining indigenous stories and myths that have been experienced and transmitted orally for generations. Through a collaboration between the British Museum’s Santo Domingo Centre of Excellence for Latin American Research (SDCelar) and Indigenous participants we will tell these stories, creating a virtual exhibition examining the coloniality of gender in their communities. Wixárika gender relations and how these were performed and transformed throughout history will be shared using interactive materials, with the aim that researchers, participants and museum users more clearly understand how colonialism shapes experiences of gender and health.
Research partners in the UK and Mexico will work with exhibition specialists Múcura and Wixárika participants to record their interpretation of the history of gender. Theatre, narratives and interactive experience-based artwork and will be used to generate content for the virtual exhibition. Evaluation will be formative and embedded, recording participants’ experience of analysing historical data and acting on their feedback.
Once completed, Global visitors to the exhibition will learn how colonialism intervened with gender structures, participants will understand how colonialism has shaped their experiences of gender, pregnancy and childbirth; and the research team will learn to critically examine their own positionality, facilitating genuinely participatory and decolonising interpretations of their findings.
Partnering with SDCelar gives Wixárika communities the ability to influence global knowledge networks and use this engagement to decolonise healthcare in their communities, with the potential for shaping future research and the focus of linked
academic publications.
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| 15/03/2021 |
£1,064,246 |
UNIVERSITY OF THE WITWATERSRAND |
Africa has the fastest growing population in the world. At the same time the continent has some of the highest rates of infertility. Most people long to have children for diverse reasons. Those unable to have children seek ways to improve their chances of conceiving. These may include biomedical interventions, vernacular healing practices, changing or adding partners or making kin through adoption and child circulation. Yet despite the diversity of lived experiences and practices of reproduction across the continent, most research and interventions into reproductive health in Africa frame it primarily in terms of risk, pathology, mortality, and irresponsibility. Doing Natality engages a team from four African countries, working across demography, social sciences, medical humanities and science and technology studies, to develop a research agenda that centers the notion of "doing natality". We aim to explore practices of doing natality as articulation of love, care, beginning something new and securing better futures in raising children. We thereby open up a new space to interrogate and explore the usefulness of the notion of "doing natality" as heuristic, theoretical and methodological tool by asking what it means for African women, men and couples to have (or not have) children.
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| 15/03/2021 |
£1,040,680 |
BATH SPA UNIVERSITY |
Social science research has long been criticised for failing to improve the life chances of disabled people. Current research agendas are determined ‘top down’ by policy makers, and researchers risk objectifying disabled participants by conducting research ‘on’ them (as opposed to ‘with’ them). Our radical and exciting proposal challenges the status quo by developing an inclusive agenda and establishing a Disabled People’s Research Network. Our vision is to place academic and non-academic disabled people at the heart of research development, and our entire project will be co-produced by working with disabled people’s organisations. Our activities will identify new salient questions and reinvent social science methodology by exploring how the arts and humanities can enable disabled people to evidence and share their lived experiences. We will develop more inclusive forms of knowledge exchange between universities and disabled people, and we will work with policy makers to maximise disabled people’s research impact. We will empower disabled people as agents of change and our activities will include a range of fellowships for disabled people and a highly innovative research training course led by disabled people. Our network will reinvent how universities work with disabled people, in addition to methodological and epistemological development.
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| 15/03/2021 |
£1,016,937 |
UNIVERSITY OF LEEDS |
LivingBodiesObjects is an experiment in the making and understanding of interactions between bodies, technologies, objects and health, designed to test and extend the boundaries of Medical Humanities research. Working with a range of partners, it will take place in the context of multi-purpose/use laboratory spaces (both physical and virtual) that invite differing conceptions and practices of health experiences, and responses to them. The ambition of the project lies in the imaginative creation of these spaces and not in any pre-emption of the materials they might produce. The laboratories will be specifically designed to figure ideas and creativity, making spaces that provoke, facilitate and respond to the ideas and questions raised by bodies as they encounter different forms of technology. Centring on the ways in which individuals and communities collaborate to produce work within dynamic and generative locations, the laboratories will also link to more traditional laboratory activities such as equipment, testing and use. As a specific research development initiative, the project will further extend interdisciplinary health research practice at the University of Leeds, where its work will inform and further develop a research culture through the foregrounding of innovation in professional research management, career development and equality, diversity and inclusion.
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| 15/03/2021 |
£996,460 |
UNIVERSITY OF HELSINKI |
The aim of this Research Development Award is to establish a leading centre for the social study of microbes. Since their discovery, microbes have been predominantly defined as pathogenic and threatening to human and animal health. Recently, however, societal, and scientific views about microbes, immunity, and antibiotics have started to acknowledge the beneficial and symbiotic qualities of bacteria, viruses and fungi. Existing social scientific language is insufficient and outdated in describing the complex and entwined relationships between humans, nonhumans, microbes, and environments. These relations with microbes raise profound challenges for the foundations of social theory.
Strategically situated within an emerging network of research, this application will establish an egalitarian and experimental research infrastructure to develop new social scientific concepts and methodology to address the challenge. The Centre will host international research fellows and an art residency, and organise social theory and methodology workshops, two academic seminars annually, and a yearly PhD Summer School to support younger generations of scholars. Not only is this work theoretically essential, it is also key to understanding and acting upon the way humans relate to microbes and other nonhumans, a vital objective for developing sustainable ways of planetary co-existence.
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| 15/03/2021 |
£733,684 |
UNIVERSITY OF CENTRAL LANCASHIRE |
Three paradoxes in global research ethics seriously harm vulnerable populations.
First, health research works. Yet, to protect vulnerable populations from exploitation, they are often excluded from it.
Second, international collaborative research works. Yet, major trust issues block collaborations with vulnerable populations who have previously been exploited.
Third, the further apart researcher and end-user experiences are, the more urgent the co-creation of research becomes. Yet, successful co-creation methods for non-clinical health research with vulnerable populations in low and middle income countries (LMICs) barely exist.
All three paradoxes restrict non-clinical health research in LMICs.
Leaving no one behind in research will build an extensive research agenda to tackle all three paradoxes by:
radically rethinking the concept of vulnerability and what appropriate protection mechanisms for the vulnerable would look like.
enabling indigenous peoples and sex worker teams to define what vulnerability means to them and how they want to be protected in research.
developing a humanities method for non-clinical health research that would make research less risky for vulnerable populations.
The above will be achieved by a highly-experienced research leader and her UK team in a network with two African teams representing vulnerable populations.
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| 15/03/2021 |
£1,019,767 |
LANCASTER UNIVERSITY |
New and emerging reproductive technologies have the potential, within a generation or two, to profoundly disrupt established social practices linked to human reproduction and parenting, as well as the concepts of relatedness and family. Better understanding the cultural, ethical, legal, and social issues that this prospect raises is the principal substantive research aim of this programme. We will examine three such technologies.
Ectogenesis could allow us to develop fetuses wholly outside the body, to create children who have not been ‘born’ (in the usual sense of that term).
Genome editing will mean that future children can be ‘chosen’ or ‘designed’ with far greater levels of precision than at present.
New methods of creating eggs and sperm will enable the creation of children with two genetic parents of the same sex, or who have multiple genetic parents, or perhaps no determinate genetic parents at all.
Using these cases as focal points, we will develop transformative new research methods and modes of interdisciplinary working - for example, by integrating speculative design methodologies with those of bioethics, law, literature, linguistics, and psychology. Our ultimate aim is for this to lead to a novel research paradigm for the study of disruptive emerging technologies.
|
| 15/03/2021 |
£1,058,630 |
UNIVERSITY OF CAPE TOWN |
In this project, we propose to create opportunities for African theory-building by fostering critical reflection, exchange of knowledge and perspectives, and collaboration and writing between African scholars from different disciplines, with a focus on exploring how African thought could influence critical engagement with the ethics of new and emerging health technologies globally. Starting with a recognition of incompleteness and the conviviality that requires, the focus of this project will be on a) developing conceptual accounts of how African thought could inform on key ethical questions raised by new and emerging health technologies, b) better understanding how we can ensure epistemic justice in our scholarship and which diversity matters; and c) understanding how particular African research contexts drive us towards academic activism. The programme seeks to create opportunities for exchange and joint reflection, in an aim to push the audacity with which African scholars can take ownership of, and lead, reflection on the ethics of new and emerging health technologies. The programme will dive into questions relating to African personhood, relational autonomy, epistemic justice and academic activism to explore how African ways of seeing and being in the world could enrich global conversations about science and technology.
|
| 15/03/2021 |
£1,190,927 |
UNIVERSITY OF MALAYA |
This programme aims to build a bioethics community in South East Asia (SEA) to establish a research agenda that brings to the forefront voices that are not well captured in current bioethics discourses, and shape policies and practices to enhance the wellbeing of individuals and communities. A distinctive feature of SEA is its diversity of language, ethnicities, cultural and religious traditions, and political and economic development. However, SEA voices are underrepresented in contemporary bioethics discourses and in the development of bioethics guidelines that have international relevance and impact. Led by the University of Malaya with initial partners in Singapore and Thailand, this initiative will initially focus on two thematic research areas: 1) emerging issues relating to healthcare for and research with mobile and marginalised populations; and 2) challenges and opportunities presented by emergent health and biomedical technologies.
The guiding principles of this initiative are threefold. First, to discover and bring into the bioethical discourse, the voices of the many cultural and religious traditions in the region. Second, to advocate for change and challenge orthodoxy; and third, to build a vibrant, inclusive and collaborative bioethics community in South East Asia.
|
| 10/03/2021 |
£18,459 |
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL |
Black, Indigenous, and People of Color (BIPOC) suffer most from the consequences of broken food systems (Petersen et al., 2019) and climate change (Morello-Frosch et al., 2009) yet are underrepresented among research leaders working to address such issues (National Science Foundation, 2018; Pearson & Schuldt, 2014). The Nutrition Research Scholars Program (NRSP) aims to build a pipeline of BIPOC scholars to become leaders in food, health, and climate research to inform policy.
Our activity will involve implementation of the pilot NRSP providing BIPOC students interested in nutrition and climate with research experience and mentorship from leaders in nutrition and food policy. We will implement a 12-week summer NRSP for two BIPOC undergraduate students to build research and professional development skills and prepare for matriculation in a PhD program. Short-term indicators of success will include objective measures (e.g., total professional development workshops and networking meetings attended) and subjective measures (e.g., satisfaction with the NRSP). Long-term indicators will include continuation of an annual NRSP, total scholars matriculating in related PhD programs, and development of a network of BIPOC scholars working with our research group.
Upon successful completion of the pilot, we will expand the program to other research groups within the UNC Department of Nutrition; disseminate program findings at nutrition conferences; and build sustainability by incorporating funding for NRSP scholars in grant proposals. With time, the NRSP will foster a pipeline of BIPOC nutrition scholars pursuing graduate training to work as researchers at the nexus of food policy, health, and environmental change.
|
| 26/02/2021 |
£79,672 |
UNICEF UK |
UNICEF proposes multi-country focus groups to gather insights on young people’s mental health and well-being. This reflects our and Wellcome Trust’s mutual commitment to engaging youth as partners in the design and implementation of action research that affects them. The proposed research will be featured in UNICEF’s flagship State of the World’s Children report, ensuring that the knowledge, expertise, and lived experiences of young people are part of the global dialogue on research, policy, and programming priorities.
Key research questions include:
How do adolescents perceive and understand mental health, both positive and negative?
What are the key emotional and behavioral challenges facing adolescents in communities around the world, and what do they identify as risk and protective factors?
What are the positive and harmful ways adolescent are coping with mental health problems?
What are the barriers and reinforcing factors to their help-seeking behavior?
What are adolescent ideas and solutions around structural, community, peer, and self-care approaches to mental health promotion, prevention, and support?
This research will create opportunities both for promoting positive youth development as well as increase youth voice in the scientific study and body of evidence around mental health of young people.
|
| 26/02/2021 |
£447,509 |
IFAKARA HEALTH INSTITUTE |
Community engagement is an essential component in clinical trials, and it is regarded as an ethical requirement of most ethics review committees before the trial protocols can be approved. However, there is a scarcity of studies that have objectively assessed the impact of best engagement practices on recruitment and retention rates.
Using an in-depth review of the literature, in-depth interviews, and focus group discussions with relevant stakeholders, we will develop clinical trial community engagement best practices. We will then establish and pilot an implementation assessment tool that would be used to assess the extent of implementation of these practices. Finally, we will conduct a randomized controlled study to assess the efficacy of best practices on the recruitment and retention rates of clinical trials in a randomized controlled trial, where trials in the intervention arm will be assigned to implement the new best practices, and control trials will implement their originally planned engagement approaches. The implementation assessment tool will be used to measure the extent of adherence to the newly established best practices in both arms. We will then assess the enhancers and barriers to the successful implementation of clinical trial best community engagement practices.
|
| 26/02/2021 |
£4,794,788 |
UNIVERSITY OF OXFORD |
The COVID-19 pandemic has once again exposed the lack of coordination and cooperation across the research and development efforts of the infectious disease community. A key indicator of this failing is the lack of international, interoperable data platforms to provide rapid insight into disease pathogenesis and treatment. Access to data is an important tool for accelerating evidence, product development, and scientific innovation.
Enhanced technology, infrastructure and systems for data platforms will increase Findability, Accessibility, Interoperability, and Reuse (FAIR), so that science can advance in a rapid, robust and innovative way, saving lives in the affected communities.
Recognising the importance and complexity of the task at hand, this project brings together the vast experience of IDDO, Vivli, and other key stakeholders to deliver a broad, effective, and sustainable data platform(s) for infectious diseases.
In this project, IDDO will:
Enhance its platform for improved findability, discovery, and persistence which ensures that data are available in the long-term;
Optimise and accelerate its data curation capacity;
Streamline and accelerate its data access workflow;
Develop a business plan to secure the sustainability and success of the platform
|
| 26/02/2021 |
£1,028,765 |
VIVLI (CENTRE FOR GLOBAL CLINICAL RESEARCH DATA) |
Data repositories (such as IDDO and Vivli) have played a significant role in making research data available for secondary use. However, access to data needs to be further enhanced for accelerated innovations on infectious diseases by addressing the friction in data contribution, discoverability, access, and reuse. There is a strong alignment between Vivli the Wellcome’s visions of improving the discovery and accessibility of Individual Participant Data related to COVID-19 in the short term, and for other infectious diseases in the long term. With this grant we seek direct support for discoverability and accessibility of data related to COVID-19, and to directly support Vivli to become an effective node in the "FAIR Data Network".
The grant will focus on the following primary objectives:
Recognition and credit for data contributions,
Accelerated access to Individual Participant Data (IPD) hosted by Vivli,
Discoverability of IDDO studies via the Vivli platform, and
Discoverability of IPD hosted by Vivli and its platform partners (including IDDO) based on rich metadata).
|
| 26/02/2021 |
£100,000 |
KING'S COLLEGE LONDON |
Treatments for inflammatory pain (IP) and neuropathic pain (NP) are frequently ineffective and have many side effects. Scientists in Professor Peter McNaughton's laboratory at the University of Cambridge have discovered that both IP and NP are abolished in mice when an ion channel is genetically deleted. This suggests that drugs blocking this ion channel will have value as novel analgesics.
IP is associated with injury, infection or chronic conditions such as arthritis; and NP is caused by nerve damage in conditions such as post-herpetic neuralgia and diabetic neuropathy. Both IP and NP can impose major limitations on lifestyle and working patterns and currently available treatments have major drawbacks. For example, non-steroidal anti-inflammatories cause gastric and renal damage; and opioids cause constipation and problems with tolerance and addiction.
The team aims to develop selective ion channel blockers, which avoid those that play essential roles in the heart and brain, and test them in animal models of IP and NP. In separate parallel studies they will use a known non-selective blocker to carry out proof-of-principle studies in human NP. |
| 05/02/2021 |
£129,030 |
UNIVERSITY OF STRATHCLYDE |
The opportunity to renew the Wellcome Trust (WT) Masters Programme Award comes at an exciting time for the M.Sc. in Health History (HH) at the CSHHH Glasgow. The purposes of the initial award were to; enable UK based applicants to study on the degree at a time of growing demand for teaching in the field; to drive connections with students from outside of the UK as Health History develops in Asia and Africa. The Centre has proven able to meet these objectives, having funded one South African and two UK students to date. All were integrated successfully into a student body that includes those from partner institutions in Shanghai through the WT funded Medical Humanities China-UK (MHCUK) programme. This proposal will secure further resources for the development of this increasingly diverse Medical Humanities student community at a time when the M.Sc. HH continues to grow new capacities for career-building and training in partnerships both within, and beyond, academia. Its international scope also prepares it to actively engage in the re-establishment of collaborations around the globe in the wake of disruption caused by COVID-19 by placing the next generation of Health History scholars at the heart of this process.
|
| 05/02/2021 |
£134,844 |
UNIVERSITY OF YORK |
Since 2016 the University of York’s MA in Medical History and Humanities has offered students invaluable perspectives on Medical Humanities, exploring the historical, literary, philosophical and political nuances of the field. Its thematic structure ensures a wide range of subjects and option modules are incorporated to provide interdisciplinary and international perspectives, and to facilitate inter-cohort learning from the diverse perspectives of students and teaching staff.
This successful course has been developed further in response to student feedback, advances in the broader field of Medical Humanities and the unique perspectives offered by staff research undertaken at the University of York and the Centre for Global Health Histories. The University specializes in interdisciplinary collaboration, and as a University for Public Good (as set out in its strategic vision statement to 2030), draws on a rich tradition of social justice and equality alongside internationalism and innovative thinking.
Renewal of the studentship grant is now being sought to further grow the course. Previously successful applicants have been of an extremely high calibre. We anticipate that the students who successfully win these scholarships will go on to match and exceed the successes of those who have completed the course thus far.
|
| 05/02/2021 |
£149,726 |
BIRKBECK UNIVERSITY OF LONDON |
This is a joint programme between HCA and ETCW, but also draws on expertise across the Humanities and Social Sciences at Birkbeck. It runs for one year full-time or two years part-time. Most students complete two core modules, two subject-specific option modules and a dissertation. But we also offer a coursework-only pathway, which is popular among students coming from health professions. Students taking this pathway complete the core modules and four option modules.
The MA addresses the cultural complexity of historical and current health issues, including infectious diseases, preventative medicine, mental health, disability, expertise, authority and medical ethics. Additionally, students learn about the emergence and organisation of the medical humanities as an academic field and the debates that shape its identity and purpose.
Many students use the MA programme to prepare for doctoral study or careers in health policy and management. Others use the MA to enrich established careers as health professionals, developing more reflexive practices and sensitive relationships with their patients. The original grant offered opportunities to students with disabilities and from disadvantaged backgrounds who would otherwise have been unable to afford postgraduate study. We would use the renewal to widen access and diversity, including opportunities for BAME students.
|
| 05/02/2021 |
£186,643 |
LONDON SCHOOL OF ECONOMICS AND POLITICAL SCIENCE (LSE) |
Renewal of the WT Award for the LSE MSc in Health and International Development (HID). To date the two WT scholarship recipients (one graduated, one current) were selected from shortlists of outstanding applicants demonstrating excellent potential for research careers. HID offers a multi-disciplinary social science approach to health. The core courses expose students to theoretical, substantive, and methodological debates in health-related research. The compulsory research design course supports students’ formation as independent researchers, preparing them to develop dissertations where they probe deeper into health-related issues on specific topics that motivate them. Optional courses from a range of disciplinary perspectives (political science, anthropology, development studies, social psychology) allow students to tailor their learning to their research career aspirations. The integration of health and development make the degree truly distinctive, and different from health degrees taught in schools or departments of health. HID graduates are analytically sophisticated, and able to grapple with complex health-related questions and evidence. Studentships are allocated on merit, but also on a highly motivated personal statement and experience. Our experience of WT studentships to date is that they allow the very best future researchers to gain confidence, flourish, and take the next steps in their health research career.
|
| 05/02/2021 |
£164,629 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
The Humanities and Social Science (HSS) Pathway supports students taking the MSc in Public Health at the London School of Hygiene and Tropical Medicine. The degree provides students with the knowledge and skills necessary to improve the health of populations, communities and groups within them. The course emphasises the use, development and critical evaluation of conceptual models, evidence and methods of analysis, and on the design of effective interventions and policies at all levels. Students holding the Studentship follow an HSS ‘Pathway’ through the degree. This involves taking specialist modules in HSS (such as history, anthropology and sociology) and producing a dissertation rooted in these disciplines.
The Pathway has improved award holders’ understanding of health and the value of HSS for interrogating this. The programme has allowed students from a humanities or social science background to develop the knowledge, understanding and skills necessary to comprehend the multi-faceted nature of ‘public health’. Renewing the studentship enables us to move the programme to the next stage by growing, diversifying and strengthening the cohort of award holders. This will help build a new generation of researchers who understand public health policies and practices and are also able to critique and contextualise them.
|
| 05/02/2021 |
£129,007 |
NEWCASTLE UNIVERSITY |
Our current MA award enables us to recruit and train students who would otherwise be deterred from studying at MA level due to a fear of incurring more debt. Despite securing studentships, and developing cogent, novel research ideas, these students doubt their ability to progress as researchers, struggle to acknowledge their own achievements, and question whether they belong in the university’s research community. Wellcome MA funding offers a rare opportunity to diversify the research community: while UKRI funding supports capable doctoral students, lack of MA funding prevents many promising students from progressing beyond a BA. Our renewal plan utilizes this opportunity, aiming to dismantle barriers that prevent talented researchers from progressing.
We also aim to prepare our students to tackle complex health challenges by highlighting the role of history and humanities within multidisciplinary and transdisciplinary health research projects. We have capitalised on institutional investment to create a sustainable and intellectually diverse cross-faculty Newcastle medical humanities network. This has enriched our medical humanities research-led teaching, facilitated cross-disciplinary supervision, and enabled students to tap into a growing number of relevant research resources, networks and activities. We will encourage our students to adopt innovative multidisciplinary agendas at the outset of their research careers.
|
| 05/02/2021 |
£114,062 |
UNIVERSITY OF BRISTOL |
Thank you for the opportunity to apply to renew our Masters programme award. We are seeking renewal so that we can continue to offer outstanding Bioethics training opportunities to promising young scholars.
Based in the Centre for Ethics in Medicine (CEM), our programme is designed for students who are interested in a research career in Bioethics, and its aim is to foster future bioethics research and develop future bioethics research leaders, through equipping MScR students with the diverse skills and knowledge needed for doctoral (and further) inquiry. We specifically aim to grow into a national feeder programme for research careers in bioethics, including as a feeder into our own PhD programmes, and support our students in applying for PhD funding.
To date we have funded three promising Bioethics scholars from diverse disciplinary backgrounds, two of whom have secured PhD funding and one is in the process of applying for it.
In our renewed programme we will be revising our selection criteria to ensure candidates can more easily adjust to unforeseen changes in their projects, offering enhanced initial training opportunities, and ring-fencing two studentships for healthcare professionals.
We look forward to continuing to support a next generation of Bioethics research leaders.
|
| 05/02/2021 |
£169,771 |
UNIVERSITY OF CAMBRIDGE |
In 2016 we began a new MPhil in Health, Medicine and Society (HMS). HMS provides students with interdisciplinary training in the history, philosophy, anthropology and sociology of health and medicine. Through taught modules, keyed to research essays supported by one-to-one supervisions, students are introduced to theories and methods, develop skills in conceptual and empirical analysis, and become acquainted with the scholarly literatures across all four disciplines. No other programme in the UK does this. Moreover, because it is situated within a vibrant international hub of humanities and social sciences research in health and medicine, students are supervised by leading scholars in the field. The programme is attracting applications from a diverse and talented body of students. The studentships we are applying for would help us to bring outstanding students from a range of backgrounds to Free School Lane, to equip them with skills of critical thinking in the humanities and social sciences, and to launch them into careers where understanding health and medicine matter.
|
| 05/02/2021 |
£140,046 |
UNIVERSITY OF WARWICK |
This application requests a series of studentships for the MA in the History of Medicine at Warwick over a three year period. Our case, in the document attached, is partly based on reviewing the type of degree that we have created, reflecting on its developing strengths and explaining why we feel the MA merits further support; but it also sets out how we plan to build on this foundation in developments that take us forward in exciting new ways. These relate to new staffing, a rethinking of aspects of curriculum in line with shifts in the field, a commitment to diversity, and our ongoing efforts to create a culture that has produced a stream of talent in the history of medicine as well as leaders in the fields of health policy and the medical humanities. We argue that the Warwick program has some unique strengths. We also however embrace the opportunity to propose a series of improvements to current practice. Our case is built around four main headings that reflect the guidelines. Our response places emphasis on enhancement, new approaches, and an underlying holistic vision that both we and our students benefit from them being integral to our research community.
|
| 05/02/2021 |
£144,840 |
UNIVERSITY OF BRISTOL |
The below proposal relates to the University of Bristol’s LLM in Health, Law, and Society. It provides:
Reflections on the impact of the award so far;
Explains how we would make the most of a renewal; and
Summarises my vision for the next three years.
The proposal involves critical self-reflection, explanation of how and why I continue to believe that the LLM is a worthy programme for this funding award, and an outline of how we would modify the running of the award in the coming years. Notably, the changes relate to: practical support for wider skills-development beyond the taught aspects of the programme; and the University of Bristol Law School’s commitment to supplement the fees on two of the scholarships to enable inclusion of students from Low and Middle Income Countries.
In the additional materials to this application, the proposal is complemented by demonstrations of institutional support, and links to wider materials that may be useful in considering the merits of the application.
|
| 05/02/2021 |
£138,975 |
UNIVERSITY OF SOUTHAMPTON |
The MSc in Global Health within the Faculty of Social Science at the University of Southampton is a multi-disciplinary programme designed to equip students with the necessary skills to understand and respond to global health challenges. Our previous award from the Wellcome Master's Programme Award in Humanities and Social Science enabled three talented students from low- and middle-income countries to attend this highly successful programme. They have gained an extensive understanding of key issues in Global Health from a social science perspective as well as strong quantitative skills that provide a firm basis for a successful career in research. They have also established enduring links with Global Health academics within the University who will continue to support and advise them.
We are now requesting funding for a further five studentships. Three will again be ring-fenced for students from low- and middle-income countries, while the other two will be open to UK students in order to build further capacity in global health research within the UK. In addition to gaining subject knowledge, quantitative expertise and transferable skills for the workplace, they will also be supported in planning their future careers and offered opportunities for networking and gaining specific training and experience.
|
| 05/02/2021 |
£140,199 |
UNIVERSITY OF MANCHESTER |
Founded in 1986, CHSTM is the largest British group devoted to the integrated historical study of science, technology and medicine. Our core belief is that these fields cannot be studied in isolation from each other or their wider socio-cultural contexts, and that history can enrich discussion of present dilemmas. Health and medicine are at the forefront of our work, initially supported through the Wellcome Unit for the History of Medicine (1986-2006) and recently through a range of PI-led research projects.
Our Master's Programme in History of Science, Technology and Medicine (HSTM) brings together first-class graduates from humanities, medicine and the sciences each year, and is underpinned by our commitment to research-led teaching. All academic staff contribute to the programme, and students are fully integrated into life at CHSTM through a range of seminars, conferences and public engagement activities.
A recent restructure of the HSTM curriculum, launched in 2020-21, increased our focus on current challenges, such as climate change, race and mental health, and doubled our student intake. This provides us with a unique opportunity to recruit outstanding candidates for the studentship and train the next generation of researchers to work at the cutting edge of health-related humanities and social science.
|
| 04/02/2021 |
£500,000 |
WALTER AND ELIZA HALL INSTITUTE OF MEDICAL RESEARCH |
The SARS-CoV-2 pandemic is a global health emergency that highlighted the need for new antiviral medicines and better pandemic preparedness. Our drug-discovery program focusses on a critical protein present in all coronaviruses, the papain-like protease PLpro. PLpro is essential for viral replication, but also stops our alarm systems to respond to viral infection, To achieve the latter, it removes ‘ubiquitin’ and ubiquitin-like signals required for inflammation and anti-viral signalling. Our world-leading experts in ubiquitin research, drug-discovery and infectious disease biology have leveraged our state-of-the-art facilities to identify new drug candidates to block PLpro. We have screened > 400,000 small molecule compounds and identified new chemical scaffolds that inhibit PLpro from SARS-CoV-2 without affecting human enzymes. Our program will deliver new antivirals to prevent or treat COVID-19 and also develop a library of efficacious drug candidates to combat future coronavirus outbreaks |
| 04/02/2021 |
£317,317 |
UNIVERSITY OF GLASGOW |
Inflammation is part of the body's defence system against a wide range of harmful stimuli.
Inflammation also plays an important role in human diseases, including stroke, Alzheimer's,
hardening of arteries, arthritis, and cancer. The ability to image inflammation inside the
human body would provide an improved understanding of this process and provide new
opportunities for diagnosing disease and guiding treatment. ABL-101 is a fluorinated oxygen
carrier which is being investigated for treatment of stroke. It is made up of a large number of
fluorine atoms that can be visualised in MRI using a detector that is tuned to fluorine (19F
MRI). Once injected, cells that are also part of the inflammatory response (macrophages)
take up ABL-101. ABL-101 could therefore be an imaging agent for inflammation. 19F MRI
uses a specially developed radiofrequency coil and some specialised programming that Dr
Santosh and the team at the University of Glasgow wish to assess as a vital step to
developing clinical uses. |
| 04/02/2021 |
£439,472 |
INTERNATIONAL VACCINE INSTITUTE |
Salmonella Typhi and Paratyphi A have a high incidence worldwide and coexist in many
areas, especially in South and Southeast Asia. S. Typhi causes an estimated 12.5 million
cases and 149,000 deaths and S. Paratyphi causes about 3 million cases and 19,000 deaths
annually. There is urgent need for better and affordable vaccines against these infections.
The aim of this project is to develop a bivalent Typhi-Paratyphi A vaccine to prevent
systemic Salmonella infections and enteric fever. Specifically, we intend to identify a bivalent
conjugate formulation, arrived through determination of optimal formulation &
characterization conditions, that induces equivalent or higher anti-OSP/Vi IgG titers than
monovalent OSP and Vi conjugate controls, and bactericidal activities against S. Typhi and
S. Paratyphi A, with/without adjuvants. |
| 04/02/2021 |
£519,278 |
UNIVERSITY COLLEGE LONDON |
Neuroblastoma (NB) is the most common extra-cranial solid cancer in children and contributes to 15% of childhood cancer deaths. Surgery to remove NB is often incomplete and poses high risks due to the significant involvement of vital organs and vessels.
We aim to develop a novel integrated surgical platform to eliminate cancer more efficiently and safely. With the synergistic use of highly innovative optical techniques, built around a core technology of using injectable probes, we aim to:
1. Specifically, "light up" cancer to help the surgeon in differentiating tumour from vital organs (colour-coded surgery).
2. Equip the surgeon with an innovative special scanner to chase small and non-visible cancer residuals.
3. Kill any minimal residual cancer, left by the surgeon, using a new technology based on light.
This original approach has the potential to improve the effectiveness of surgery in eradicating solid paediatric and adult cancers, leading to better survival and fewer complications. |
| 04/02/2021 |
£476,489 |
EPICENTRE |
Malaria remains a key driver of high mortality in sub-Saharan Africa, particularly in Niger. Malnourished children are particularly vulnerable to malaria, and more likely to die from it. Malaria drug resistance to several commonly used drugs has emerged and spread. As a new approach to treat multi-drug resistant malaria, we have proposed to increase the number of drugs to 3 in malaria treatments (i.e. triple-artemisinin combination therapies, TACTs). Epicentre Niger is one site in a multicentre RCT evaluating TACTs, and is uniquely placed given the high rate of malnutrition. We will use Wellcome funding to evaluate the pharmacokinetic properties of TACTs in this critical population of malnourished children, with the aim of understanding the complex relationship between malnutrition and drug efficacy. This funding will specifically target aid for a vulnerable and neglected population, while providing evidence to reduce the impact of two of the most devastating crises in the region. |
| 04/02/2021 |
£504,936 |
KING'S COLLEGE LONDON |
Coronary artery disease (CAD) is the most common cause of death in the UK. Modern medical
imaging scans, such as cardiac magnetic resonance imaging (CMR), allow an accurate, noninvasive
and radiation-free diagnosis of CAD and the early identification of patients that would
benefit from available treatments, before complications such as heart attack and heart failure
develop.
There are not enough doctors in the UK trained to accurately interpret these scans, and this
results in an underutilisation of CMR, also with significant regional variations. We will bridge
this gap by creating computer programs based on artificial intelligence that, acting as expert
digital doctors, will facilitate the interpretation of the scans and guide the clinical team in
the management of patients with suspected CAD. This technology will enable advanced
imaging to be rolled out in any hospital equipped with a suitable magnetic resonance scanner,
regardless of the presence on-site of trained doctors. |
| 04/02/2021 |
£320,413 |
ROYAL COLLEGE OF SURGEONS IN IRELAND |
Epilepsy affects around 50 million people worldwide. Temporal lobe epilepsy is the most common and drug-resistant form in adults. A particular microRNA involved in brain structure and function has emerged as a potential new disease-modifying target. This project will develop a gene therapy-based treatment to inhibit this microRNA. The study will adapt an already clinically-approved gene delivery technology to ensure the therapeutic is delivered to the right part of the brain. The outcome will be a clinical trial-ready gene therapy with a unique mechanism of action that can reduce and prevent seizures in this devastating form of epilepsy |
| 04/02/2021 |
£494,777 |
UNIVERSITY OF CAMBRIDGE |
Although cancer immunotherapy has come of age, such therapies are currently only beneficial for some patients, particularly those with tumours with lots of mutations. Therefore, new therapies desperately need to be developed. Our approach is to make tumours look like virally infected cells enabling a patient's own naturally pre-existing immune cells to recognise and destroy tumours. There are many advantages to our innovation. As it utilises natural immunity, it will be less toxic with fewer side effects compared to other treatments. The immune responses can be highly controlled. We can target solid tumours, which are often not treatable with current immunotherapies. Furthermore, our treatment will be cheaper than cell-based therapies. We expect our work to widen cancer immunotherapy as a valid treatment option to a larger cohort of patients, including those with disease resistant to current immune based treatments, and to bring tangible clinical benefits to patients. |
| 04/02/2021 |
£501,343 |
UNIVERSITY OF OXFORD |
Fat deposition in the liver is now the commonest chronic liver condition, affecting one-in-three individuals. It can lead to liver problems including cirrhosis and liver cancer as well as increasing your risk of heart attacks and strokes. Simple blood tests are often normal, and the current gold-standard test for assessing NAFLD severity is a liver biopsy. This is an invasive procedure that is associated with significant complications, including pain and bleeding. We have developed a urine test that measures natural steroid hormones and provides an accurate reflection of how the liver is functioning in patients with NAFLD. We wish to extend our findings to a large cohort of patients with NAFLD to ensure that our test is accurate and reliable. If successful, our urine test could be used by GPs and hospitals reducing liver biopsies and making a significant advance to patient care. |
| 04/02/2021 |
£310,300 |
CENTRE SUISSE DE RECHERCHES SCIENTIFIQUES - COTE D'IVOIRE |
Insecticide resistance in malaria vectors has been clearly identified as one of the major obstacles for malaria control. While developing new chemicals for bednets is expensive with no guarantee of success, a less expensive option can be developing a physical method for killing resistant mosquitoes. Studies using infrared cameras revealed that more than 75% of mosquito interactions with bednets occurred on the net roof; by exploiting this natural behavior, Dr Mouhamadou will develop an insecticide-based mechanical solution that kills mosquitoes regardless of their insecticide resistance status. Dr Mouhamadou will design and develop a long-lasting insecticide-treated mosquito trapping bednet for mass mosquito trapping and killing, the "LLI-TNet". The LLIN-TNet will be field-evaluated in Africa against wild free flying high resistant malaria vector Anopheles gambiae population. The goal is to develop a cheap strategy which can be widely used to overcome the problem of insecticide resistance in malaria vector control. |
| 04/02/2021 |
£756,386 |
UNIVERSITY COLLEGE LONDON |
The larynx is a sphincter whose main function is as a sphincter to prevent food, drink and saliva passing onto the lungs ("aspiration"). Therefore, neuromuscular and mechanical disturbances of laryngeal function lead to considerable problems managing secretions, eating and drinking and recurrent pneumonia. 30% of persons with acute stroke develop aspiration, whilst it is the commonest cause of death in patients with neuromuscular diseases and throat cancer survivors. Our vision is to transform the lives of those losing laryngeal sphincter function by combining the cutting-edge technologies of bioengineering and soft robotics into an implantable sphincter device. Our team partners leading surgeons, engineers and scientists with patients and business experts. Preliminary work completed includes: i) biomaterials testing in the laboratory and patients; ii) creation of a valve generating sound at speech frequencies; iii) electrical systems capable of accurately controlling speech, swallowing and breathing. Here, we integrate these components in a single, soft robotics based, device. We will (a) trial internal and external power solutions; (b) compare internal and external sensors for control; (c) compare electrical and magnetic actuator solutions; (d) include patients and healthcare workers in project planning and management; (e) identify the evolving pathways to healthcare implementation for complex implantable devices. If successful, this project will deliver the world’s first soft-robotics-based implantable healthcare solution and provide proof-of-concept for novel solutions to other, diverse and common unmet patient needs, especially those involving sphincters (e.g., incontinence).
C7 Post award |
| 04/02/2021 |
£503,771 |
UNIVERSITY OF ABERDEEN |
Over 1 million people die every year from a serious fungal disease. One major cause of these diseases is the fungal pathogen Candida. Treatment is restricted to three main classes of synthetic drugs which are poorly tolerated and have increasing problems due to drug resistance. Biologics, such as monoclonal antibodies (mAbs), have revolutionised the treatment of other diseases. We are developing first-in-class antifungal mAbs to address the unmet need for safer antifungal drugs which are effective against drug-resistant infections. We have cloned naturally occurring mAb genes from the B cells of recovered patients. These mAbs protect mice from Candida bloodstream infection and show great potential for treating drug-resistant infections. We will optimise these mAbs for therapeutic use and test in mouse models of drug-resistant infection, accelerating development of this urgently required new class of antifungals. Ultimately, these new agents have great potential to improve patient outcomes and reduce healthcare costs. |
| 04/02/2021 |
£764,285 |
UNIVERSITY OF CAMBRIDGE |
Advances in medical and digital technology are generating large volumes of patient mental health data. Interpreting these rich data is key for improved early diagnosis, patient stratification and new drug discovery. Specifically, in the case of dementia, diagnosis at early stages of neurocognitive decline has major implications for timely clinical management. We currently intervene too late and often target the wrong patients. Here, we propose an innovative AI-guided healthcare solution that uses machine learning to improve early precision diagnosis and prognosis from low-cost, non-invasive data. Our aim is to deliver a clinical decision support system that will: a) help clinicians assign the right patient at the right time to the right diagnostic or treatment pathway, b) improve patient wellbeing and reduce healthcare costs, as patients undergo fewer, less invasive, less expensive tests, c) guide patient selection for clinical trials to enhance their efficacy and pave the way to drug discovery. |
| 29/01/2021 |
£50,000 |
UNIVERSITY OF GLASGOW |
This grant will support the 2021 International Genetically Engineered Machine Competition (iGEM), by supporting UK undergraduate students from the synthetic biology community to take part in it.
The provided funding will be used to support the students’ stipends, some consumable and travel support for the teams that have successfully applied to the competition.
Wellcome has funded the iGEM programme for several years as this is an interesting model to develop interdisciplinary thinking and skills for students. Funding is provided in partnership with BBSRC who also make available a £50k contribution.
Wellcome (Luigi Martino) will be involved at the selection stage and receive a brief report about the respective activities at the end of the year.
COVID-19 effect on the competition. The hope is that this year’s teams will have the ability to undertake wet-lab-work. If this is made impossible by the potential restricted access to lab spaces, the selected teams will be asked to submit a written proposal reporting the design and strategy to build their chosen genetically engineered machine. |
| 29/01/2021 |
£773,978 |
UNIVERSITY OF OXFORD |
Aims and key deliverables;
To provide consistent technical support to national testing programmes for SARS-CoV-2 in Kenya, Malawi and South Africa.
To support epidemiological research, clinical trials, immunological studies and genomics work
To consolidate and maintain positive relationships with national policy makers.
Our respective Wellcome AAPs/Centre (i.e. MLW, KEMRI-Wellcome, AHRI and CIDRI-Africa) have responded to the COVID-19 pandemic by making resources and staff available for SARS-CoV-2 testing, accounting currently for significant proportions of the local and/or national testing capacities, especially during surges. It is ethically imperative to provide national support alongside research-driven testing, and we have found this testing provided an opportunity to develop stronger relationships with national Government, with the potential for research that is better aligned to informing policy and with a better position to communicate. The immediate need has been covered by re-allocating resources for paused activities. The proposal here will bridge the gap between our immediate response and more sustainable long-term funding. This will allow us to sustain the enhanced relationships developed through our response to the pandemic, and will avoid the reputational risks that might be associated with failing to support the obvious ongoing need while establishing more sustainable long-term projects and core provisions.
|
| 29/01/2021 |
£115,046 |
CODE FOR SCIENCE AND SOCIETY |
Research software is a critical component of open research, and an increased focus on research software challenges will further the objectives of Wellcome Trust’s Open Research programme to maximise research impact. The Research Software Alliance (ReSA) advances the vision that software is valued as a fundamental component of research. This proposal will support ReSA to bring research software communities together to collaborate on the advancement of research software, utilising application of the FAIR principles as a catalyst for this global endeavour.
This project seeks USD$157,250 to engage the research software community to apply the FAIR principles to research software. to achieve three aims:
FAIR4RS WG project direction to develop agreed FAIR for research software principles
FAIR4RS Roadmap leadership to map FAIR for research software projects into a longer-term strategic framework
People Roadmap to support the development of career paths and reward structures to complement the FAIR4RS Roadmap
This proposal will accelerate the development of an open research system that recognises and supports research software. This will provide researchers with the skills and resources to fully utilise research software, in a system where policy makers and funders value research software, and where organisations adequately reward staff with software expertise.
|
| 29/01/2021 |
£338,472 |
WORLD HEALTH ORGANIZATION, SWITZERLAND |
Antivenoms are bespoke biologicals that have been the mainstay of snakebite treatment for 125 years. Requirements for production, safety and efficacy vary across regulatory environments. Shortages of effective antivenoms have emerged as important public health issues, particularly in Sub-Saharan Africa. The variability of current products in this market present substantial challenges. WHO is exploring a pathway for prequalification of antivenoms and identified a need to develop target product profiles (TPPs) to support optimisation of current and emerging products. TPPs can play a central role in the drug discovery and development process towards desired product characteristics, including access, equity and affordability considerations. At present, there are no available public-interest TPPs for snake antivenoms. We will develop public-interest WHO TPPs with preferred and minimally acceptable profiles for antivenom therapeutics, with an initial focus on Sub-Saharan Africa. The work will be a collaboration between WHO and DNDi following the 2018 WHO TPP Generic Methodology. The resultant WHO TPPs will be widely shared through diverse communication channels and publications, and listed in the WHO Health Product Profile Directory. TPPs will assist product standardization and guide more targeted research and development of antivenoms.
|
| 29/01/2021 |
£1,485,631 |
WORLD HEALTH ORGANIZATION, SWITZERLAND |
Sub-Saharan Africa has a high snakebite burden, compounded by a lack of safe, effective and affordable treatments that are accessible to victims. Across seven East African countries (Ethiopia, South Sudan, Uganda, Kenya, Tanzania, Rwanda and Burundi) there are an estimated 89,940 (95% Confidence Interval: 74,511-105,385) cases of snakebite each year, while in seven West African nations (Cameroon, Nigeria, Chad, Togo, Benin, Ghana and Burkina Faso) there are 70,712 (95% CI: 58,348-84,791) cases annually. Access to snake antivenoms for the treatment of snakebite envenoming in sub-Saharan Africa has been declining since at least the 1970’s and current data provided to WHO suggests that
|
| 29/01/2021 |
£639,793 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
Nepal, as for much of Asia, has high levels of labour migration, particularly to neighbouring India and the Middle East. The SARS-CoV-2 pandemic has caused a chaotic mass return migration event. While the government has attempted to quarantine and test returning migrants the fragile infrastructure has been rapidly overwhelmed and repeated migration waves have occurred into remote rural areas.
The epidemic in Nepal is now entering the rapid escalation phase. Despite this surge, the government has been forced to raise the lockdown, imposed since March 24th, due to the economic and political consequences. There is limited understanding of the pattern and extent of transmission in this context due to limited and sporadic testing.
Understand how return migration is influencing the epidemic dynamics in rural vs. urban contexts.
Understand how the reported data from the core government testing system compares to estimated community prevalence dynamics to predict testing capacity gaps and refine future response.
Determine sensitivity and specificity of GeneXpert Xpress testing using nasopharageal swabs or saliva against RT-PCR for SARS CoV-2 infection.
Sequence a cohort of 500 SARS CoV-2 samples to understand the patterns of repeated introduction, seeding and transmission occurring in rural and urban areas as the epidemic unfolds.
|
| 29/01/2021 |
£4,059,969 |
COALITION FOR EPIDEMIC PREPAREDNESS INNOVATIONS (CEPI) |
A large-scale study in the Democratic Republic of Congo (DRC) to deliver Janssen's candidate Ebola vaccine regimen VAC52150 (Ad26.ZEBOV, MVA-BN-Filo). The vaccine Ad26.ZEBOV (5x1010 viral particles[vp]) will be given as the first dose and the vaccine MVA-BN-Filo (1x108 infectious units [Inf U]) will be given as the second dose 56 (-14 day +28 day) days later, to adults, and children aged 1year or over. Evaluation of this intervention will include the estimation of the effectiveness of the two-dose vaccine regimen to prevent Ebola Virus Disease (EVD) and a qualitative component of the understanding and perceptions of individuals of this study. The primary objective is to estimate the effectiveness of vaccination of the population with the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen for the prevention of EVD in adults and children aged 1 year or above. The study sponsor will be the London School of Hygiene and Tropical Medicine (LSHTM). The study PI will be Professor Jean-Jacques Muyembe-Tamfum from the DRC Institut National de Recherche Biomédicale (INRB).
|
| 19/01/2021 |
£325,774 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
This research will investigate the ethics of British public health over the period 1920-2020, through the lens of public health law. In so doing, it will develop the ‘public health humanities’ as a mode of designing and implementing interdisciplinary research in public health. My goals are to discover how the implicit and explicit ethical frameworks of public health law have changed over the period in question; to analyse how and why these changes came about; and to explore methods for investigating public health ethics from interdisciplinary perspectives. I will use documentary and archival sources to locate and interrogate moments of morally inflected controversy in public health law, and will work collaboratively with public health practitioners and researchers to explore novel methods of data generation and analysis. Attention to ethics and public health law in Britain 1920-2020 disrupts assumptions that ethics in this time and place has been neutral and unchanging, and examines relationships between shifting ethical frameworks and factors including the post-war welfare state and its subsequent roll-back, decolonisation, migration, epidemiology, HIV/AIDS, and bioethics. The project will historicise ethics, connect past and present, and provoke cross-disciplinary interrogation and integration, for the benefit of the humanities and public health alike.
|
| 19/01/2021 |
£263,061 |
UNIVERSITY OF EDINBURGH |
Who delivers health care, where and why? The COVID-19 pandemic has underscored stark global inequalities in answers to these questions. ‘Community participation’, an enduring pillar of interventions in the Global South, has been leveraged in response to COVID in Africa via Community Health Workers (CHWs). Key agencies who recruit Africa’s army of Community Health Workers (CHWs) have declared them to be COVID’s emerging ‘first line of defence’. This research will examine the structural factors that lead to the recruitment of CHWs and which contribute to the persistent undervaluing of CHWs’ work in Kenya. The research will innovate in its combination of discourse analysis, informed by critical/feminist/postcolonial thought, with detailed ethnographic fieldwork in Kenya's marginalized north. The research will firstly provide a critical reading of the ‘imperial remains’ within CHW recruitment practices on the part of health agencies and INGOs. The research will secondly provide a historicized reading of (gendered) narratives regarding citizenship, public service and voluntarism in postcolonial Kenya. This research will then be brought into dialogue with detailed interviews with and ethnography of/by CHWs in Isiolo, northern Kenya, with implications for CHW policy but also for rethinking the desirability and justness of one of global health’s core assumptions.
|
| 19/01/2021 |
£175,664 |
UNIVERSITY OF MANCHESTER |
Novel social and cognitive science, approaching people and places as indivisible assemblages, challenges dementia research’s traditional humanism (people as exceptional entities) and neuroreductionism (brains as cognitive supercomputers). However, these traditional ideas permeate current "dementia-friendly" strategies, positing that agentic persons inhabit inactive spaces. Resulting initiatives assume that architectural refinement will maximise individuals’ intrinsic cognitive capacities, overlooking the complex distribution of cognition throughout evolving atmospheric spaces. They often lack user perspectives and sophisticated theoretical grounding. In response, I will combine cutting-edge scholarships to explore cognition-environment relations through a sensory ethnography of Manchester’s public transport, a target for dementia-friendly initiatives. I will accompany 25 passengers with dementia, documenting the journeys through interviewing, fieldnotes, photography and mapping. Participants will capture photographs and videos for an exhibition across the transport network. The exceptionally rich dataset, comprised of audio-visual media, sensory ethnographic data and maps, will be made available to future researchers. The project will challenge outdated assumptions in dementia research and policy, developing proposals for improving each. It aligns with policy priorities and will propose service improvements in collaboration with key stakeholders. It will generate an unprecedented open-access dataset for analysing dementia-friendliness and cognition-environment relations, and pioneer methods for inclusive ecological dementia research.
|
| 19/01/2021 |
£161,826 |
UNIVERSITY OF READING |
My project will investigate images (drawings, illustrations, and photographs) as central to scientific research into causes of the disease and the mechanisms of its spread in British India between 1890 and 1940. Despite Ronald Ross’ own emphasis that his experiments on malaria were visual revelations, visual representations of malaria have remained neglected in historiography so far. I intend to explore how images informed research on malaria and influenced future inquiries into the development of tropical medicine and the processes of their institutionalisation. This project enriches the scholarship on malaria in colonial India by bringing into focus the importance of visuality in knowledge-making. This will facilitate an exploration of the power of images in strengthening, as well as shaping resistance to British imperialism; and also how medical visual culture gave meaning to human-animal relationships within an imperial context. In so doing, beginning with scientific images produced in the laboratory, I move into the domains of British administration and that of the vernacular reception, translation, and appropriation of the malarial iconography. By examining the interactions between the fields of arts and medical science, this project will be a major contribution to the historiographies of British colonial medicine and modern South Asia.
|
| 19/01/2021 |
£154,510 |
UNIVERSITY OF WARWICK |
This project will produce a cultural and social history of speech therapy in twentieth-century Britain that is ambitious in seeking to account for the entwined relationship of speech therapy to stammering activism, not simply in a relationship of medical professional to patient. Municipalities employed speech therapists from c.1906 to ‘correct’ what (in contemporary language) were considered ‘defects’ of children’s speech. Early therapists were often female, trained in drama-school elocution and only later became medicalised. Consequently, they were as marginalised as the disabled subjects they sought to ‘treat’. Conversely, individuals who stammered long pointed towards the uniqueness of their position and voice to militate for improved therapy. In short, this project allows an ambitious study that cuts across normally polarised voices of ‘medical professional’ and ‘patient experience’ to explore the boundaries of what encompasses ‘the medical’ itself: both as practices (elocution therapeutics and activism) and as theories (what ‘stammering’ meant). ‘The Child’s Speech’ therefore offers a unique case study into the margins of disability studies which can point towards new frameworks for thinking about professionalisation; its relationship to competing, but also harmonising, forms of expertise, patient voice, experience and activism; and wider gender, race, class and disability dynamics within these.
|
| 19/01/2021 |
£210,087 |
UNIVERSITY OF LIVERPOOL |
The research project offers an in-depth analysis of the conflation between biomedical practice, care and antiblackness in the colonial wake. Using historical, geographic and ethnographic methods, it examines how the history of enslavement and colonialism is entangled with notions and practices of Western biomedical care and the spatial organisation of a postcolonial hospital. As a location for this study I have chosen Connaught Hospital in Freetown, Sierra Leone. Situated on Freetown's Northern coast between White Man's Bay and Susan's Bay, this was both the setting for mandatory quarantines for liberated slaves and the site of the British-built Colonial Hospital. Working with Sierra Leonean healthcare staff, I will examine the hold this violent past has on Sierra Leonean conceptions of care and trust in biomedicine. This allows me to 1) explore how biomedicine's conflation with antiblackness shapes biomedical encounters in postcolonial Sierra Leone and 2) examine how biomedical spaces and infrastructures perpetuate feelings of distrust and exclude other forms of care. In doing so I will 1) challenge the traditional geographical remit of Black Studies, 2) study how antiblackness weaves its way through medicine and care and 3) give Fanon's analyses of colonialism, racism and biomedicine a contemporary & geographic dimension.
|
| 19/01/2021 |
£246,365 |
KING'S COLLEGE LONDON |
Data-driven health research, and the technologies it produces (DHRTs), are increasingly driving the UK health sector. DHRTs, which rely on advanced computing sciences and ‘big data’, have the potential to make a profound impact on society, and the pace of development is staggering. Equally, the databases, infrastructures, and software supporting DHRTs have important environmental and health impacts: their heavy energy requirements lead to high carbon dioxide emissions, and the reliance on minerals to develop their technological components can lead to unsustainable and/or toxic mineral extraction and e-waste disposal. While the environmental footprint of DHRTs may be considered unproblematic because of improvements in energy efficiency and the move to renewable energy, the speed of innovation is set to outpace the world’s renewable energy sources, leading to increases in carbon emissions when other sectors are decreasing their energy use. Moreover, issues of unsustainable mineral extraction/e-waste disposal still remain. It is imperative that the environmental footprint of DHRTs is considered through responsible innovation that targets environmental sustainability. This project’s aim is to use a UK perspective, qualitative case-study approach, that builds an empirical knowledge base that identifies the ethical, social and regulatory issues associated with DHRT’s environmental impacts.
|
| 19/01/2021 |
£276,979 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
As people live longer, the coexistence of multiple conditions in one individual – ‘multimorbidity’ – becomes more common. Scholars across the biomedical sciences have expressed concern that research, training and care systems remain organised along single-disease and single-organ-system lines and that new ways of producing knowledge about multimorbidity are needed. Medical anthropologists, with well-established strengths in illuminating and unsettling dominant frameworks, are ideally equipped to collaborate with biomedical scientists to articulate and respond to the challenge posed by multimorbidity. Using the analytic frame of ‘epistemic infrastructures’, referring here to the fragmented global assemblages through which knowledge about (multi)morbidity is produced and legitimised, I will investigate how individuals in different settings and communities of practice understand and engage with multimorbidity. Further, I will co-produce with them a conceptual framework for responding to this complex bio-social phenomenon. To achieve this, I propose a collaborative multi-site ethnographic study in global health institutions in the UK and research, training and care institutions in Zimbabwe, involving participant-observation, in-depth interviews and participatory methods. These activities, culminating in a symposium, will iteratively build the proposed framework. By involving biomedical researchers throughout, my research will be uniquely positioned to open new pathways to influence research, policy and care.
|
| 19/01/2021 |
£177,775 |
UNIVERSITY OF LEICESTER |
This project will produce a history of grief and loss in late-Georgian Britain (c.1760-1830) that re-evaluates current perceptions of grief as unhealthy, and will redress the imbalance in historical and literary studies that have focused overwhelmingly on assessments of bereavement, mourning and mortuary rituals. It will recover the full range of Georgian experiences of grief to show how understandings of grief extended far beyond the immediate emotional upheaval associated with death, encompassing much wider definitions than those we attribute to grief today. Grief awarded meaning to interpersonal relationships, offerering avenues for self-reflection and providing comfort during periods of separation. This project will apply historical and literary research techniques to a linguistic and material culture analysis of grief, and engage with research in psychology, sociology and philosophy. It will interrogate grief across three main themes: Sadness and Separation; Bereavement; Loss and Abandonment – which are embedded within acts of resilience, remembrance and recovery. The main goals of this project are (1). to investigate what it meant to grieve in late-Georgian Britain (2). to examine the relationship between grief, loss, comfort and well-being, and to (3). assess to what extent experiences of grief were regulated by conventions and mediated through socio-cultural codes.
|
| 19/01/2021 |
£333,089 |
UNIVERSITY OF SHEFFIELD |
There is a growing recognition that Alzheimer’s-like dementias need to be understood in environmental, rather than simply genetic, terms. Head injury has been identified as one such environmental antecedent to dementia and a new class of dementias known as TReNDs – Traumatic brain injury Related NeuroDegenerative disorderS – has emerged. This recasting of Alzheimer’s-like dementias as environmental conditions has significant implications for professions, patients, and publics and potentially transforms the classification, diagnosis, treatment, and regulation of neurodegeneration.
This project is based around a multi-sited ethnography, undertaken with scientists in molecular neuroscience; neuropathology; and sports science. Sitting at the intersection of medical sociology and Science and Technology Studies, the project asks:
Q1: How does depicting Alzheimer’s-related dementias as environmentally-induced change understandings of the classification, cause, and diagnosis of neurodegenerative disease?
Q2: How is research into traumatic brain injury shaping novel therapeutic interventions for neurodegenerative diseases? What are the consequences for patients?
Q3: How are regulations embedded into research on environmentally-induced dementias? What are the envisaged risks, regulations, and wider policy implications of this biomedical research?
In asking these questions, this project is amongst the first to empirically explore the societal and scientific implications of these emerging sciences of dementia.
|
| 31/12/2020 |
£50,000,000 |
AMR ACTION FUND GP, LLC |
The AMR Action Fund aims to bridge the funding gaps and technical barriers that antibiotic developers face as they head into later-stage development and ensure new treatments for drug-resistant infections are available to the patients who need them the most. We aim to bring 2-4 new antibiotics to patients by 2030. We will work with partners to create market conditions that enable sustainable investment in the antibiotic pipeline. |
| 31/12/2020 |
£147,298 |
TASK FORCE FOR GLOBAL HEALTH |
Early 2019, a group of global health leaders with expertise in influenza, vaccinology and pandemic preparedness convened in London, for a Wellcome Trust-supported "Shaping Meeting to explore the value of a coordinated work plan for epidemic and pandemic influenza vaccine preparedness." Ready2Respond was formed as a global collaboration of partners committed to enhancing lower income countries’ readiness to respond against influenza and respiratory viral pandemics. With a Secretariat established at The Task Force for Global Health, Ready2Respond identified challenges and actionable solutions to promote pandemic preparedness. Though initially based on influenza preparedness, these priorities now include COVID-19.
Three Expert Working Groups will design and execute cross-collaborative projects within three strategic priorities.
Burden of Disease
Risk Communication and Community Engagement
Vaccine Access
Ready2Respond seeks an initial grant from the Wellcome Trust of US$ $196,650. This initial grant will allow to:
retain a Director, tasked with developing a comprehensive action plan with potential projects to start in 2021.
execute a mapping study of organizations and agencies working on global seasonal and/or pandemic vaccine preparedness to ensure the relevance of Ready2Respond’s mission and activities in the preparedness ecosystem.
support communication activities to secure funds for identified projects from potential partner organizations.
|
| 31/12/2020 |
£4,575,696 |
UNIVERSITY OF CAPE TOWN |
In the WHO AFRO, there is a need for sustainable mechanisms to provide scientific and technical EIDM support for vaccines and immunisation. We propose to establish a Regional Scientific Hub (RSH) to support NITAGs with EIDM. The RSH’s mission is to enable NITAGs in the WHO AFRO to strengthen EIDM with respect to vaccines and immunisation practices. The RSH will offer the EIDM support to NITAGs in close collaboration with the WHO. Public health professional members working within immunisation programmes, technical partners and other health groups will also be supported by the RSH. The support provided by RSH will strengthen the effectiveness of African NITAGs, resulting to an enhanced access to existing and new vaccines in the region.
Through the provision of the EIDM support, the RSH key goals are:
- Enhance access and use of EIDM resources and tools by members of NITAGs
- Empower NITAGs to produce timely and independent evidence-based recommendations that inform national decisions on vaccines
- Foster an increased national ownership of immunisation programmes in the region.
- Accelerate the strengthening of national immunisation programmes
Achieving these goals will result to increased immunisation rates and improved introduction of new vaccines in the WHO AFRO.
|
| 31/12/2020 |
£3,750,237 |
UNIVERSITY OF OXFORD |
The ACORN project will establish a network of hospitals and clinical laboratories in Asia and Africa to implement efficient patient-focused antimicrobial resistance (AMR) surveillance. Network data will be used to determine AMR disease burden, risk factors, and patient and economic impacts for key clinical syndromes and associated pathogens.
ACORN will address the need for better systems for linked clinical and microbiology data analysis to enable clinicians and ministries of health to understand and respond to the locally and nationally relevant AMR challenges and to engage meaningfully with international surveillance efforts. ACORN will provide simple to use data collection, visualisation, and analysis tools along with a framework for sites to improve clinician utilisation of diagnostic microbiology resources. Targeted clinical and outcome data collection will enable local use of pathogen and antimicrobial susceptibility data, for example by identification of high-risk patients and for development of empiric treatment guidelines.
Global AMR surveillance and mitigation endeavours are weakened as a result of limited active healthcare provider engagement via local data use. Project engagement efforts will focus on promotion of widespread adoption of ACORN, through collaborative links with key AMR stakeholders, to ensure that future global surveillance has meaning, from the ground up.
|
| 31/12/2020 |
£2,283,242 |
INTERNATIONAL VACCINE INSTITUTE |
The need for vaccines against invasive non-typhoidal salmonella (iNTS) is now increasingly being recognized, but there is no iNTS vaccine available for use in humans. Several potential candidate vaccines against iNTS are being developed. Vaccine development considerations include a bivalent iNTS vaccine (Typhimurium and Enteritidis) or possibly a trivalent vaccine (Typhi/iNTS). Such financial investments not only need public-private partnerships, but also demand economic and public health justification. The World Health Organization (WHO) and other global partners have recently highlighted the need to justify investments in vaccines from a multi-stakeholder perspective.
The overall objective of this project is to develop a Full Value of Vaccine Assessment (FVVA) to understand the value of investment in an iNTS vaccine from a multi-stakeholder perspective. The long-term goal of this proposal is to pave the way for the development of a safe and efficacious iNTS vaccine, in-country licensure (marketing authorization in the country of manufacture), any necessary policy recommendations from the WHO Strategic Advisory Group of Experts (SAGE) on Immunization, WHO prequalification (PQ), Gavi financing, UNICEF purchasing and national technical advisory groups recommendations for vaccine use. This will be achieved as a joint IVI/WHO leadership and collaboration through a consensus process in partnership with multiple stakeholders." |
| 31/12/2020 |
£1,418,660 |
EUROPEAN BIOINFORMATICS INSTITUTE |
In the next five years, the necessity for open science to solve global challenges will become increasingly apparent, and the need for Europe PMC as a critical piece of infrastructure will crystallise in the minds and usage patterns of researchers. The world of scientific publishing will undergo major changes, as routes for rapid and transparent publishing emerge, and efforts such as Plan S push towards universal open access. Europe PMC will support these goals by aggregating millions of articles and making them widely available. With a leading role in preprint aggregation and standards development, Europe PMC will be the go-to resource for searching life sciences literature from publication through review, revision, and citation. Publications at all stages need to be grounded in unambiguous links to supporting data, authors and reviewers, funding, and institutions, to build transparency and trust in the content; building these links will be a major direction for Europe PMC. Finally, transformative change in content search and retrieval will come from the development of AI methods that work on open access full text, encouraged by the Europe PMC platform for text and data mining, as well as the demonstration of machine learning benefits in user interfaces.
|
| 31/12/2020 |
£244,662 |
UNIVERSITY OF OXFORD |
Not available |
| 08/12/2020 |
£777,721 |
UNIVERSITY COLLEGE LONDON |
Despite successfully suppressing HIV infection with antiretroviral therapy (ART), cerebrovascular disease, including stroke and cognitive impairment, remains a dominant complication in this population. I have shown that HIV is a leading risk factor of stroke in the young and can contribute to 15-30% of overall stroke presentations in endemic regions. There is good evidence that atherogenesis is part of the mechanism. Chronic inflammation and antiretrovirals are amongst confounders that obscure delineating the exact pathway to atherogenesis. The Neurovascular Unit (NVU) which consists of the cerebrovascular endothelium supported by astrocytes and pericytes is pivotal to maintaining blood vessel function and impeding HIV to enter the brain. To date, scientific advancement has been limited by developing experimental systems that replicates the NVU in its normal environment. My fellowship proposes to use a powerful new in vitro multicellular 3D model of the NVU, with blood brain barrier (BBB) properties similar to those found in vivo, to investigate how HIV crosses the BBB, establishes NVU infection, and triggers endothelial dysfunction, a precursor for atherogenesis. Finally, I will exploit an established cohort of HIV patients with ART and phenotyped for cerebrovascular disease in Malawi, to verify the mechanistic insights from my in vitro findings.
|
| 08/12/2020 |
£1,194,434 |
UNIVERSITY OF OXFORD |
Entrapment neuropathies are the most common conditions causing nerve-related pain. Even though Physiotherapy is the recommended treatment, research suggests only modest benefits. A major road-block is the lack of adequate patient stratification. My fellowship will address this by investigating the role of neuroinflammation in precision physiotherapy. The key goals are to 1) characterise human neuroinflammation, 2) validate magnetic resonance neurography (MRN) as a non-invasive marker and 3) determine whether physiotherapeutic exercises (neurodynamics) can reduce neuroinflammation. I will use longitudinal cohorts of patients with carpal tunnel syndrome (CTS) and Morton’s neuroma undergoing surgery as model systems with unparalleled access to injured tissues (e.g., nerve, skin, tenosynovium, blood). I will characterise neuroinflammation and its relationship to symptoms in these samples using gene/protein expression and histological analyses. By directly comparing MRN with histological findings, I will determine its validity as a non-invasive marker for neuroinflammation. I will then perform a mechanistic trial to investigate whether neurodynamic exercises reduce neuroinflammation by measuring MRN before and after exercises or control interventions in CTS patients. My project will provide novel biological insights into neuroinflammation, and may revolutionise its clinical detection. The development of precision physiotherapy has high potential to reduce patients’ suffering and decrease healthcare costs.
|
| 08/12/2020 |
£658,017 |
IMPERIAL COLLEGE LONDON |
Antibodies are fundamental to defence against a wide range of infectious agents and yet antibody responses vary markedly from individual to individual. Although the reasons for this remain unclear, there is strong reason to suspect a role for immunoglobulin gene regions, not least because these are amongst the most variable in the human genome. In earlier work, I linked the immunoglobulin heavy chain (IGH) locus to susceptibility to the most serious diseases caused by Streptococcus pyogenes, a major global health concern, and I now wish to determine the biological basis for this association. This proposal therefore aims to test my hypothesis that common genetic variation in this locus impacts antibody-mediated immunity to S.pyogenes in a manner that alters disease susceptibility. To do this, using an innovative high-throughput long-read sequencing approach, I will establish the extent and nature of germline IGH variation in children and adults with and without severe infection. I will then assess the relationship between IGH variation and antibody-mediated immunity as well as susceptibility to severe infection. Moving forward, I plan to use this approach to identify and prioritise antigens for rationale design of highly targeted vaccines and antibody-based therapeutics to combat a range of infectious diseases.
|
| 08/12/2020 |
£1,155,073 |
UNIVERSITY OF LIVERPOOL |
Worldwide many women require drug treatment during breastfeeding, but data surrounding transfer of drug from mother to breastfed infant are scarce and of very low quality. This fellowship will provide robust pharmacological data to inform evidence-based decision-making, through collaboration between University of Liverpool, UK; Infectious Diseases Institute, Makerere University, Uganda (IDI); and University of Cape Town, South Africa (UCT).
The drug exposure of infants of breastfeeding mothers requiring treatment for TB (drug-sensitive or drug-resistant), malaria and peri-partum infection, identified as local priorities, will be described. Intensive pharmacokinetic sampling of maternal plasma, breastmilk and infant blood will be undertaken. Bioanalysis will be done in the country of study, with capacity building at IDI supported by Liverpool and UCT. Consolidation of an integrated clinical and modelling approach for clinical pharmacology at IDI will ensure the generation of high-quality, robust data, and a sustainable group generating fresh ideas and proposals alongside the fellowship.
South-north knowledge transfer will help define research priorities for the UK and build expertise in lactation pharmacology in Liverpool. Public engagement activities in both the UK and Uganda will communicate about study activities and harness the views and concerns of community members and healthcare workers about medication use in breastfeeding.
|
| 08/12/2020 |
£1,148,941 |
NEWCASTLE UNIVERSITY |
Generative models of perception, such as predictive coding, are mainstays of contemporary neuroscience. Whilst there is abundant evidence and theory concerning what is predicted and when it is expected, little is known about how predictive models influence how strongly sensations are received (i.e. their intensity, or its perceptual counterparts such as loudness).
This proposal builds upon the handful of studies demonstrating the existence of predictive processing of intensity, and on my own published work demonstrating that pathological states of perception (i.e. tinnitus) can be understood, and objectified, as pervasive states of aberrant sensory predictions. Its goal is a clear picture of the function and neurobiological basis of predictive intensity processing, which might subsequently lead to diagnostic and therapeutic avenues for clinical disorders such as tinnitus, chronic pain and fibromyalgia.
The investigative approach is multifaceted, examining a range of hierarchical levels through a progression of paradigm complexity, and using complementary neuroimaging modalities, including electroencephalography (EEG), magnetoencephalography (MEG), electrocorticography (ECoG) and functional MRI. The predominant focus is auditory intensity (and loudness) in normal-hearing controls, with a subset of successful paradigms being run in clinical populations (to demonstrate the practical relevance of measures obtained), and in the somatosensory system (to demonstrate modality-independent commonalities).
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| 08/12/2020 |
£811,808 |
UNIVERSITY OF CAMBRIDGE |
I recently discovered the function of a previously uncharacterised gene, FAMIN, that is linked to Crohn’s disease, leprosy and arthritis. A multifunctional purine enzyme, FAMIN is the pacesetter for purine recycling and hence determines cellular redox status, pH balance and energy production. Altogether, these control macrophage functions, such as bacterial killing and cytokine production. Importantly, my work has established this therapeutically targetable purine pathway as a direct driver of human inflammatory disease. However, further investigation of this pathway is currently limited by the inability to directly visualise and study purine metabolites in-situ, in real-time, and at single-cell resolution. Thus, the spatiotemporal dynamics of purine metabolism are mostly unknown. Assessing these dynamics will be crucial in understanding how purine dysfunction emerges in individual cells and can influence disease pathogenesis, for example through affecting redox state. Samie Jaffrey has pioneered technology that could overcome this hurdle. His group has generated programmable RNA-biosensors capable of live-imaging metabolites in single cells. I intend to learn these techniques and will engineer bespoke sensors for purine metabolites. I shall use these biosensors to dynamically track purine metabolism, and interrogate how environmental triggers can cause the purine dysfunction seen in numerous pathological contexts including chronic inflammatory diseases.
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| 08/12/2020 |
£1,588,250 |
KING'S COLLEGE LONDON |
The sex chromosomes underscore basic differences between males and females, and the X and Y chromosomes have specialized functions in the gonad and germ cells. Sex chromosome aneuploidies, i.e. Klinefelter (XXY), Turner (XO) and double-Y (XYY) syndromes), form the largest group of chromosomal abnormalities and are associated with infertility. While recent studies have defined the mechanisms for germ cell loss in XO and XYY mice, Klinefelter syndrome (KS) infertility remains poorly understood. KS males experience an early spermatogonial block and germ cell loss initiates in utero. The early loss of gonadal function has significant long-term consequences.
Gametogenesis in males occurs throughout their lifespan and relies on germline (spermatogonial) stem cells (SSCs), differing with females. Recent work from our group has identified the concerted activity of gene networks in driving spermatogenesis, and unique regulation of X-linked genes during this process. We observe that a number of X-genes express specifically in SSCs. However, regulation of SSCs self-renewal vs. differentiation dynamics, and the functional importance of X-linked genes in this process, remain poorly understood. We aim to understand physiological gene regulatory networks functional in SSCs using a combination of single-cell methods, to explain how perturbation in X-gene dosage in SSCs may cause infertility.
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| 08/12/2020 |
£611,636 |
QUEEN MARY UNIVERSITY OF LONDON |
My proposal is focused on understanding the genetic basis, and consequently the pathophysiology, underpinning disordered human puberty.
Pubertal disorders are common, but associated with severe comorbidities. Delayed puberty presents a diagnostic challenge in adolescence, as conditions of gonadotropin deficiency and isolated delayed puberty display the same clinical and biochemical phenotype. However, correct management is vital because the former is associated with infertility and requires intensive reproductive therapy, whereas the latter is self-limiting but associated with a shortened reproductive lifespan. The biological mechanisms of precocious puberty, a condition associated with increased long-term cardiovascular and cancer risk and thus with significant impact on public health, remain similarly opaque.
The identification of causal genetic defects in disordered puberty allows interrogation of the key regulators of human puberty.
I will use whole genome sequencing, comparative transcriptomics and methylomics studies in my large human cohort with disordered puberty, to define shared exonic and regulatory mutations resulting in delayed and precocious puberty. I aim to characterise the biological mechanisms underlying pubertal disorders through functional characterisation of novel genomic defects using cellular assays and animal models. These findings will ultimately translate to improved diagnostics, tailored therapeutic management and improved long-term outcomes for patients with disorders of puberty.
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| 08/12/2020 |
£807,333 |
UNIVERSITY OF LEEDS |
Patients with type 2 diabetes(T2D) are ‘cardiac energy-deficient’ and this deficiency contributes to their excess heart failure(HF) risk. The key mechanisms for cardiac energy deficiency are reduced myocardial blood flow, loss of metabolic flexibility over the choice of energy fuels and mitochondrial dysfunction. The contribution of these changes to the development of HF has not been systematically studied.Recent studies have highlighted the potential role of ketone bodies as a significant fuel source, and suggested an association between mild ketosis and improved clinical outcome in T2D.
Two work packages will be performed. Work-package1 aims to:
Elucidate the mechanisms of the energy-starved state of the heart in diabetes;
Determine how alterations of cardiac energy metabolism differ between prediabetes, T2D, and concomitant T2D and HF;
Determine if ketones induce a differential response in mitochondrial respiration and whether this differential response varies along the continuum of diabetic heart disease.
Data will be acquired from patients undergoing aortic valve surgery for comprehensive assessments including: cardiovascular magnetic resonance imaging and spectroscopy; coronary sinus sampling studies; high resolution respirometry and liquid chromatography-triple quadrupole-mass spectrometry metabolomics from heart samples.
Work-package 2 will explore the impact of ketone infusion on cardiac energy generation and contractile function in T2D patients.
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| 08/12/2020 |
£321,092 |
UNIVERSITY COLLEGE LONDON |
Congenital athymia causes life-threatening T-cell immunodeficiency. The only definitive treatment is thymus transplantation (TT). Despite lack of major histocompatibility complex (MHC)-matching between donor and host, transplanted thymus, repopulated by recipient bone marrow-derived lymphoid progenitors, supports functional T-cell development restricted to host MHC alleles. Though lifesaving, TT results in subnormal circulating T-cell numbers and frequent autoimmune complications. I aim to dissect the cellular and molecular mechanisms of lympho-stromal crosstalk and thymopoiesis in the context of MHC-mismatched TT by using single-cell and spatial genomics on pre-transplantation cultured thymic tissue and post-transplantation graft biopsies. Donor thymocytes, possibly including long-lasting lymphoid progenitors, remaining at the time of transplantation despite lympho-depleting preparatory culture, may contribute to this crosstalk and assist thymic epithelial cell (TEC) homeostasis. Other recipient-derived haematopoietic cells may migrate into the graft to replace direct interactions between developing host thymocytes and TECs. Alternatively host TECs may develop in the transplanted thymus. I hypothesise that partial MHC-matching improves crosstalk signalling, achieving better immunoreconstitution and less autoimmunity. Optimising in vitro differentiation and maturation of TECs derived from pluripotent stem cells will make the in-depth investigation of MHC-TCR interactions and downstream signalling possible. New insights into TEC biology will advance alternative approaches to thymus replacement therapy.
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| 08/12/2020 |
£99,012 |
WELLCOME SANGER INSTITUTE |
Congenital athymia causes life-threatening T-cell immunodeficiency. The only definitive treatment is thymus transplantation (TT). Despite lack of major histocompatibility complex (MHC)-matching between donor and host, transplanted thymus, repopulated by recipient bone marrow-derived lymphoid progenitors, supports functional T-cell development restricted to host MHC alleles. Though lifesaving, TT results in subnormal circulating T-cell numbers and frequent autoimmune complications. I aim to dissect the cellular and molecular mechanisms of lympho-stromal crosstalk and thymopoiesis in the context of MHC-mismatched TT by using single-cell and spatial genomics on pre-transplantation cultured thymic tissue and post-transplantation graft biopsies. Donor thymocytes, possibly including long-lasting lymphoid progenitors, remaining at the time of transplantation despite lympho-depleting preparatory culture, may contribute to this crosstalk and assist thymic epithelial cell (TEC) homeostasis. Other recipient-derived haematopoietic cells may migrate into the graft to replace direct interactions between developing host thymocytes and TECs. Alternatively host TECs may develop in the transplanted thymus. I hypothesise that partial MHC-matching improves crosstalk signalling, achieving better immunoreconstitution and less autoimmunity. Optimising in vitro differentiation and maturation of TECs derived from pluripotent stem cells will make the in-depth investigation of MHC-TCR interactions and downstream signalling possible. New insights into TEC biology will advance alternative approaches to thymus replacement therapy.
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| 01/12/2020 |
£2,387,230 |
UNIVERSITY COLLEGE LONDON |
The vast majority of DNA is non-coding, repetitive, encompasses a significant proportion of disease risk and is divergent across populations. Major bottlenecks in the past restricted our understanding of this genomic region, including limited analysis techniques, inability to sequence large repetitive, homologous regions and the paucity of population control datasets. These restrictions have largely been overcome, and through early translation we have highlighted the importance of non-coding genomic factors with the identification of pathogenic recessive repeat expansions, homologous replicated regions and gene amplification events as major causes of neurological disease.
The overarching theme of this proposal is to investigate four large diverse neurology cohorts, where genome sequencing has explained less than one-third of cases. Initially, we will examine non-coding, short-read genome sequencing data using optimised and newly developed algorithms. Next, to overcome the limitations of short-read sequencing, we will apply and integrate long-read Oxford Nanopore genome sequencing and optical genome mapping to a range of neurological disease trios and paired brain and blood samples. Finally, we will comprehensively interpret and validate data, reannotate against diverse control genomes, compare disease-relevant transcriptome builds, interrogate collaborator cohorts and use transcriptome sequencing to inform on pathogenicity, identify mechanisms and pathways impacted by genetic vulnerability.
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| 01/12/2020 |
£2,298,141 |
UNIVERSITY OF GLASGOW |
Leishmania parasites cause a neglected disease on the WHO priority list. During their life cycle, these single-celled parasites must migrate through the sandfly (promastigotes), pre-adapt for mammalian infectivity (metacyclic promastigotes) and proliferate inside macrophages (amastigotes) while withstanding host immune defences. Adaptation to these radically different environments involves many changes, including metabolic and cell structure specialisations, ensuring survival and transmission. However, current understanding of these processes is disjointed and biased towards predicted/expected pathways. Half of Leishmania’s protein-coding genes, including most unique to Leishmania, have no known or predicted function, (the "dark genome"), leaving potentially exploitable parasite biochemistry untapped in the search for new therapeutics. We aim to identify all major parasite pathogenicity factors. We will determine a) the subcellular localisation of all proteins with poorly predicted function (~50% of the genome) and b) the fitness cost of gene deletion in each life cycle stage (100% of the genome). Integrative analysis of this deep dataset will identify key pathways in 1) organelle adaptation for an intracellular parasitic lifestyle and 2) host interaction, which we will then functionally dissect. This will identify virulence factors on a genome scale, determine the most important pathways required for parasitism and illuminate the ‘dark genome’.
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| 01/12/2020 |
£2,010,416 |
KING'S COLLEGE LONDON |
Depression and anxiety are leading contributors to the burden of disease among adolescents in low- and middle-income countries (LMIC), and they disproportionally affect adolescents living in poverty. Yet, the evidence base for interventions that effectively prevent depression and anxiety among adolescents living in poverty is weak. One major shortcoming is that interventions often fail to address poverty-related social determinants of mental health and neuropsychological consequences of poverty (such as impaired self-regulation). The aim of this study is to develop and pilot-test an intervention that equips adolescents with skills to escape poverty and strengthens self-regulation, thus preventing adolescent depression and anxiety in urban LMIC settings.The study objectives are to: (1) develop a theoretical model of the causal mechanisms linking poverty, self-regulation, and depression and anxiety among adolescents (age 10-19 years); (2) collaboratively develop a multi-component selective prevention intervention targeting self-regulation and skills for academic and employment success among adolescents at high risk of developing depression or anxiety living in urban poverty in Colombia, Nepal and South Africa; (3) adapt and validate key instruments to measure eligibility, implementation, mediators, and outcomes of the intervention; and (4) undertake a 4-arm pilot randomized controlled trial of the selective prevention intervention in each site.
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| 01/12/2020 |
£2,946,454 |
UNIVERSITY OF SUSSEX |
How does a circuit of neurons process sensory information? And how is processing adjusted in relation to changes in the sensory environment or internal state of the animal? These questions will be investigated in larval zebrafish, where visual circuits and the behaviours they drive are altered in the context of
i) changes in the visual environment, such as luminance or contrast,
ii) information arriving through chemical and mechanical senses,
iii) the internal state, such as arousal or satiety, and
iv) circadian mechanisms.
To investigate how visual processing is adjusted under these different conditions we will use larval zebrafish to image neural activity through the retina and brain of the behaving animal. Zebrafish generate distinct motor responses to stimuli of different contrasts, size and speed, allowing us to investigate the plasticity of computations directly linked to behaviour.
Our guiding hypothesis is that the plasticity of visual circuits reflects use-dependent changes in synaptic strength and the actions of neuromodulators that reconfigure signal flow. A comparison of computations carried out in different circuits will be key to identifying general mechanisms by which the brain adjusts sensory processing to the sensory environment and/or internal state of the animal.
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| 01/12/2020 |
£2,367,251 |
UNIVERSITY COLLEGE LONDON |
Cognitive decline represents a significant and debilitating co-morbidity for patients with epilepsy which is poorly understood with an urgent clinical need for diagnostic, preventative and treatment strategies. Large epilepsy MRI datasets confirm progressive cortical atrophy and white matter abnormalities ; age-accelerated Tau protein accumulation has been reported in surgical resections, correlating with cognitive decline. We propose a comprehensive evaluation of mixed neurodegenerative processes integrating cross-sectional and longitudinal MRI, DWI, DCE-MRI and Tau-PETimaging with quantitative neuropathology measurements of cortical, white mater atrophy and vascular pathology and pTau in resected surgical specimens in the context of cognitive impairment and genetic risk. We aim to characterise tau forms in surgical and post-mortem cohorts compared to Alzheimer's disease and other tauopathies. In prospective surgical cohorts, Tau-PET will be correlated with CSF markers, tissue levels using autoradiography and extent of cortical atrophy with high resolution in-vivo 7T and ex-vivo 9.4T MRI. In addition, cellular drivers for tau accumulation, as MTOR and seizure activity, will be explored through human slice culture experiments with gene-expression analysis and the kinetics of tau incorporation through SILK studies and mass spectroscopy of tissues. These studies will elucidate pathomechanims of cognitive impairment, identify early disease-stage biomarkers enabling prediction and preventative strategies.
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| 01/12/2020 |
£1,212,397 |
UNIVERSITY OF OXFORD |
In vivo methods for mapping brain connections are increasingly used in systems neuroscience but are yet to have significant clinical impact. We propose to develop new computational approaches that bridge information from precise but invasive methods in animals to enhance in vivo methods in humans. We translate this framework into clinical care in surgical patients:
In Aim 1, we will leverage a unique resource of macaque tracers currently being digitised. We will use state-of-the-art machine learning to automate quantification, and image processing for mapping histology to MRI, to produce a unique resource of macaque ground truth connectivity.
In Aim 2, we will develop computational approaches to enable macaque anatomical tracers, alongside multimodal MRI in macaques and humans, to be used to improve the accuracy of methods developed in humans.
In Aim 3, we will build end-to-end approaches for connectivity-based functional localisation, and deploy this as a tool to aid pre-surgical planning for localisation of subcortical targets in deep brain stimulation and for localisation of eloquent cortex in tumour surgery.
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| 01/12/2020 |
£1,969,785 |
UNIVERSITY OF OXFORD |
Plasmids are responsible for virulence and antimicrobial resistance in many bacteria. We will dissect fundamental mechanisms of plasmid maintenance in the obligate human pathogens, Shigella spp. and Neisseria gonorrhoeae, declared as high priority organisms by WHO/CDC. Toxin:antitoxin (TA) systems (addiction systems) are important for plasmid maintenance by eliminating bacteria failing to inherit a plasmid after cell division. For example, the VapBC TA system is essential for maintaining the 210kb Shigella virulence plasmid. Additionally, TA systems (including VapBC) are increasingly recognised for their role in antibiotic tolerance, often a precursor to resistance. Despite this, little is known of how plasmid maintenance is integrated with the bacterial host, and how TA systems are activated after plasmid loss/during tolerance. Combining our understanding of variation in VapBC and the VapC toxin target tRNAfMet with multidisciplinary approaches (mutagenesis/structural:function studies/single cell analysis), we will define mechanisms of TA system activation and the temporal dynamics of events following plasmid loss that culminate in cell death. We will examine the acquisition and maintenance of resistance plasmids in Shigella and N. gonorrhoeae, and the interactions between plasmids and their contribtion to tolerance and horizontal transfer.
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| 01/12/2020 |
£1,465,345 |
UNIVERSITY COLLEGE LONDON |
This project uses computational modelling, machine learning, and big-data analysis to address key unknowns on the biology of neurodegenerative disease: when and where it starts; how it spreads over the brain ("propagates"); how it varies among diseases, subtypes, and individuals; how risk factors influence mechanisms. Current models linking imaging and other clinical data to propagation mechanisms are crude, and evaluation remains largely qualitative. The project introduces a powerful Bayesian inference framework, accounting for uncertainties throughout the data-processing pipeline, to enable robust evidence quantification of new and detailed computational models of disease propagation. The approach demands a rethink of contributing technologies. First, we unravel patient heterogeneity, which confounds propagation-model evaluation, through a new generation of data-driven disease progression models that identify fine-grained disease subtypes characterised by temporal trajectory of multi-modal biomarkers. Second, propagation models use brain connectome estimates and are confounded by high connection-error rates. We establish a new probabilistic connectomics paradigm that quantifies likelihoods of false positive and negative connections enabling models to mitigate their inevitable presence. We use the framework to provide the first truly quantitative evaluation of propagation models against state-of-the-art data sets leading to fundamental new insights on the mechanisms of pathology propagation in neurodegenerative diseases.
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| 01/12/2020 |
£1,661,908 |
UNIVERSITY OF DUNDEE |
IL-33 is a critical cytokine in allergy, obesity, helminth infection, sepsis, and respiratory viral infection. Blockade of IL-33 (or its receptor, ST2) is currently being trialled in a range of allergic and inflammatory conditions, including Covid-19. The cytokine has a short half-life on release, but conversely has effects at distal sites and over long periods. Furthermore, innate immune cells in the intestine are poorly responsive to IL-33, but susceptibility to intestinal helminths is strongly controlled by IL-33.
This project will investigate:
1) How, at a protein structural level, parasite proteins effectively block IL-33 responses. Determination of the effects on the parasite and host of blocking parasite modulation of the IL-33 pathway.
2) What are the roles and targets of IL-33 released from the intestinal epithelium, both locally (in parasite infection) and systemically (in diet-induced obesity).
3) The role of soluble IL-33 receptor in stabilisation of IL-33, and its effects at distal sites.
To achieve these aims will we will use structural biology, in vivo models of IL-33-dependent responses, creation of cell-specific ST2-deficient mouse strains, and generation of a soluble ST2-deficient mouse. Finally we will use human blood samples and three-dimensional culture methods to ensure translation of these findings to humans.
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| 01/12/2020 |
£1,509,343 |
KING'S COLLEGE LONDON |
Asthma is an airway inflammatory disease, defined by bronchoconstrictive attacks that can be life-threatening. The two essential tissue components of the bronchioles are the airway epithelium and the underlying smooth muscle. In asthma, the smooth muscle is remodelled and becomes hyper-responsive, leading to excessive contractility. We have shown that epithelia are exquisitely sensitive to mechanical forces. Cell crowding triggers cell extrusion, while stretching triggers cell division. We recently discovered that the asthmatic bronchoconstrictive attack, causes excess airway epithelial extrusion and damage, compromising the barrier function, leading to inflammation. We propose that in healthy lungs, epithelia and smooth muscle communicate with each other to ensure sufficient epithelial cells numbers, essential to a tight barrier. However, in asthma, excess epithelial extrusion signals smooth muscle remodeling, actuating further rounds of more intense bronchoconstriction. This feed-forward cycle could perpetuate asthma attacks. We believe that our mechanochemical and cell biological insight into asthma will reveal novel ways to prevent it. We will investigate this hypothesis by addressing the following questions:
1) How are airways remodelled to cause an attack?
2) Do epithelia regulate constriction?
3) Does extrusion shed rhinovirus, yet trigger asthma attack
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| 01/12/2020 |
£1,906,940 |
UNIVERSITY OF CAMBRIDGE |
Before mitosis, cells must make two accurate and complete copies of their genome, to ensure genetic stability across cellular generations. This challenging biochemical task requires complex molecular systems that duplicate chromosomal DNA and repair lesions that stall DNA synthesis. Sporadic or inherited defects in the cellular apparatus of genomic duplication cause genetic instability, which is responsible for developmental and degenerative pathologies and for cancer predisposition.
Our knowledge of the molecular basis of eukaryotic DNA replication and related repair processes is incomplete, and this is especially true of genomic duplication in human cells, the most relevant to our health. Our proposal aims to provide a high-resolution view of the molecular mechanisms of DNA replication, using state-of-the-art biochemical and biophysical approaches. We will focus on components of the human replisome, the multi-protein assembly responsible for DNA synthesis in our cells.
There is intense medical interest in the molecular mechanisms responsible for genomic integrity and the rationale for the consequences of their occasional failure. In this respect, the work of our proposal is highly significant as it aims to deliver a comprehensive description in atomic detail of the complex and dynamic processes of DNA replication, when our genome is at its most vulnerable.
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| 01/12/2020 |
£1,551,260 |
UNIVERSITY OF LEICESTER |
Recent chromosome capture experiments have revealed a hierarchical 3D organisation of the genome ranging from Topologically Associating Domains (TADs) to larger-scale active, euchromatic and inactive, heterochromatic compartments. TADs arise through chromatin loop extrusion by cohesin/CTCF while compartments arise through epigenetic modification of the chromatin polymer. It has long been known that dynamic histone acetylation switches between repressive and permissive chromatin, a key event in transcriptional activation. We aim to capture cohesin in different structural states to understand how it is regulated and catalyses large-scale chromatin transactions. We also aim to understand the molecular mechanism behind acetylation-dependent activation of chromatin a reaction that is critical for the establishment of active euchromatin and may contribute to genome compartmentalisation and enhancer-promoter interaction. This proposal has the potential to transform our understanding the molecular mechanism behind two key reactions that contribute short- and long-range 3D genome architecture. It is possible that both mechanisms are interconnected and provide unifying principles to explain gene regulation with broad implications for health and disease.
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| 01/12/2020 |
£2,107,440 |
UNIVERSITY OF CAMBRIDGE |
Lungs possess a remarkable regenerative capacity by dynamic multicellular responses following injury. However, chronic damage makes these responses persistent, leading to fibrosis. We will define the mechanisms by which productive regeneration programmes are diverted to disease remodelling, with the ultimate goal of uncovering therapeutic strategies that can treat or prevent lung fibrosis.
We recently identified Damage-Associated Transient Progenitors (DATPs), a functional mediator of alveolar stem cell differentiation, emerging during lung regeneration. Notably, chronic inflammation leads to accumulation of DATPs displaying defective differentiation, resulting in impaired alveolar regeneration. We aim to identify strategies to target DATPs in chronic injury by dissecting changes in them and their niche environments. Specifically, we will define (1) key DATP-niche interactions during different phases of regeneration, and how to these evolve during disease progression utilising a novel niche-labelling system; (2) transcriptional and epigenetic changes mediating damage-associated reprogramming following injury at single-cell resolutions, and key signalling modules conferring lineage flexibility of stem/niche cells; (3) conserved regenerative programmes and potential therapeutic targets in preclinical 3D human lung disease models we have developed. Our work will provide fundamental insights into defining the cellular and molecular basis of lung regeneration as well as identifying selective therapeutic targets in lung diseases.
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| 01/12/2020 |
£2,064,491 |
UNIVERSITY OF CAMBRIDGE |
The goal of this proposal is to transform our understanding of the molecular mechanisms that control early human development. The mechanisms that regulate early cell fate decisions in human development remain poorly understood, despite their fundamental biological importance and wide-reaching clinical implications for understanding infertility, miscarriages, developmental disorders and therapeutic applications of stem cells. We seek to uncover when and how human embryonic epiblast cells are established and maintained, and to understand the molecular mechanisms that distinguish these pluripotent cells from extra-embryonic cells during embryogenesis. We will further develop pioneering methods to investigate gene function during human embryogenesis using CRISPR-Cas9-mediated genome editing, TRIM-Away protein depletion, constitutively active and kinase dead variants of proteins and small molecule inhibitors and activators. These approaches will enable us to directly test the function of genes involved in Hippo and TGFb signalling, and key transcription factors downstream of these pathways, which we hypothesize are involved in the first and second cell fate decisions, respectively. Altogether, we expect this program to make significant advances in our understanding of the molecular programs that shape early human embryogenesis, which has the potential to provide fundamental insights and to drive clinical translation.
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| 01/12/2020 |
£4,161,648 |
UNIVERSITY COLLEGE LONDON |
The overarching goal of this collaborative project is to make a step change in knowledge of dementia biomarkers by focusing on plasma proteome. We hypothesize that plasma is biologically informative due to the presence of protein signals: imprints of subclinical dementia progression that can be identified via repeated proteomic profiling decades before clinical symptoms, providing novel candidate targets for preventative treatments.
We will use the largest plasma proteome platform currently available, with three aims, to (1) prospectively examine 4,993 plasma proteins in relation to subsequent accelerated cognitive decline and clinical dementia across multiple cohort studies; (2) determine whether the protein hits identified in aim 1 have a causal association with dementia, whether modifiable and druggable, using analysis stratified by time between protein measurement and dementia onset and Mendelian Randomization framework in relation to novel genome-wide, and druggable-genome arrays; and (3) examine whether proteins predicting dementia risk are imprints of risk factors for dementia.
The expected new outcomes include protein targets for drug development; improved identification of potentially modifiable lifestyle risks; dementia trials surrogate outcomes; improved diagnostic markers, plus data resource for future in-depth research on the multisystem aetiology of dementias and proteomics of a range of major diseases beyond dementia
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| 01/12/2020 |
£1,181,059 |
UNIVERSITY COLLEGE LONDON |
Depression is amongst the most burdensome disorders world-wide because it is a common disorder with frequent relapses. Relapse risk is increased by maladaptive thinking patterns such as rumination and helplessness, and by antidepressant discontinuation, which in turn increases maladaptive thinking patterns.
Maladaptive thinking patterns shape emotions and are influenced by emotions. However, we do not know the neurobiological mechanisms underlying these interactions. First, I propose to study this by measuring maladaptive thinking patterns directly using a decoding approach to magnetoencephalography (MEG). MEG decoding reveals fast sequences of stimulus representations during tasks. These sequences can then be compared to computational models to understand the algorithms the brain uses to prioritize information processing.
Maladaptive thinking patterns are targeted by psychotherapeutic interventions and are sensitive to serotonergic manipulations. I will examine how psychotherapeutic interventions influence the interaction between thoughts and emotions, and how an acute reduction in serotonin through tryptophan depletion affects them. The latter study will be performed in remitted depression and allow us to test whether the mechanisms are involved in subsequent relapses.
Overall, I aim to provide a comprehensive account of how objectively-measured thought processes relate to emotions and to the prevention of depression relapses.
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| 01/12/2020 |
£1,973,118 |
KING'S COLLEGE LONDON |
TDP-43 is a conserved RNA binding protein central to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 normally autoregulates its expression by binding to the 3’UTR of its cognate transcript. We have linked disrupted TDP-43 autoregulation to disease, showing that disease-linked TDP-43 missense mutations disturb TDP-43 autoregulation causing a gain of function, finding that ALS patients harbour non-coding variants in the 5’ and 3’UTRs of TDP-43 that could disturb TDP-43 expression and observing that TDP-43 misregulation in mice causes selective brain atrophy reminiscent of human ALS-FTD. We will follow these leads to understand the causes and consequences of TDP-43 misregulation and elucidate therapeutic targets and biomarkers for ALS-FTD. Specifically, we will dissect the TDP-43 autoregulation protein interactome in wild-type and TDP-43 missense mutant cells by performing in-cell protein-RNA interaction studies and native mass spectrometry. To determine the significance of ALS-linked UTR variants in regulating TDP-43 expression we will perform an in-vitro CRISPR/Cas9 mutagenesis screen with parallel genomic and transcriptomic sequencing. To understand how TDP-43 misregulation causes regional and cell type-specific neurodegeneration we will use in situ sequencing of mouse brain sections to obtain transcriptomic information with single cell resolution.
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| 01/12/2020 |
£1,490,731 |
KING'S COLLEGE LONDON |
The overarching goal of this proposal is to elucidate the functional diversity of the pancreatic mesenchymal lineage. In embryonic tissues, epithelial progenitors receive paracrine signals from the surrounding mesenchymal niche, which can modulate their ability to proliferate and differentiate. The pancreas consists of a variety of specialized epithelial cells, including endocrine and acinar cells, surrounded by a poorly defined heterogeneous mesenchyme. We hypothesise that different mesenchymal lineages define local instructive microenvironments, including cell–cell crosstalk, ECM and signalling molecules, which eventually trigger distinct differentiation programmes from pancreatic progenitors. Sc-RNA-sequencing has generated a transcriptional map of the pancreatic mesenchyme in the mouse embryo. Here, we will unravel the spatial architecture of the identified mesenchymal cell states, linking their position to emerging pancreatic cell identities. Next, we will assess if mesenchymal lineages with a distinct spatial address underlie unique niche regulatory functions, promoting acinar or beta-cell differentiation. Finally, we will study the organisation and function of the identified niche microenvironment(s) in human tissue and pluripotent stem cells. The proposed programme will yield novel insight into pancreas biology and will set the stage for manipulating combinatorial pancreatic niches - an important step towards engineering functional beta-cells for regenerative medicine applications.
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| 01/12/2020 |
£1,904,154 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
Invasive pneumococcal disease causes over a million deaths per year worldwide, particularly in sub-Saharan Africa. Streptococcus pneumoniae strains vary considerably in virulence, but the reasons for this are unclear. Capsular serotype 1 strains are particularly invasive and cause a major proportion of severe infections, including meningitis, but are poorly studied, partly because they have been genetically intractable. We want to understand why serotype 1 strains are highly invasive, and to identify mechanisms that distinguish aggressive S. pneumoniae strains from less aggressive variants. Furthermore, a low-cost serotype 1 vaccine is urgently needed, especially in sub-Saharan Africa. In this project, we will combine and exploit (i) recently-developed in vitro and in vivo infection models, (ii) bacterial RNAseq data (including our data obtained from cerebral spinal fluid from Malawian meningitis patients) and (iii) our methodologies for mutating serotype 1 strains, to identify and characterise the roles of multiple novel genetic determinants important for the pathogenesis of invasive S. pneumoniae infections. We will also characterise in detail the zwitterionic capsular polysaccharide that defines serotype 1 strains and assess its role in pathogenesis. Finally, we will exploit Protein Glycan Coupling Technology (pioneered by the applicants) to produce a much-needed and affordable glycoconjugate serotype 1 vaccine.
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| 01/12/2020 |
£2,188,451 |
UNIVERSITY OF OXFORD |
The overarching goal of my research is to understand the relationship between membrane proteins and their lipid surroundings. This is important since many membrane proteins are unable to retain their structure and function when extracted from their native environment and reconstituted into a membrane mimetic. Dynamic proteins, for example G-protein coupled receptors, solute carriers and sigma receptors, are intimately connected to their membrane environments and prone to loss of function and activity in detergent micelles. To overcome this disconnect we will develop and apply our mass spectrometry approaches to examine dynamic drug targets within their membrane context. Our key goals will be to challenge these receptors and transporters with agonists, antagonists, inhibitors and lipids effectively in situ. Examples include solute carriers which during tumour progression respond to the need for an altered metabolism by increasing expression. Analogous methods will be used to uncover the targets of mitochondrial and lysosomal therapies. Many of our research themes converge on consequences of the COVID-19 pandemic. While this remains an area of intense scientific scrutiny we will focus on the less-studied receptors and ‘infection enhancers’, and contribute to understanding the roles of lipids in the endocytosis and viral recognition pathways.
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| 01/12/2020 |
£2,336,909 |
UNIVERSITY OF OXFORD |
The overarching aim is to understand the neural mechanisms of learning, decision-making, and motivation in humans. We will examine how they emerge from distributed patterns of activity across networks of subcortical nuclei such as the basal forebrain and dorsal raphe nucleus. While we know about such subcortical areas from animal studies, they have been under-investigated in humans. New imaging and uni- and multivariate analysis methods now make it possible to examine the distributed patterns of activity that arise in these areas. We have recently shown that we can record from these areas of the human brain using ultra high field magnetic resonance imaging. In addition, we know that these nuclei interact with cortical areas, especially in orbitofrontal, anterior cingulate, and insula cortex (regions that are especially prominent in humans and other primates). We aim to record from both cortical and subcortical areas and to understand how they interact during learning, decision making, and motivation. The final aim is to assess whether new ultrasound stimulation tools that make it possible to alter neural activity in a minimally invasive manner even in brain areas far from the surface can be used to manipulate brain activity in these circuits in humans.
|
| 01/12/2020 |
£1,492,837 |
UNIVERSITY OF GLASGOW |
Cell migration is essential to processes throughout biology, especially embryonic development and immune function. Migration must be steered to be physiologically effective. Steering cues are not well understood; we know a lot about how cells interpret them, but relatively little about how they are generated.
The basic premise of this work is that the cells often generate their own cues, by breaking down attractants that are widely present (and thus initially give no steering information) into local gradients. Attractant breakdown and migration happen simultaneously. This mechanism - chemotaxis up self-generated gradients (SGGs) - is hard to dissect because it is complex, and based on positive feedback loops. We therefore propose a four-pronged, iterative approach, in which we combine less challenging components to create an understanding of the underlying biology.
Key goals are:
(1) explore possible mechanisms and new extensions using computational models;
(2) test outcomes using chemotactic Dictyostelium in custom microfluidic devices;
(3) verify these data by establishing cultured T cells chemotaxing to CCL19 as a model SGG;
(4) combine findings from parts 1-3 to make a 3D, SGG-based model of a lymph node.
Together they will illuminate chemotactic steering in general, by focussing on one physiologically important system.
|
| 01/12/2020 |
£2,059,266 |
UNIVERSITY OF OXFORD |
Central obesity is a leading contributing cause of illness and death across the world. Currently available strategies for prevention and treatment of this condition are manifestly inadequate. The research proposed here aims to identify fundamental processes involved in the development of central obesity. I plan to harness the power of human genetics, fused with deep molecular characterisation of the adipocytes to generate novel insights into the biology of central obesity. This ‘multi-omics’ approach will provide the basis for more effective preventative and therapeutic approaches that reduce the burden of central obesity and associated disease.
|
| 01/12/2020 |
£1,271,158 |
JOHN INNES CENTRE |
ATP and GTP switches are extensively used to control conformations and functions of proteins in a wide range of biological processes. However, CTP switches have rarely been found in biology. Recent work from our laboratory and others has shown that ParB is a founding member of a CTPase protein family that uses a CTP switch to regulate bacterial chromosome segregation. We hypothesize that CTP switches are currently unappreciated and may be widespread. In the proposed work we will exploit the tripartite ParABS system from Caulobacter crescentus to elucidate the structure, function, and mechanism of the CTP switch that ensures faithful chromosome segregation. Next, we will investigate how other CTP switches regulate membrane association and gene expression by employing Noc and KorB (proteins crucial for chromosome integrity and plasmid transmission, respectively) as models. Lastly, we will identify and characterize other CTP switch proteins in C.crescentus and systematically discover putative CTP-binding/CTPase proteins across all sequenced bacterial genomes. Altogether, this work will provide fundamental knowledge on the mechanism and evolution of CTP switches and open new and unexpected horizons in numerous fields beyond bacterial chromosome segregation. Moreover, our immediate research on plasmid/chromosome segregation and transmission may inform strategies to combat plasmid-borne antibiotic resistance.
|
| 01/12/2020 |
£4,079,159 |
UNIVERSITY OF CAMBRIDGE |
The clinical manifestations of placental dysfunction include pre-eclampsia, gestational hypertension and fetal growth restriction. Women who experience placental dysfunction have a two-fold risk of cardiovascular disease (CVD) and diabetes in later life compared to women with uncomplicated pregnancies. However, it is unclear whether placental syndromes have a direct adverse effect on cardiometabolic health, whether a healthy pregnancy is protective, or whether women who experience a placental syndrome simply had poorer cardiometabolic health prior to pregnancy. If placental syndromes do lead to CVD and diabetes independently of established cardiometabolic risk factors (e.g. by causing end organ damage), a focus on CVD/diabetes prevention in this high-risk group of women is likely to reduce the burden of these diseases. Conversely, if pre-pregnancy factors are more important, improving cardiometabolic health in young women prior to conception is key and could reduce the incidence of placental syndromes. We plan to assess cardiometabolic risk factors and validated intermediate phenotypes of CVD/diabetes before conception, during pregnancy, and post-partum to determine whether placental syndromes affect post-partum maternal cardiometabolic health independently of pre-conception cardiometabolic health. This will help to determine the optimal timing and nature of prevention strategies to reduce the burden of diabetes/CVD in women, in future trials.
|
| 01/12/2020 |
£1,947,704 |
KING'S COLLEGE LONDON |
Progressive hearing loss is very common but there are no medical treatments to slow down or reverse it. Histopathological reports suggest three main sites of lesion in the cochlea can be involved: sensory hair cells; synapses of hair cells with cochlear neurons; and the stria vascularis which produces a potassium-rich fluid with an endocochlear potential of +100mV that is essential for hair cell sensitivity. This research has three goals that will provide the scientific underpinning for development of new treatments for hearing loss. Firstly, we will investigate whether hearing loss in each of the three pathological categories can be reversed and hearing improved. Secondly, the research will determine what the limiting factors to reversal of hearing loss are and how these define the critical period for intervention. Thirdly, we will develop new diagnostic tools to distinguish the three sites of lesion using objective measures of auditory responses, to establish the underlying pathological contributions to hearing loss in an individual, and hence determine the optimum treatment. To achieve these goals, we will use mouse mutants with well-characterised cochlear pathology as examples of each site of lesion, and a new approach to reactivating a mutant gene after the onset of hearing loss.
|
| 01/12/2020 |
£1,793,281 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
Bluetongue virus (BTV), a complex non-enveloped virus with a genome of ten double-stranded RNA segments, is an important pathogen and model for many similar large non-enveloped viruses (including the medically important rotaviruses). Previous studies have provided a well-understood replication cycle, a large range of research reagents and many novel assay systems, all complemented by high resolution atomic structures of many viral proteins. Notably, the recent structure of the viral polymerase in situ, a critical point of replication, has provided a unique opportunity to investigate many details involved in the virus life cycle. To achieve this we will will use state-of-the-art techniques such as cryoEM, cryo-ET, FCS and FRET in addition to our established in vitro and in vivo assays to determine how BTV entry to the cell causes the polymerase to initiate genome transcription from the 10 genomic dsRNAs and how this process differs from the later process of genome replication which follows the packaging of RNA during assembly. We will define how these processes link to the maturation of newly assembled virus particles and their exit from the cell. Our findings will have the potential to develop laboratory data to translational applications in future design of antiviral and vaccines.
|
| 01/12/2020 |
£1,827,981 |
UNIVERSITY OF EDINBURGH |
The type I interferon (IFN) response is the major antiviral pathway in mammals but needs to be tightly regulated to ensure effective defence against viruses whilst avoiding the negative consequences of their overproduction, resulting in autoimmune and autoinflammatory diseases.
I have recently demonstrated a central role for microRNAs (miRNAs) in maintaining optimal IFN levels, and conversely, that IFNs are important regulators of miRNA expression. These results led me to hypothesise that there is a tight interaction between the IFN and miRNA pathways, which contributes to specific traits of human diseases where one component of this interaction is altered.
Supporting this hypothesis, our unpublished results show that diseases characterised by altered miRNA expression, such as 22q11.2DS, exhibit a dysregulated IFN response. Vice versa, diseases characterised by an abnormal IFN response, such as systemic lupus erythematosus, display altered miRNA levels. I aim to identify the mechanisms by which the miRNA biogenesis and IFN pathways interact and study the role of this interaction in diseases where the IFN or miRNA biogenesis pathways are altered. These results will provide a mechanistic perspective to some of the common but unexplained traits presented in these diseases and provide novel targets for intervention strategies.
|
| 01/12/2020 |
£2,051,884 |
UNIVERSITY OF BIRMINGHAM |
gammadelta T-cells have been retained in vertebrates for ~500million years, and are of increasing therapeutic interest, but their mode of ligand recognition and immunological niche has remained largely mysterious. Here we build on the emergence of parallel innate-like and adaptive human gammadelta T-cell paradigms to address unresolved ‘keystone’ questions in gammadelta T-cell biology. Firstly, we will exploit multidisciplinary approaches to explore the diversity of innate-like and adaptive gammadelta biology in different tissues, their coordination with other immune responses, and how these change in disease states such as inflammation and cancer. Secondly, we will identify molecular targets of gammadelta-TCRs from innate-like subsets and structurally characterise their TCR/ligand interactions and cellular/molecular recognition mechanisms, focussing significantly on the strong emergence of Butyrophilin family molecules as critical TCR-ligands for such populations. Thirdly we will exploit cytomegalovirus infection as a unique human model to identify novel ligands for antigen-experienced adaptive-like gammadelta T-cell subsets. Finally, we will develop and apply new methodology to image and phenotype distinct human gammadelta T-cell subsets in solid tissues, using multispectral immunofluorescence and digital spatial profiling. This programme should help revolutionise our understanding of gammadelta T-cells, and provide a solid foundation for ongoing efforts to therapeutically harness the gammadelta T-cell compartment.
|
| 01/12/2020 |
£2,488,909 |
UNIVERSITY OF EDINBURGH |
Trypanosomes undergo development in both their mammalian host and in the tsetse fly to optimise their disease spread. In mammals, the parasites use quorum sensing (QS) to control their virulence and prepare for tsetse uptake through the generation of arrested stumpy forms, which are found in Trypanosoma brucei but not other African trypanosome species (namely, Trypanosoma congolense or Trypanosoma vivax). We recently discovered that oligopeptide signals can drive QS in Trypanosoma brucei, this activating a signal transduction cascade, some components of which we have already identified. We will now explore how the external signal connects to the identified signalling cascade to drive the differentiation response and how this is disrupted in laboratory-selected and naturally occurring trypanosomes that show reduced QS (so-called 'monomorphs'). We will also compare the distinct mechanisms used by different trypanosome species to prepare for transmission to tsetse flies. This will include characterisation of a cryptic 'stumpy like' stage in T. congolense and its developmental loss of the adherence phenotype characteristic of that species. Our research questions are:
How do trypanosomes generate, detect and transduce external QS signals?
How is QS lost in laboratory and natural parasite populations?
How do different trypanosome species prepare for transmission?
|
| 01/12/2020 |
£1,964,639 |
QUEEN MARY UNIVERSITY OF LONDON |
Neutrophils contribute to the killing and clearance of pathogens as well as initiate inflammation resolution and tissue repair processes. Furthermore, the established phenotypic and functional diversity of neutrophils have markedly extended the physiological and pathological roles of these myeloid cells. Building on the developing concept of neutrophil heterogeneity in disease settings, and significant mechanistic and pathophysiological data from the applicant, the present project aims to acquire an in-depth understanding of one population of disease-inducing neutrophils, namely neutrophils that have exhibited reverse transendothelial cells migration (rTEM). This phenomenon describes cells that initiate diapedesis, engage with endothelial cell (EC) junctions but then exhibit retrograde motility and re-enter the vascular lumen. Crucially, we have ample evidence that rTEM bestows an activation state on neutrophils in vivo, and that rTEM neutrophils are aligned with remote organ damage. Thus, exploiting recent technological advancements and capabilities, the current proposal aims to gain an in-depth understanding of the prevalence, molecular signature and pathogenic role of this "subset" of neutrophils, most notably in ageing. Furthermore, hypothesizing that the activation state of rTEM neutrophils maybe beneficial for the host, the project will for the first time explore the potential protective, and thus physiological, role of rTEM neutrophils against pathogens.
|
| 01/12/2020 |
£4,031,379 |
UNIVERSITY OF OXFORD |
Sensory systems are typically viewed as being organized hierarchically, with stimulus features being progressively extracted as information flows from the sense organs to the neocortex. However, the responses of sensory neurons at each level are continually shaped by a vast network of poorly-understood descending projections. These ascending and descending circuits have largely been studied in isolation and little is known about how they interact to produce the remarkable neuronal adaptability crucial for auditory perception.
We will use coordinated computational and experimental approaches, involving cutting-edge methods for measuring, decoding and manipulating neural activity, to investigate sensory processing during active listening and learning. We will focus on the recurrent neural circuits that enable the brain to adapt to long- and short-term changes in auditory inputs and to integrate other sensory and motor signals. Our goal is to understand three aspects of these circuits: the computational principles behind their representational transformations, the dynamic interplay of bottom-up and top-down signals that enables neurons to adapt to changing auditory and behavioural demands, and the neural and behavioural consequences of hearing-loss related plasticity. Together, this work will transform our understanding of the recurrent, dynamic nature of auditory circuits and how they are affected by hearing loss.
|
| 30/11/2020 |
£249,100 |
NATURAL HISTORY MUSEUM |
Not available |
| 30/11/2020 |
£1,786,326 |
WORLD HEALTH ORGANIZATION, SWITZERLAND |
The WHO Global Ethics Unit is part of the newly formed Science Division and would like to capitalize on the potential of the division and the global leadership shown by the team during the current COVID-19 pandemic, to truly embed ethics at the heart of decision-making at WHO.
This proposal focuses on adding value to our current work programme. Additional technical and coordinating capacity will allow us to better leverage our vast bioethics networks and collaborative partnership with bioethics groups around the world to: support regional and in-country bioethics capacity needs; further develop a community of ethics experts; develop the global ethics agenda and focus on key areas of unmet or continuing need, including health emergency preparedness and response. Additional resource will also allow us to be more responsive to demand set by the WHO and global research and health communities.
|
| 30/11/2020 |
£44,838 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
Not available |
| 30/11/2020 |
£45,045 |
UNIVERSITY OF OXFORD |
Not available |
| 30/11/2020 |
£43,573 |
UNIVERSITY OF SUSSEX |
Not available |
| 30/11/2020 |
£45,043 |
UNIVERSITY OF WARWICK |
Not available |
| 30/11/2020 |
£100,000 |
CANNON AND MORLEY PRODUCTIONS LTD |
Typist Artist Pirate King is an innovative and accessible dramatic feature film drawn from the extensive archives of art, diaries and letters held at Wellcome of artist and mental health survivor, Audrey Amiss. The film is a first person account and offers a rich insight into how Amiss saw and experienced the world.
Amiss described herself as someone who people crossed the road to avoid. The film does not ‘other’ her, and, for those who did cross the road to avoid her, creates the opportunity to identify with her. The film is a powerful contribution to conversations about mental health stigma and plays an important role in creating representation that can help erase stigma.
For the many people who define themselves as mental health patients/ clients/ users/ former users/ survivors, the film is actively speaking to them. It does not merely address a so called "neuro-normal" audience but represents how ways of thinking, experiencing and seeing the world are diverse and urgently deserve to be represented in their complexity for all to see and engage with.
We anticipate a significant international release of the film, followed later by it being used as valuable study material within academia.
|
| 30/11/2020 |
£4,178,641 |
IMPERIAL COLLEGE LONDON |
In the current COVID-19 emergency, a controlled SARS-COV-2 human infection model (CHIM) has the potential to accelerate the understanding of pathogenesis, induction of immunity and immune mechanisms of resistance to disease, as well as a means to test novel diagnostics and treatments, especially between waves of the pandemic, when occurrence of natural disease is relatively uncommon. A large number of SARS-COV-2 vaccine candidates are at various stages of development internationally including those which have recently entered mid-late stage clinical testing in field studies. In order to make the greatest public health impact, there is an urgent need to select the most promising vaccines in the shortest possible timeframe. In addition, human infection challenge can contribute to the identification of correlates and mechanisms of protection against infection and shedding of virus in vaccinated volunteers. Finally, the model may be useful in the determination of the durability of protection in seropositive individuals with documented prior wild type infection. This proposal is a dose titration study to generate two GMP challenge agents and establish the safety of a wild-type SARS-COV-2 controlled infection in the upper respiratory tract of young healthy volunteers that will allow swift and robust assessment of vaccine efficacy.
|
| 30/11/2020 |
£2,134,694 |
UNIVERSITY OF OXFORD |
The Phase 3 RECOVERY platform has been a success, recruiting over 13,500 patients and producing 3 clear, world practice-changing results in the first 100 days of recruitment. The RECOVERY team has been approached by clinical investigators from various LMICs who wish to participate in RECOVERY. As it becomes clear that this pandemic will continue at various locations and paces over the next 24 months, there is an opportunity to increase the impact of the RECOVERY trial by expanding internationally. Expansion has the potential to speed up the assessment of novel treatments, increase the global relevance of the trial results, build capacity, and reduce wasted efforts on small uninformative studies. The key goal is to establish RECOVERY internationally, initially in Indonesia, Nepal and Vietnam, with a view to opening sites also in Africa.
|
| 30/11/2020 |
£1,120,861 |
UNIVERSITY OF OXFORD |
Understanding the nature, effectiveness and durability of the human immune response to SARS CoV2 is crucial for vaccine development and effective public health management. We are beginning to understand the pattern and kinetics of the humoral response to natural infection but are less certain about other aspects of the response. We are unable to establish with certainty whether an individual with a particular titre of antibody, or a particular T cell response, is likely to be protected from reinfection and, if so, for how long. These are central questions for the development of an effective vaccine. A controlled human infection model will provide a more detailed understanding of the protective immune response. It will provide the opportunity to interrogate the full extent of the immune response at the time of exposure and will also allow the evaluation of the durability of immune responses of all kinds and how they correlate with protection.
Key goals:
To establish an MHRA-approved SARS CoV2 viral stock for use in a controlled human infection model
To determine a challenge dose which is safe and allows virus to be recoverable from infected subjects
|
| 30/11/2020 |
£1,911,840 |
SCIENCE MUSEUM |
Not available |
| 30/11/2020 |
£350,000 |
UK RESEARCH AND INNOVATION |
Renewal of funding for Centre for Macaques (CfM) to August 2022
|
| 30/11/2020 |
£928,074 |
HEALTHY BRAINS GLOBAL INITIATIVE |
Healthy Brains Global Initiative (HBGI) is a collaboration of global leaders in neuroscience, policy, and financing working to improve the lives of those living with mental and neurological disorders and bend the unsustainable US$3 trillion global cost curve borne today by all countries. HBGI is developing an umbrella set of financing mechanisms to leverage billions in financing and fuel an unprecedented increase in brain science breakthroughs. We are currently in the mobilisation stage with a view to a formal launch in 2021.
The Co-Founders and Co-Chairs of the Board are Victor Dzau (National Academy of Medicine) and Garen Staglin (One Mind), and Brad Herbert is the interim CEO. The Wellcome Trust is involved in multiple ways. Ed Whiting is a member of HBGI’s Interim Board, and Miranda Wolpert is Co-Chair of the Use of Proceeds Working Group and Andrew Welchman is also part of the group.
We value the expertise that the Wellcome Trust is providing to us and are requesting US$1.2 million to contribute to HBGI's running costs for the start-up phase. This will fund us to design and launch a governance structure, determine the optimal use of proceeds, confirm metrics for ROI, and design and launch financing mechanisms.
|
| 30/11/2020 |
£505,090 |
INTERNATIONAL DEVELOPMENT RESEARCH CENTRE, CANADA |
Wellcome Trust and IDRC will be supporting the building of an agenda for action on the transition to a zero-carbon food system in Latin America. This work will be conducted in parallel to the work conducted by the Rockefeller Foundation and IDRC in East Africa, which aims to "improve the health and wellbeing of low-income and vulnerable populations who face the double burden of malnutrition and environmental threats like climate change" (see annexed document for more information). The work conducted in both regions are part of a growing initiative entitled "Catalysing change for healthy and sustainable food systems", launched by the three institutions. The initiative will provide research grants to leading evidence builders in low- and middle-income countries (LMICs), with the aim of strengthening the contribution and engagement of LMIC research and civil society institutions in regional and global discussions about healthy and sustainable food systems.
|
| 26/11/2020 |
£150,445 |
UNIVERSITY OF MELBOURNE |
We propose to address two key areas of research enrichment and public engagement related to our current Wellcome funding (establishing an Australia-wide clinical registry and clinical trials and translation network for early psychosis, the Australian Early Psychosis Collaborative Consortium, AEPCC). The first is co-design a comprehensive and world leading infrastructure for the meaningful involvement of young people and carers with lived experience of psychosis to support the national network of research trials, including necessary training and support. Secondly, utilising this infrastructure for lived experience engagement we will co-design at least two community engagement projects aimed to increase community knowledge and research uptake in young people experiencing a first episode of a psychotic disorder. At the end of the activity we will have developed a co-designed approach of embedding and prioritising the lived experience of young people and carers in the projects that will be prioritised by the AEPCC. We will also have crystallised our ideas as to how and where people with lived experience would like to be involved in promotion and leadership of the AEPCC. Both these outcomes involve scoping training needs and delivering long-term training and support for young people and carers to perform their roles. By the end of the activity we will have achieved a truly collaborative approach within the network to embed the voice of young people and carers with lived experience or early psychosis that will be able to continue and evolve as the AEPCC continues beyond the initial Wellcome grant period.
|
| 26/11/2020 |
£75,710 |
UNIVERSITY OF DERBY |
We will develop a collaborative relationship between the Addressing Health enrichment project and the public to improve access to archives and enhance understanding of the history of workplace health. This will be achieved through a programme of online and face-to-face outreach activities on a variety of project topics, with regular evaluation touchpoints to capture learning and improve processes. These activities will support and enhance the Zooniverse project, which will transcribe c. 30,000 postal pension records.
There are three key aims:
to develop archival and content creation skills for our growing community of citizen-scholars.
to enrich public knowledge about histories of workplace health through public-driven research.
to make our data and findings freely accessible through resources including a database of Post Office pensioners 1858-1908, interactive data visualisations, and other co-produced content.
Our project will develop a significant community of citizen-scholars with an understanding of histories of workplace health. These citizen-scholars will engage with the project in different ways: as data explorers using freely available data visualisation resources; by attending seminars, workshops, museum events, and conversation cafés, and through active participation as transcribers and volunteers. We will work with these citizen-scholars to develop research skills, frame new research questions, and co-create content such as blogs and podcasts. By taking our project ‘on the road’, we will also foster stronger links between TPM, local museums, past and present postal workers and citizen-scholars. Through our activities, the project will help facilitate new forms of collaborative research on histories of workplace health.
|
| 26/11/2020 |
£245,520 |
UNIVERSITY OF GLASGOW |
Supported by public engagement experts, local organisations and creatives, MEIRU researchers will co-design and deliver three core public engagement activities (PEA) mapped to key research themes of the HLM and GM programmes.
PEA1: Primary school engagement on early origins of long-term conditions
Students will create dramatic, musical, oral and poster presentations exploring the role of their parents’ health and childhood environment on future health and wellbeing for sharing with their communities, District Management Teams and researchers to start community conversations about their influence on health.
Y1 Creation, Y2/3 Presentation
Partners: School Health and Nutrition programme, Schools, UNICEF.
PEA2: Sharing voices of women and families affected by maternal mental health conditions
Creation of a resource (audio and video vignettes) to make women’s narratives of maternal mental health visible in communities, policy discussions (presenting to the Reproductive Health Unit and Mental Health Technical Working Group) and international meetings to agenda set and impact policy.
Y2 Creation, Y3/4 Dissemination
Partners: African Alliance for Maternal Mental Health (AAMMH), St John of God Mental Health Services
PEA3: Documenting family journeys and infant development in birth cohort families.
Documentary style interviews, observations with families on repeat occasions during cohort follow-up, to include filming of cohort procedures and interviews about cohort membership as well as footage of child development and family aspirations, to give context and meaning to statistics on child and family health in Malawi.
Y1 Recruitment, Y2-4 Filming, editing and dissemination
Partners: Art and Global Health Centre Africa (www.artgloafrica.org), UNICEF, film makers
|
| 26/11/2020 |
£63,053 |
UNIVERSITY OF YORK |
The Covid-19 pandemic has generated widespread interest in viruses. This public engagement initiative is an opportunity for members of the general public to explore the science underpinning viruses and showcase the opportunities for antiviral therapy generated by Wellcome Trust funded research. Viano - a fusion of the words "virus" and "piano" - is a virtual instrument for playing viral genome data-generated music in concert with 3D virus visuals. Its aim is to communicate the concepts of mutation and selective pressures in viral evolution, the challenges they pose for antiviral intervention, and the opportunities for therapy arising from our discovery of genetically robust features in viral genomes. Viano will be offered as a gallery exhibit and for home use as an app. In the Lowry Museum gallery, Viano will work on a large scale: the main virus 3D image will be projected on the wall (7m x 7m) and users will have access to a large projected musical keyboard on the floor with over 29,000 keys representing the virus’ genomic sequence. Both image and keyboard will be operated via body movement in a Covid secure manner, and a musical genome keyboard on the screen will also be accessible via an Android/Apple mobile and tablet app. Viano will come with a full programme of workshops and debates and will give the public the ability to save and share their musical viral compositions online.
|
| 25/11/2020 |
£611,008 |
UNIVERSITY OF OXFORD |
Control of HIV and hepatitis C virus (HCV) requires multi-pronged approaches, including development of curative treatment and effective vaccines, identifying drivers of epidemics, and optimal deployment of interventions. Mathematical modeling and evolutionary analysis of viral genetic data is an important component in achieving these goals, by identifying the drivers of viral spread and evolution.
Chronic viruses evolve rapidly within individuals, meaning transmitted viruses are different from the strain(s) that initiate infections. HIV is arguably the most studied pathogen in history, yet key unknowns remain, including the drivers of within-host evolution, and which viruses are transmitted. Less is known about HCV, which is further complicated by its complex within-host structure. Nevertheless, methodologies developed for HIV can be immediately employed for HCV, fast-tracking the analysis of this virus
A major obstacle has been the short-read nature of viral deep-sequencing, limiting the power of analyses. I will refine and use new long-read deep-sequencing approaches we have developed to sequence and analyse viral populations from an unprecedented number of longitudinally sampled individuals. I will determine the drivers of within-host evolution, with a view to characterise transmitted viruses, develop better methods to infer viral spread and predict evolution in populations, enabling better targeting of interventions.
|
| 25/11/2020 |
£711,213 |
UNIVERSITY OF MANCHESTER |
The mucosal immune system is critical for human health; mediating both immunity against pathogens and maintaining mutualism with the microbiota. In contrast, dysregulation of mucosal immune function and homeostatic host-commensal interactions results in chronic inflammatory and metabolic disease e.g. Inflammatory Bowel Disease, obesity and liver disease. Within the intestinal tract, Immunoglobulin A (IgA) is secreted in huge quantities by tissue-resident Plasma Cells to ensure a mutualistic balance of commensal microbial species, which metabolise dietary nutrients to the benefit of the host.
We demonstrate the magnitude of intestinal IgA secretion is entrained by signals associated with feeding, which imprint circadian rhythms onto Plasma Cells that act to align metabolically demanding immune surveillance with times of waking activity. In turn, circadian IgA secretion imprint daily oscillations in commensal microbial species. Despite our findings, the mechanistic basis and physiological relevance of this complex dialogue remain poorly understood. Here we will comprehensively define the molecular pathways that dictate IgA rhythmicity, and determine the consequences of this cross-regulation for host-microbial interactions, immunity and disease. Together this study will provide a step change in our understanding of how the diet, microbiota and mucosal immune system engage in complex temporal crosstalk to ensure metabolic and immune health.
|
| 24/11/2020 |
£120,000 |
KILIMANJARO CLINICAL RESEARCH INSTITUTE |
The primary aim of this study is to use next generation sequencing to investigate the T and B cell receptor repertoire in the conjunctival tissue in those susceptible to repeated ocular infection with Ct and those resistant despite similar exposures.
RNA samples selected from archived conjunctival swab samples from a 4-year longitudinal study of children with progressing trachomatous scarring and non-progressing will be used. Sequences will be aligned to their germline V-, D-, and J-genes and assigned according to the IMGT/GENE-DB reference directory. The average length of CDR3 regions, as well as the frequency of shared CDR3s will be compared. The usage of specific V genes, families and their frequency will also be compared. Initial analysis will be conducted on 25 progressors and 25 non-progressors at the final time points. Based on the results of the data obtained, a sufficient number of samples will be selected for further analysis from earlier timepoints in the cohort.
The project has the potential to contribute toward the evaluation and progression of current and future human clinical trials of Ct vaccines.
|
| 24/11/2020 |
£97,200 |
KEMRI-WELLCOME TRUST RESEARCH PROGRAMME |
Enteric pathogens are a major cause of hospitalisation among children and are associated with diarrhoea, enteric dysfunction, dysbiosis, and increased risk of mortality and readmission especially in low- and middle-income countries. When admitted to hospital, treatment failure may occur despite following guidelines. Furthermore, carriage of pathogens or disturbance in the intestinal microbiome may be hospital-acquired and/or resistant to first-line antimicrobials potentially increasing the risk of readmission. I aim to determine whether molecular evidence of enteric pathogens and gut dysbiosis at hospital discharge, when children were judged as clinically well, is associated with readmission post-discharge among children across the nutritional stratum. This case-control study is nested within the completed CHAIN cohort study (six countries) that aims to characterise demographic, clinical, and social risk factors for mortality among children
|
| 24/11/2020 |
£22,800 |
WELLCOME TRUST SANGER INSTITUTE |
Enteric pathogens are a major cause of hospitalisation among children and are associated with diarrhoea, enteric dysfunction, dysbiosis, and increased risk of mortality and readmission especially in low- and middle-income countries. When admitted to hospital, treatment failure may occur despite following guidelines. Furthermore, carriage of pathogens or disturbance in the intestinal microbiome may be hospital-acquired and/or resistant to first-line antimicrobials potentially increasing the risk of readmission. I aim to determine whether molecular evidence of enteric pathogens and gut dysbiosis at hospital discharge, when children were judged as clinically well, is associated with readmission post-discharge among children across the nutritional stratum. This case-control study is nested within the completed CHAIN cohort study (six countries) that aims to characterise demographic, clinical, and social risk factors for mortality among children
|
| 24/11/2020 |
£120,000 |
UNIVERSITY OF OXFORD |
There are an estimated 100-400 million cases of dengue worldwide per year with the highest burden of disease in Asia. The virus (DENV) is a positive-sense single stranded RNA virus belonging to the genus Flavivirus. There are four serotypes: DENV1 to DENV4. Dengue virus RNA dependent RNA polymerase has no proof-reading activity, resulting in accumulation of mutations at each replication cycle.
Therefore, within an infected individual, there is diversification of the DENV genome sequence leading to the presence of intra-host genetic variants (quasispecies), which may then lead, under selective pressure, to the emergence of a new strain of higher virulence. Previous findings suggested that immune pressure drives intra-host diversity.
My research will explore whether serotype-specific past immunity influences intra-host DENV genetic diversity during acute infection.
Objectives:
To describe intra host DENV genetic diversity in patients with primary and secondary infections
To compare quasispecies profiles between primary and secondary infections
To compare quasispecies profiles in secondary infections between two patient groups previously exposed to a different serotype.
Impact :
We expect the findings of this project would permit a better understanding of processes leading to viral genetic variation, and could eventually be useful for improving viral surveillance systems and epidemic forecasting.
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| 24/11/2020 |
£580,378 |
UNIVERSITY OF CAPE TOWN |
While prevention of mother-to-child transmission (PMTCT) success has resulted in the decline in paediatric HIV infection, the number of HIV-exposed uninfected (HEU) infants has rapidly risen. In 2018, the population of HEU children in sub-Saharan Africa was estimated to be 13.2 million. In utero exposure to HIV may exert detrimental influences on the intricate neurodevelopmental processes during the first five years of life, with long-lasting effects on cognitive performance and behaviour. Our understanding of the pathophysiological mechanisms that are involved in conferring risk for neurodevelopmental deficits due to HIV exposure remains limited.
Altered neuroimmune regulation during pregnancy and early life may negatively affect neurodevelopment in children and in the context of maternal HIV infection may, in part, explain the delayed neurodevelopment observed in HEU children. However, the temporal regulation of neuroimmune markers during the critical period of the developing brain in HEU children remains unexplored. Importantly, it is also unknown at which stage (from in utero through to five years of age) the developing brain in children with HEU is affected. This study proposes to investigate longitudinally the association between maternal and infant neuroimmune function and brain development and neurodevelopmental outcomes in South African HEU children.
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| 24/11/2020 |
£149,986 |
CENTRE NATIONAL DE RECHERCHE ET DE FORMATION SUR LE PALUDISME |
Long-Lasting Insecticide-Treated Nets (ITNs) are the most successful method for malaria vector control in Africa. Growing evidence indicates changes in mosquito vector biting and resting behaviours in several African settings where high ITN coverage has been achieved. These combined with growing resistance to pyrethroids, the insecticide class used in all nets, can reduce intervention success. This is the case in Burkina Faso where high outdoor biting and pyrethroid resistance is reducing the efficacy of standard ITNs. In response to this Burkina Faso, adopted the newly developed ‘Next Generation Nets’ in its 2019 mass distribution campaign, becoming the first country to deploy Interceptor G2 (IG2), a net combining a pyrethroid with chlorfenapyr, an insecticide that should be effective against pyrethroid-resistant vectors. However, my initial results from laboratory and semi-field studies on mosquitoes from the Cascades Region of Burkina Faso indicate much lower moralities with IG2 nets than expected from earlier trials raising concerns that local vectors may have already developed resistance to this insecticide class.
Combining field and laboratory works in the Cascades Region I will assess for chlorfenapyr-resistance, its potential mechanisms and the impact of IG2 on Anopheles gambiae s.l. demography, behaviours (resting and biting) and malaria transmission potential.
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| 24/11/2020 |
£157,795 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
The World Health Organisation recommends use of sulphadoxine-pyrimethamine (SP), administered with routine immunisation, for intermittent preventive treatment of malaria in infancy (IPTi) in areas of moderate to high transmission in sub-Saharan Africa. However, there is limited uptake of this recommendation and increasing resistance of malaria parasites to SP. Fortunately, another antimalarial drug, dihydroartemisinin-piperaquine (DP), has shown higher protective efficacy than SP. However, there is paucity of evidence to guide its optimal dosing in infants. Additionally, IPTi is usually given to infants born to women who received SP or DP for intermittent preventive treatment of malaria in pregnancy (IPTp). The impact of using DP for IPTp on subsequent metabolism and efficacy of DP in infancy is not well understood.
In this Fellowship, I will develop optimised dosing regimens of DP for IPTi by applying population pharmacokinetic-pharmacodynamic modelling techniques on data obtained from:
Evaluating the pharmacokinetics, efficacy and safety of DP for IPTi, in a randomised-controlled trial, in infants born to Malawian women who received DP compared to SP for malaria prevention in pregnancy.
Understanding age-related changes in piperaquine pharmacokinetics during infancy.
This work will provide the much-needed evidence to inform DP dosing for IPTi, when administered with routine immunisation.
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| 24/11/2020 |
£152,610 |
UNIVERSITY OF THE WITWATERSRAND |
The persistence of under- and over-nutrition, in conjunction with poor adherence to movement guidelines and lack of stimulation evident among South African children, is indicative of a generation being raised in an environment that is not conducive to optimum early childhood development. This perpetuates an intergenerational cycle of health inequality.
Nurturing care is essential for early childhood development, and relies on responsive and sensitive interactions between caregivers and infants. Considering the importance of caregiver-infant interaction, as well as of infant movement behaviours, I hypothesise that encouraging interactive play could improve childhood growth and developmental through both the biological pathways linked to infant movement, and nurturing care pathways that promote attachment and emotional development.
This study proposes to test this hypothesis by designing, implementing and testing the efficacy of an intervention that encourages interactive play during infancy. This study uses a novel objective assessments of interactive play, as well as rapid participant feedback tools and an adaptive intervention design to enhance behaviour change and therefore intervention adherence.
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| 24/11/2020 |
£574,957 |
KEMRI-WELLCOME TRUST RESEARCH PROGRAMME |
Sickle cell disease (SCD) is the most important genetic disorder in sub-Saharan Africa, where over 280,000 affected children are born every year. Although children with SCD represent only 1-2% of all births within the region, they receive between 10 and 25% of all the blood transfusions administered to children
My fellowship has two main aims. First, I will describe the prevalence and consequences of alloimmunization among children attending the SCD clinic at Kilifi County Hospital in Kenya. Second, I will explore potential risk factors for the development of alloimmunization, including levels of inflammation within transfusion recipients and red blood cell genetic diversity in both donors and recipients. By identifying risk factors that contribute to alloimmunization, I will contribute to the development of better strategies that reduce the chance of development of alloimmunization for the transfusion management of patients with SCD in Africa.
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| 24/11/2020 |
£347,486 |
KEMRI-WELLCOME TRUST RESEARCH PROGRAMME |
Globally, acute malnutrition affects 8.5 million infants under 6 months of age (u6m). Malnourished infants u6m are at elevated risk of death during admission and after discharge from hospital and of subsequent neurodevelopmental impairment. WHO nutritional rehabilitation guidelines for u6m focus on re-establishing exclusive breastfeeding (EBF) with discharge when consistent weight gain ( > 5g/kg/day) is achieved on breastmilk alone. My pilot study examined breastfeeding peer supporters to facilitate guideline implementation among hospitalised malnourished infants. We achieved 81% exclusive breastfeeding by discharge with 67% attaining the WHO recommended growth velocity on breastmilk alone. However, criteria for full nutritional recovery were generally not met 6 weeks after discharge. I now hypothesise that providing support during transition to home will improve nutritional recovery. In Phase 1 I will develop and pilot a breastfeeding support intervention among 30 recovering infants u6m. In Phase 2 I will apply a randomised controlled trial to evaluate effectiveness of the finalised intervention compared with standard care among 250 malnourished infants (4-12 weeks old) recovering from an illness. The primary outcome is growth (weight gain) assessed at age 6 months, with follow up to 12 months. Results will inform efforts to improve post-discharge management of recovering vulnerable infants u6m.
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| 24/11/2020 |
£211,407 |
UNIVERSITY OF CAPE TOWN |
Approximately 30% of pregnant women in South Africa are HIV-infected resulting in over 300 000 infants exposed to HIV in utero every year. Rates of infectious mortality are reportedly higher among HIV-exposed uninfected infants (iHEU) compared to HIV-unexposed uninfected infants (iHUU). Studies evaluating the effects of maternal HIV infection on vaccine responses in their respective infants show that iHEU have similar antibody titres as those elicited in iHUU. These results imply efficacious vaccination in iHEU which contradicts the observed higher morbidity and mortality rates in iHEU. Therefore, I hypothesise that exposure to HIV in utero may impact the maturation of B cells leading to production of antibodies with poor Fc functions. Our preliminary analysis revealed altered B cell phenotypes across age in iHEU compared to iHUU. Therefore, in this study I aim to characterise B cell properties such as reduced somatic hypermutation for affinity maturation among iHEU using RNA-sequencing. Furthermore, I will analyse IgG Fc glycosylation that is associated with Fc-FcR affinity and Fc effector functions. Subsequently, I will develop in vitro models to measure antibody dependent cellular phagocytosis (ADCP) and cytotoxicity (ADCC) specific to early childhood vaccines.
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| 24/11/2020 |
£467,629 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
Context:
There are 2.2 billion visually impaired people globally. About 90% of these live in low-and-middle- income countries, 80% have avoidable conditions, which are amenable to well-established cost- effective interventions. WHO is promoting Universal Eye Health through integration of Primary Eye Care (PEC) into Primary Health Care (PHC). However, there is little evidence how and what interventions work to effectively and sustainably integrate PEC services into PHC in low-income settings.
Proposed Research:
The following studies will be conducted in Ethiopia in four phases:
Phase 1: Population-based cross-sectional studies to assess eye care need, inequalities, eye health-seeking behaviour and capabilities.
Phase 2: Health System Preparedness Evaluation Study to assess the health system's capacity and gaps to deliver integrated PEC interventions.
Phase 3: Intervention Development, informed by Phase 1 & 2, through Participatory Action Research (PAR) to develop contextually appropriate, feasible, community owned-and-led integrated & sustainable PEC services.
Phase 4: Iterated testing and piloting of the identified PEC interventions both individually and as integrated package at community, health facility, and healthcare organisation level to identify a working PEC intervention that will inform scaled-up delivery of equitably accessible, quality, and sustainable PEC services integrated with PHC.
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| 24/11/2020 |
£1,535,040 |
UNIVERSITY COLLEGE LONDON |
Generation of functional HSC from pluripotent cells and robust HSC expansion in culture are limited by our incomplete understanding of the self-renewal process. My goal is to unveil the regulatory pathways that sustain HSC self-renewal, based on modulation of gene expression at pre- (chromatin modification) and co-transcriptional (transcriptional elongation and RNA polymerase II pausing) levels and as directed by the metabolic state of the cell. I will carry out my scientific goals with the following aims:
Determine the regulation of HSC self-renewal though modulation of transcriptional rate and RNA polymerase II activity.
Understand the role of HSC metabolism and nutrient availability in the regulation of the HSC self-renewal gene regulation machinery.
Modulate HSC transcriptional regulation to achieve successful HSC generation in culture.
These research avenues will lead to a better understanding of the molecular basis of self-renewal and will provide a foundation to improve the generation and expansion of engraftable human HSCs in culture, in order to fully exploit their potential for clinical applications. This work will expand our current knowledge of the HSC self-renewal process and provide new insights into the molecular features of stemness, with implications for other tissue stem cells and the cancer field.
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| 24/11/2020 |
£1,185,742 |
UNIVERSITY OF GLASGOW |
Landscape changes disrupt infectious disease dynamics, requiring new approaches to characterise risks and prevent outbreaks. Focusing on emerging (Chikungunya, Zika) and epidemic (malaria, dengue) zoonotic and vector-borne diseases in Malaysia and the Philippines, I aim to design and evaluate enhanced surveillance systems linking health and environmental data to detect and prevent pathogen spillover and transmission. By developing novel models relating social and ecological processes across spatial and temporal scales, I will bridge critical gaps linking environmental change with human behaviour and health systems. Fine-scale studies of human mobility, behaviour and infection risks will be integrated within a large-scale experiment on tropical forest modification to understand how landscape change both interacts with and alters environmental factors (e.g. seasonality, biodiversity) and socioeconomic and biological factors (e.g. demography, mobility, immunity) to determine disease dynamics. Statistical and mathematical models will be used to explore factors across ecological settings, integrating routine surveillance data, population-based serological surveys and multitemporal Earth Observation data to reconstruct historical disease transmission over major environmental shifts. Predictive models will be designed to identify how future land use can reduce disease risks and how control programmes can use environmental data from new sources of real-time Earth Observation data to improve disease surveillance.
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| 24/11/2020 |
£886,561 |
UNIVERSITY OF EDINBURGH |
Ageing-related cognitive decline carries a huge personal, societal, and financial cost. Understanding its underlying mechanisms with a view to ameliorating age-related cognitive decline is a huge challenge. It is essential to identify biomarkers of cognitive ageing and their potential determinants. Brain structural imaging markers in older age, their correspondence with proteomic and other biomarkers, and their potential determinants, are poorly characterised. Our understanding is informed by cross-sectional studies (which cannot fully reflect the dynamic within-person processes of ageing) and mainly univariate longitudinal data (i.e. describing how brain regions individually decline over time): most aspects of brain structure decline, on average.
However, these approaches do not tell us whether there are important patterns of coordinated change, nor are they well-aligned with other levels of biological explanation. Such information could potentially aid stratification of risk and identification of important clusters of determinants of brain and cognitive ageing.
I will apply cutting-edge factor-analytic methods to large longitudinal datasets to detect and validate patterns of correlated biological changes (brain structure, serum proteomic and DNA transcriptomic). I will test how these dimensions of ageing are associated with each other and with cognitive ageing, and use several techniques to ascertain their lifestyle, genetic and epigenetic predictors.
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| 24/11/2020 |
£1,320,618 |
JOHN INNES CENTRE |
The project aims to investigate the mechanism of peptide transformations carried out by YcaO enzymes and to use this knowledge to create novel antimicrobials.
Bacterial YcaO proteins are essential for the biosynthesis of multiple classes of peptide natural products through their ability to introduce important structural modifications including heterocycles, macrocycles, and thioamides. YcaO repurposing and swapping between different pathways offers exciting possibilities to create novel artificial peptides bearing such modifications. Despite much recent progress, we still do not really understand how these proteins work, and how their activities are coordinated within multisubunit enzyme complexes. I will use cryo-EM in combination with X-ray crystallography to solve the structures of YcaOs within their native complex assemblies trapped at different catalytic stages. In parallel, I will discover and characterise new YcaO proteins to further expand their known catalytic repertoire.
Finally, the promiscuity of YcaOs allows for the production of large genetically encoded peptide antibiotic libraries. I will generate these by co-expressing randomised precursor genes along with modification systems. A high-throughput fluorescence-based version of a Waksman platform will be used for screening, where nano-sized "Petri dishes" (hydrogel beads) will be inoculated with both producer and reporter strains and sorted by FACS.
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| 24/11/2020 |
£1,334,770 |
UNIVERSITY OF OXFORD |
Many RNA viruses (e.g. SARS-CoV-2, HIV-1) have evolved ways of reprogramming translation to expand the coding capacity of their small genomes. ‘Recoding’ events such as -1 frameshifting, stop codon read-through and StopGo peptide release are necessary for viral replication, producing viral proteins in optimal ratios for efficient assembly. Recoding is regulated by a complex interplay between the elongating ribosome, cis-acting elements in the mRNA or nascent peptide, and trans-acting protein factors. Elucidating the structural basis of recoding is essential to understand viral pathogenesis. However, classical biochemical approaches cannot accurately capture kinetics or per-ribosome heterogeneity, making it difficult to define a window of opportunity for structure determination. Recent technological advances allow single-molecule fluorescent imaging of translation in real-time. I will apply these methods to study recoding in vitro and in live cells, starting with -1 frameshifting in SARS-CoV-2, HIV-1 and EMCV, which utilise topologically-distinct stimulatory elements. I will determine the structure of key ribosomal states by time-resolved cryo-EM, and investigate the structure and stability of stimulatory elements using crystallography, single molecule FRET and optical tweezers. Longer-term, this approach will be applied to investigate other recoding events, thus revealing universal and case-specific mechanistic principles, and highlighting new avenues for therapeutic intervention.
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| 24/11/2020 |
£1,110,044 |
BABRAHAM INSTITUTE |
Wnt and Hedgehog signalling regulate intestinal stem cell dynamics to ensure intestinal renewal, function and integrity is maintained. The activation of these two pathways involves crosstalk and communication between the mesenchymal and epithelial layers of the intestine. However, a puzzling conundrum is that both Wnt and Hedgehog carry hydrophobic lipid moieties that are required for receptor binding and signalling but that also hinder their solubility and diffusion and hence ability to move between intestinal cells. In Drosophila, the glypican Dally-like protein (Dlp), which possess a lipid binding pocket, binds and shields the lipid moiety of Wnts to aid transport. Dlp is also essential for initiating Hedgehog signalling but its precise mechanism of action is unknown. I will determine if Dlp also binds the lipid moieties of Hedgehog and what such binding means for Hedgehog solubility, transport and receptor engagement. I will determine if mammalian homologues of Dlp also bind the lipid moieties of Wnt and Hedgehog to regulate their activity and whether they are required in the mouse intestine for Wnt and Hedgehog signalling to orchestrate stem cell dynamics. A deep understanding of how glypicans modulate Wnt and Hedgehog signalling will answer major questions in developmental and stem cell biology.
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| 24/11/2020 |
£993,004 |
UNIVERSITY OF OXFORD |
Altered cardiac metabolism is now recognized as an important component of many cardiovascular diseases, including heart failure. Accurate assessment of cellular energetics promises significantly better disease staging and treatment monitoring in such conditions. Current non-invasive techniques based on magnetic resonance spectroscopy (MRS) are not precise enough to reliably define cardiac energetics in individual patients.
In this fellowship, I will develop new highly-sensitive MRS techniques for complete cardiac energetics assessment at 7T. The main goals of this research are:
To establish a robust, patient-specific platform for cardiac energetics quantification, by developing novel approaches to overcome a range of technical challenges associated with 31P-MRS;
To develop advanced methods that will allow for complete assessment of cardiac energetics, including quantification of Gibbs free energy of adenosine-triphosphate (ATP) hydrolysis (deltaG), and of complete myocardial ATP fluxes;
To demonstrate the sensitivity of these novel methods to measure impairments in total cardiac ATP dynamics in patients with type II diabetes and to detect changes in cellular energetics that accompany the transition to heart failure.
These new measures will help provide unique insight into the pathophysiology of the failing heart and will be applicable in future studies monitoring novel metabolic therapies in cardiovascular disorders.
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| 24/11/2020 |
£1,091,843 |
UNIVERSITY OF BRISTOL |
The distinct activities of polytopic channels, transporters and receptors are essential for cell signalling in response to external stimuli, and their dysfunction is frequently associated with disease. My research has revealed that these plasma membrane proteins undergo Conformational Surveillance by intramembrane proteases: their distinct conformations are recognised and subsequently downregulated by transmembrane domain cleavage. Substrates have never been identified for many intramembrane proteases; I propose this is largely due to a previous lack of systematic screening approaches, and that proteins with more than one transmembrane domain have not been fully explored as substrates.
The overarching aim in this fellowship is to discover the mechanisms that underpin Conformational Surveillance, and to reveal its full repertoire of functions.
My four main goals are:
1) to explore newly identified examples of Conformational Surveillance;
2) to examine whether intramembrane proteases of different families share this molecular activity;
3) to understand the mechanistic coupling of intramembrane proteolysis and lysosomal degradation;
4) to investigate Conformational Surveillance in neurons, where many intramembrane proteases are highly expressed.
Overall, this research programme will shed light on a potentially widespread yet overlooked branch of cell surface proteostasis.
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| 24/11/2020 |
£1,121,260 |
UNIVERSITY OF OXFORD |
Meiotic recombination is essential for creation of haploid gametes. Errors in this process cause miscarriage, infertility, and developmental disorders. Recombination proceeds via repair of programmed DNA breaks; however, the molecular mechanisms ensuring their repair are not well understood. My work reveals that these breaks are a significant mutagenic force, leading to de novo mutations (DNMs) in 1 in 3 sperm and 1 in 13 eggs. My proposed research will harness cutting-edge experiments in genetically-engineered mouse models to generate novel data and will further leverage existing population-scale human genetic and phenotypic data. I will integrate these data through sophisticated statistical analyses to answer the following questions:
What are the properties, causes and impacts of recombination-associated mutations on human health? I will characterize these mutations comprehensively in humans and infer their molecular causes. I will investigate their impact on common and rare diseases.
What is the mechanism of break repair in recombination? I will build on my recent work and interrogate meiotic break repair through specialised experimental assays on key proteins in genetically-engineered mice.
What is the mechanism of mutagenesis? I will characterize the impact of pathways that are identified above as causal by disrupting them in genetically-engineered mice.
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| 24/11/2020 |
£1,136,115 |
NEWCASTLE UNIVERSITY |
Necrotising enterocolitis (NEC) is a leading cause of death in babies born extremely preterm. NEC infants generally have increased gram-negative bacteria compared to matched controls, potentially resulting in an LPS-stimulated increase in TLR4 and inflammatory cytokines in the intestinal epithelium, ultimately leading to the breakdown of epithelial integrity and necrosis. My recent work has shown that human milk oligosaccharides (HMOs) promote the establishment of a protective microbiome in the infant gut, which is associated with reduced risk of NEC.
This project will identify specific HMOs and bacteria that promote gut health and reduce NEC in preterm infants. The project will take advantage of a host-microbe model system I have recently developed. This will provide new insights into NEC pathogenesis, potentially leading to the development or refinement of therapeutics. I will achieve this by answering four critical questions:
1. What specific HMOs and microbial species are associated with NEC or gut health?
2. Do HMOs directly influence the epithelial integrity and inflammation observed in NEC?
3. How do specific bacterial species interact with the preterm intestinal epithelium?
4. Can a combination of HMO (prebiotic) and bacteria (probiotic) promote gut health and protect against NEC?
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| 24/11/2020 |
£667,750 |
INTERNATIONAL CENTRE OF INSECT PHYSIOLOGY AND ECOLOGY |
Malaria remains a major human burden in Africa despite the scale-up of control interventions. Factors driving the persistent transmission remain poorly characterised. In Kenya, the mosquito Anopheles funestus has gained prominence in malaria transmission, and we have documented genetic subdivision in the species locally with varied Plasmodium infection rates. Potentially, the discrete populations possess unique genetic variants conferring fitness advantage coupled with greater transmission role in specific ecologies. Moreover, the populations may present different adaptation to insecticide-based control interventions such as LLINs impacting local malaria epidemiology and control outcome. The proposed 5-year project will address these knowledge gaps by elucidating the underlying biological and ecological drivers influencing the vectorial role of An. funestus in persistent malaria transmission and impact of insecticide-based interventions. Field-based evidence will be generated to inform decisions on how to overcome major barriers in malaria control towards elimination. The project will be implemented under the guidance of a strong interdisciplinary team of scientists from the UK (Prof. Charles Wondji, vector biology, Liverpool School of Tropical Medicine), Greece (Prof John Vontas, vector biology, IMBB-FORTH) Africa (Prof. Baldwyn Torto, vector ecology; Dr Henri Tonnang, disease modeling; icipe), Dr. Luna Kamau (vector biology, KEMRI), and Dr Cyrille Ndo (CRID, Cameroon).
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| 24/11/2020 |
£131,673 |
TRANSCULTURAL PSYCHOSOCIAL ORGANIZATION (TPO) NEPAL |
Depression is a highly prevalent mental health condition which has enormous emotional and financial burden on individuals, families, and society as a whole. Despite the availability of effective treatment, a large number of people needing depression care do not receive treatment. Individual often delay or avoid seeking help for depression due to various reasons including stigma and negative attitude towards services. The aim of this study is to develop and test the feasibility, acceptability, and appropriateness of a social contact-based community psychosocial intervention in order to improve help-seeking behavior of people with depression in Nepal. The objectives of the study are to; (1) systematically review the interventions that have shown effectiveness to improve help-seeking attitude, intension, and behavior among people with depression in LMICs; (2) assess the perceptions of people with depression, their family members and key community stakeholders about barriers for seeking depression care and potential strategy to address those barriers; (3) develop a social contact-based community psychosocial intervention in order to improve negative attitude and intention towards seeking depression care; and (4) test the feasibility, acceptability, and appropriateness of the social contact-based community psychosocial intervention through a pilot cluster randomized controlled trial in Jhapa district of Nepal.
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| 24/11/2020 |
£339,911 |
ACADEMIA NACIONAL DE MEDICINA |
Dry eye is a highly prevalent ocular surface disorder in which a localized CD4+ T cell response and corneal nerve dysfunction are core pathophysiological mechanisms. Both aspects of the disease develop concomitantly in murine models but their connection is unclear. Our preliminary data suggests that the pathogenic immune response is linked to corneal nerve damage and that transient receptor potential vanilloid 1 (TRPV1) signaling promotes nerve-initiated (neurogenic) inflammation. Neurodegeneration is induced by TRPV1 overactivation and leads to neurogenic inflammation in other settings. Therefore, we hypothesize that 1) CD4+ T cells damage corneal nerves in dry eye; and that 2) increased TRPV1 activation promotes nerve damage and neurogenic inflammation, thus worsening the disease (vicious cycle). We will explore the first possibility by using T cell-deficient mice and adoptive transfer of T cells; and the second, with TRPV1-deficient mice and a unilateral surgical model of dry eye in which neurogenic inflammation manifests in the opposite eye. We will explore corneal nerve morphology and function, the possible autoimmune origin of neural changes, and the accompanying T cell response in these models. These findings could serve to develop a dry eye treatment that addresses corneal nerve damage and its associated neuropathic pain.
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| 16/11/2020 |
£6,504 |
UNIVERSITY OF BRISTOL |
Although science prides itself on objectivity, in reality scientists harbor biases (conscious or otherwise), which inevitably influence their research. Consequently, UK (and arguably Global North) biomedical science has become pregnant with non-inclusive research practices. Practices such as the majority of cancer cell lines being derived from patients of European descent, an historic exclusion of female animals from biological research and heterosexist attitudes in study design(3) mean the majority of biomedical research is based on White, heterosexual men.
The Inclusive Research Collective (IRC) aims to educate staff and students on non-inclusive research practices and to challenge these methodologies within University of Bristol biomedical research. It is our aim that the IRC brings together the University of Bristol’s research community, amplifying the voices and experiences of individuals who are often side-lined in the academic sphere while creating a culture of awareness and accountability. We will create a repository of resources produced for future University of Bristol researchers to access, and we hope that this work will form a template for other institutions to deliver their own inclusive research series.
Truly inclusive research requires more than just an awareness of exclusionary practices and the tools to challenge and change them. It requires an inclusive and diverse academic environment, where under-represented individuals are supported fully. It is our aim that the IRC brings together the University of Bristol’s research community, amplifying the voices and experiences of individuals who are often side-lined in the academic sphere, while creating a supportive culture of awareness and accountability.
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| 16/11/2020 |
£19,450 |
KING'S COLLEGE LONDON |
'Visible Skins' will deliver a collaborative programme of workshops and events addressing the presence of Black skin in Renaissance European art and culture, aimed at overcoming issues of underrepresentation at two critical junctures: first the absence of BME voices in scholarly conversation, and second the relative absence of Black identities in the study of the Renaissance.
Visible Skins takes the subject matter of Black skin in the Renaissance and uses it as a focal point to provide more inclusive scholarship, showcase underrepresented voices and reflect on the implications of a more diverse Renaissance.
Through a series of workshops, we will collaborate with BME academics such as Nick Jones of Bucknell University, and BME artists such as artist-practitioner and performer Peter Braithwaite. Inspired by Peter’s online Rediscovering Black Portraiture series, Visible Skins will create new narratives, placing the lives and stories of diverse ethnicities, center stage. Accompanying events will include an exhibition to promote the works of the artists, a panel discussion in conjunction with an academic workshop, and artist Q & A’s – all to be made available online.
By enabling a dialogue driven by artist-led practice rather than academic sources, we will broaden and strengthen our project’s engagement with material culture, better incorporating BME viewpoints into our own understandings. Outputs will expand perceptions of what is too often an elite, white, male canon. By showing that the population of Renaissance Europe was more diverse, we will contribute to awareness of the construction of racial norms and ideas in later periods.
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| 11/11/2020 |
£300,000 |
UNIVERSITY OF GLASGOW |
Apicomplexan parasites, which include Toxoplasma and Plasmodium, cause deadly human diseases, such as toxoplasmosis and malaria. Understanding their divergent cell biology could inform strategies to combat them. The apicomplexan mitochondrial electron transport chain (mETC) is essential for their survival and transmission, and highly divergent from the human mETC. Cytochrome bc1 is an mETC protein-complex that is essential, and a key target for drugs, like atovaquone. Yet its composition is unknown, and the mechanism of function and inhibition poorly understood. I propose to investigate how the cytochrome bc1 complex functions and interacts with inhibitors.
Using Toxoplasma as a model, I will uncover the role of my newly discovered apicomplexan cytochrome bc1 subunits, and decipher the role of respiratory super-complex formation, in parasite energy metabolism and survival. Using cryo-EM technology I will solve this complex’s structure to elucidate its mechanism of action, highlighting key differences with the human complex, and understand the way inhibitors disrupt the electron flow essential for energy conversion.
These studies will provide a mechanistic understanding of the essential apicomplexan cytochrome bc1 complex and how inhibitors stop its function. This work will fill a critical gap in our knowledge of fundamental parasite cell biology, and likely inform drug discovery.
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| 11/11/2020 |
£300,000 |
UNIVERSITY OF LEICESTER |
COVID-19 is an infectious respiratory disease with a global devastating health impact. Genetic and environmental factors influence COVID-19 susceptibility and outcomes, including the development of acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. These lung pathologies have a high mortality and there are no specific treatment options or effective prognostic methods for patients. Therefore, there is an urgent need to identify effective biomarkers of disease prognosis. The aim of this research is to perform a genomic epidemiology study of ARDS and pulmonary fibrosis in patients with COVID-19. For that purpose, we will perform genetic overlap studies that will include genetic correlation analyses, polygenic risk score approaches, and assessments of overlap of individual genetic variants, followed by fine mapping studies, bioinformatic approaches to identify the likely causal genes, and further experiments to evaluate their role in disease and their potential as drug targets. Results of these analyses will allow us to identify novel genetic risk factors and to develop risk prediction models, which could enhance COVID-19 patient stratification for those at increased risk of lung sequela. Furthermore, the project will reveal novel therapeutic strategies, which would translate into improved and more personalised clinical care for patients at risk of lung fibrosis.
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| 11/11/2020 |
£458,214 |
NEWCASTLE UNIVERSITY |
Critically ill patients with pneumonia often have impaired neutrophil function and disruption of alveolar-capillary barrier integrity. During inflammation, excessive polycation generation activates the calcium-sensing receptor (CaSR), which can potentially compromise neutrophil function and barrier integrity. My over-arching hypothesis is that, during critical illness, CaSR, activated by polycations, mediates impairment of neutrophil, alveolar epithelial and pulmonary endothelial function, leading to reduced bacterial clearance and disruption of alveolar-capillary barrier.
To test the hypothesis, I shall use a range of complementary methods to (a) assess the effect of positive and negative allosteric CaSR modulators and polycations on a range of functions in neutrophils and monocytes from critically ill patients at high risk of developing nosocomial infection; (b) isolate human primary alveolar epithelial cells and culture primary human pulmonary microvascular endothelial cells, and assess the effect of CaSR modulators on barrier function, inflammatory signatures, and antimicrobial functions; (c) perform the first temporal assessment of CaSR expression (and effect of CaSR inhibition) in extravasated neutrophils and alveolar macrophages from human healthy volunteers receiving inhaled lipopolysaccharide (LPS) or control; and (d) create neutrophil-specific CaSR knockout mice, assessing the influence of neutrophil CaSR on the natural history of acute pulmonary infection, inflammation, and alveolar-capillary barrier disruption.
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| 11/11/2020 |
£300,000 |
UNIVERSITY COLLEGE LONDON |
The cerebellar cortex is thought to form predictive associations between sensory inputs and motor commands: animals leverage these associations to coordinate and adapt movements to contextual changes in the environment. This sensory-motor control depends on Purkinje neurons, each of which receives sensory, motor and cognitive signals from one climbing fibre as well as thousands of parallel fibres, the axons of granule cells. Despite years of anatomical work, cerebellar sensory-motor representations have not been mapped at the cellular scale; similarly, the functional circuit connectivity underlying sensory-motor integration remains unexplored.
To reveal the functional architecture of the mouse cerebellar cortex, I propose to use rabies monosynaptic tracing to map and functionally characterise the presynaptic ensemble of individual Purkinje neurons. I will validate my functional connectomics strategy with electron microscopy and elucidate whether the anatomical organisation of presynaptic circuits converging on Purkinje neurons is modular or random (Aim1). Then, I will harness functional imaging and optogenetics to map the topography of cortico-cerebellar representations, and discover whether Purkinje neurons pool inputs from related sensory-motor presynaptic modules (Aim2). Finally I will train mice in a sensory-guided forelimb task, and ascertain how these circuits are engaged by sensory-motor events, and their timing, during adaptive behaviour (Aim3).
|
| 11/11/2020 |
£300,000 |
UNIVERSITY OF MANCHESTER |
Polymicrobial infections consisting of Aspergillus fumigatus and Pseudomonas aeruginosa are associated with poorer patient outcomes and are often much harder to treat. There are a very limited number of drugs available to treat fungal infections, and both bacterial and fungal resistance is rapidly spreading in environmental and clinical settings. Determining the effect of inter-kingdom interactions between these pathogens upon the evolution of antimicrobial resistance is vital for the treatment of polymicrobial infections.
Multispecies biofilms caused by coinfection of these two key respiratory pathogens create a physical barrier preventing drug penetration leading to protection from antimicrobial treatment. However, we understand very little about how competitive interactions within such communities can alter the mutational drivers of resistance or how coexistence changes the pleiotropic fitness costs associated with resistance. The aim of the project is to understand how coexistence and competition between A. fumigatus and P. aeruginosa alters the rate of resistance evolution in the presence and absence of antimicrobial treatment and how interactions change the fitness landscape of resistant mutants within both species.
Understanding the drivers of resistance in polymicrobial communities may increase our ability to predict resistance evolution and aid the design therapeutic of strategies that limit the emergence of resistance.
|
| 11/11/2020 |
£300,000 |
UNIVERSITY COLLEGE LONDON |
Dopamine (DA) neurons in the ventral tegmental area (VTA) are thought to provide a reinforcement signal that is essential for learning. Despite recent advances, how VTA-DA neurons coordinate and modulate communication and synaptic plasticity across brain regions to drive behavior is still an open question. We hypothesise that 1) DA enhances communication of behaviorally relevant information across cortex and striatum and 2) the content of the information varies across corticostriatal regions. To test this model, we propose an ambitious research program in mice, using state-of-the-art in vivo electrophysiology, optogenetics, neuropharmacology and computational techniques. First, we will use high density in vivo electrophysiology (Neuropixels) to record neural activity across different corticostriatal regions, while optogenetically manipulating VTA-DA neurons in mice performing a visuospatial decision-making task. We will then use advanced computational methods to examine how and what information is communicated across corticostriatal regions, and how this process is modulated by DA. Finally, we will causally evaluate how DA mediated changes in cross-region communication depend on the receptor, synapses and the neuronal populations involved. In conclusion, we propose a comprehensive study of how DA modulates cross-region communication to drive behavior, providing a needed bridge between our systems and synaptic level understanding of VTA-DA.
|
| 11/11/2020 |
£300,000 |
UNIVERSITY OF OXFORD |
Steroid hormone dysregulation has been linked to nearly all leading causes of death, notably cardio-metabolic diseases. Despite this, the aetiological contribution of steroid hormones to such disease is poorly understood and its potential as a therapeutic target remains largely unexplored. To fill this gap, I seek to pioneer a new aetiological understanding of steroid hormone dysregulation and its health consequences through multiple complementary data-driven approaches. I will do the following:
Identify the genomic basis of steroid regulation through large-scale genetic studies of steroid hormones, steroidogenic enzymes, and regulating peptides.
Pinpoint the tissues, genes and biological mechanisms involved in steroid dysregulation in men and women, through the vertical integration of genetics with tissue-specific molecular trait data. As part of this, I will set up an omics atlas of the adrenal gland and the ovary.
Map out the metabolic and regulatory relationships between steroid hormones and related traits through the identification of genetically determined multi-dimensional steroid traits.
Conduct a genomics-driven identification of new therapeutic pathways and protein targets to correct disease-causing steroid imbalances.
In short, this research agenda will not only uncover the aetiological pathways linking the steroid endocrine system to cardio-metabolic disease, but also instigate novel treatment strategies.
|
| 11/11/2020 |
£300,000 |
UNIVERSITY OF BIRMINGHAM |
Cardiac arrhythmias are a common pathway for multiple cardiovascular diseases, the leading cause of death in the world. Ablation of cardiac arrhythmias is a recommended and common treatment option for arrhythmia patients, but success rates are poor. Cardiac electroanatomical mapping systems (EAMs) are used to identify ablation targets. EAMs generate a wealth of raw data that is ideal for developing algorithms to tailor treatments to an individual patients’ pathophysiology and improve treatment options. However, no platform exists for developing and testing algorithms.
Specific groups have developed closed-source software to identify ablation targets however, these results have not been widely reproducible. There is an acute need for an open-source and cross-vendor EAM analysis software to facilitate sharing methods, increase rigor and transparency and increase access to advanced processing tools.
I will develop expandable open-source software for analysis of EAM data. I will incorporate established and novel analysis methodologies, including machine learning approaches. Algorithms will be robustly validated using clinical, pre-clinical and in silico datasets. The software I will develop will enable myself and others to utilise routinely collected clinical data, to better treat cardiac arrhythmia. I will apply these approaches to identify mechanistic drives of atrial fibrillation as an exemplar application.
|
| 11/11/2020 |
£300,000 |
UNIVERSITY OF EDINBURGH |
Despite new developments in treatment, cancer remains the second leading cause of death worldwide. Breast cancer is the most common cancer within the UK, with death generally caused by the formation of metastasis. I intend to investigate the hypothesis that immune responses at the metastatic site determine the long-term outcome of therapy.
I will compare immune responses at the primary and metastatic sites upon administration of checkpoint inhibitors that have different clinical success rates. Flow cytometry and t-SNE analysis will provide insight into the affected cell populations and timings. I will then utilise newly developed intravital imaging technologies to visualise immune responses in vivo at multiple cancer sites. I will measure cytotoxic cell activity and tumour cell death as indicators for anti-cancer response. Further, I will examine the ability of a combination of checkpoint inhibitor and focal adhesion kinase inhibitor to fully eradicate tumour cells. An inhibitor will be fluorescently tagged to study its access to tissue and interaction with immune cells dependent on combination therapy.
The proposed research will help to elucidate the role of immunotherapy on the metastatic foci and will provide the first insights into the benefit and limitations of combination therapy on secondary site immune responses.
|
| 11/11/2020 |
£300,000 |
UNIVERSITY OF GLASGOW |
Sleep/wake cycles are arguably the most important circadian behavioural output controlling many aspects of animal physiology. However, some infections induce disruptions to these cycles, leading to pathology. Sleeping sickness is an infection caused by the African trypanosome Trypanosoma brucei. One of the most puzzling symptoms of this disease is the profound alteration in sleep patterns, which is now recognised as circadian disorder. This disease provides an ideal framework to study how pathogens disrupt host circadian behaviour.
I will use single-cell transcriptomics to profile the responses of key hypothalamic nuclei controlling circadian behaviour during infection. I will also characterise the population of parasites residing in the brain compared to bloodstream parasites to identify mechanisms of glial activation, neuroinflammation, and parasite survival in the CNS. These outputs will provide novel and unprecedented insights into the host-pathogen interactions in the hypothalamus that lead to disruptions of sleeping patterns.
My ultimate aim is to understand how pathogens interfere with the function of the central nervous system leading to changes in physiology and behaviour. The outcomes of my fellowship will provide a new understanding of infection-induced circadian disorders and will reveal factors that can be exploited for intervention and treatment of infections affecting the brain.
|
| 11/11/2020 |
£300,000 |
KING'S COLLEGE LONDON |
Individuals at the early stages of psychosis already suffer from neuroanatomical, neurofunctional and neurocognitive alterations. However, it is not clear how these alterations interact with each other and, more importantly, how this interaction may help predict who will become unwell. The aim of the proposed study is to uncover previously hidden relationships between brain anatomy, function and cognition that can improve our understanding of the first signs of the illness and help predict illness trajectory at the individual level. This will be achieved by triangulating, for the first time, data fusion, machine learning and a unique longitudinal dataset of individuals at the prodromal stage or with a recent first episode of psychosis. This combination of methods will allow me to address three main objectives: 1) identify previously unknown relationships between anatomy, function and cognition in healthy individuals; 2) develop a model that captures the normative pattern of these hidden relationships and determine by how much each patient deviates from this pattern; 3) use these deviations to predict each patient’s longitudinal clinical outcomes. I will also develop an open access tool that allows non-expert researchers to perform data fusion on their own data. Keywords: psychosis, data fusion, machine learning, outcome prediction.
|
| 11/11/2020 |
£300,000 |
UNIVERSITY COLLEGE LONDON |
The gut-brain axis is at the heart of Parkinson’s disease (PD) etiology. Pathological alpha-synuclein accumulates early in the gut, potentially affecting the enteric nervous system (ENS) and spreads to the brain. However, we lack insights into how pathological alpha-synuclein affects ENS integrity and cellular mediators underlying their spread. Here, I propose to study the role of a unique subset of gut macrophages (gMacs), the ENS-gMacs, that coordinate neuronal function in their unique ENS niche. I hypothesize that ENS-gMacs critically dependent on LRRK2 for alpha-synuclein clearance. LRRK2 is a risk factor for PD, regulates alpha-synuclein clearance in macrophages and is highly enriched in ENS-gMacs compared to microglia and neurons. First, using state-of-the-art single cell RNA and in-situ sequencing techniques I will examine how ENS-gMacs and microglia become dysfunctional in PD mouse models. Second, using in vivo and in vitro tools, I will dissect whether mutant LRRK2 signaling in ENS-gMacs affects neuronal function and survival upon PD patient-derived pathological alpha-synuclein. Finally, I will investigate how ENS-gMacs contribute to alpha-synuclein pathology and spread. Insights obtained will create new avenues to study neuroimmune pathways along gut-brain axis for the future, as well as novel targets for early therapeutic interventions in PD.
|
| 11/11/2020 |
£300,000 |
UNIVERSITY COLLEGE LONDON |
Children develop and interact in complex, multimodal environments. I will investigate how deaf children with cochlear implant (CIs) integrate visual information from the talker’s face to supplement sound.
This is important because CIs provide a degraded sound that lacks pitch and much affective information, placing high cognitive demand on the developing brain and increasing reliance on visual information and audio-visual integration.
I will conduct experiments comparing adolescents with early-onset deafness and bilateral CIs to hearing controls. Eye tracking will be used to understand allocation of visual attention during word and emotion perception and the interaction between these processes. Visual evoked potentials will be measured using electroencephalography to understand the efficiency of cortical processing during visual perception. Psychophysics and pupillometry will be combined to estimate the benefit gained from audio-visual speech integration and the impact on cognitive effort. Functional near-infrared spectroscopy will enable cortical imaging of CI users without interference from CI-generated artefacts. Correlations between activity in temporal and occipital cortices will be examined to understand audio-visual cortical connectivity and to specify mechanisms of audio-visual integration.
This work will enable us to better understand the role for visual cues in augmenting current auditory-only rehabilitative interventions to help deaf children communicate effectively.
|
| 11/11/2020 |
£300,000 |
UNIVERSITY COLLEGE LONDON |
Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease targeting motoneurons, leading to paresis and death. Changes in spinal microcircuits have been suggested to be part of an early homeostatic response to preserve motor output, possibly involving substantial alterations at the level of premotor synapses. Supported by solid preliminary data, I hypothesize that changes in these circuits precede motoneuron degeneration, and thus propose to address these aims: (1) define early disruptions in connectivity to motoneurons in ALS and (2) determine the genetic profile of these abnormalities. I will characterize well-known spinal synaptic pathways such as Ia excitation, disynaptic reciprocal inhibition and pre-synaptic inhibition in wildtype mice and 2 different models of ALS (SOD1G93A and TDP-43-A315T). I will do this both in vitro, by using a novel isolated mature mouse spinal cord preparation, and in vivo by performing intracellular recordings of motoneurons and EMG recordings with chronically implanted multielectrode arrays. These experiments will be complemented with transcriptomic analysis using single-cell patch seq and laser capture microscopy to reveal if changes in specific spinal microcircuits are accompanied by changes in expression profile of motoneurons and interneurons. This project will reveal if early degeneration in ALS results in generalized circuit impairment.
|
| 11/11/2020 |
£300,000 |
BEATSON INSTITUTE FOR CANCER RESEARCH |
Pancreatic ductal adenocarcinoma (PDAC) and hepatocellular carcinoma (HCC) are leading causes of cancer-related deaths. Despite knowing these cancers’ driver mutations, there are no effective therapies. A universal yet understudied feature of both PDAC and HCC is their aberrant glycosylation. Glycosylated serum proteins act as clinical biomarkers, but it is unknown how altered glycosylation – driven by gene expression changes and mutations of glycosyltransferases/glycosidases – contributes to disease progression.
First, I propose to establish a new HCC mouse model combining genetic alterations with chronic alcohol consumption, a major risk factor. Second, I will systematically uncover the glycosylation changes in primary cells of this new HCC model and established PDAC models using unbiased mass spectrometry-based glycomics and lectin microarrays. By applying glycobiological techniques to this setting, I will bring together two hitherto disparate research fields. Third, based on these data, I will manipulate the glycosyltransferases/glycosidases most likely responsible for the glycosylation changes and examine disease progression, yielding new targetable oncogenes. In parallel, based on preliminary data, I will investigate the tumour suppressive mechanism of the fucosidase FUCA1 in mouse models of PDAC and HCC, using glycomics as a starting point. Finally, I will validate my findings in human PDAC and HCC samples.
|
| 11/11/2020 |
£630,613 |
QUEEN MARY UNIVERSITY OF LONDON |
Diabetic cardiomyopathy (dbCM) is a complication of type II diabetes (T2D), characterised by systemic inflammation, impaired cardiac function and disrupted metabolism. However, the impact of systemic inflammation on the development of the myocardial inflammation and cardiac metabolic derangement that lead to dbCM remain unknown. This study will address how chronic adaptive inflammation driven by systemic metabolic stress in T2D causes cardiac dysfunction. Specifically, I hypothesise that it is caused by inflammation due to T-cell infiltration and not by direct metabolic perturbations that can lead to impaired energetics (reduced PCr/ATP ratio). Specifically, the aim is to use integrated experimental approach combining metabolic analysis with T-cell phenotypic profiling in murine and human T2D to address three research challenges:
A. Does infiltration of cardiotropic T-cells impair cardiac substrate plasticity and energetics in dbCM?
B. Do myocardial succinate efflux and signalling via SUCNR1 promote cardiac Teff and/or Treg activation by modifying T-cell metabolism and do they enhance pro-inflammatory T-cell differentiation?
C. Does stimulation of GCK-mediated glycolysis increase regulatory T-cell migration to the heart causing a switch in the nature of immune response from pro-inflammatory to immunosuppressive? Does the resultant reduction in myocardial exposure to pro-inflammatory cytokines improve cardiac function and mitochondrial performance?
|
| 28/10/2020 |
£149,995 |
RESTLESS DEVELOPMENT |
Restless Development will identify, train and empower 20 Young Leaders (18-24) in Zimbabwe, working in pairs across 10 rural and urban communities in 2 districts, to develop evidence based solutions to address the impacts of global heating on health. These Young Leaders will bring unique perspectives from the communities in which they live and work, first using a youth-led research methodology to develop evidence on current levels of young people and their community’s knowledge and understanding of global heating and health as interconnected issues, then using that evidence to conduct global heating and health advocacy work to develop community-based solutions. Acting as agents of change, Young Leaders will translate knowledge and research to their communities in order to improve the knowledge of the global heating and health related issues. By the end of the 12 month initiative, the project will have investigated and tested different methods young people can use to increase the understanding of the links between global heating and health, the subsequent impact on their communities, and identified local solutions to identified challenges.
|
| 28/10/2020 |
£193,379 |
CLIMATEWORKS FOUNDATION |
Healthy Food, Healthy Planet (Europe) (hereafter HFHP) is a collaboration of philanthropic and civil society organizations. Our goal is to support the formation of a movement across Europe advocating for a global food system compatible with climate, health, biodiversity, animal welfare, and just transition goals.
To execute a scoping strategy and facilitate scoping phase grantmaking of HFHP, ClimateWorks Foundation will establish a pooled fund with an option for aligned funding. The HFHP Fund has a target size of approximately USD $1 million, and will be managed by ClimateWorks.
The project will have two phases. The first phase will run from June to October 2020. It will culminate in an investment prospectus indicating opportunities for donors to support a European food movement. The second phase will run from October 2020 to July 2021 and will culminate in a strategic framework describing tactics for the movement.
The activities of both phases of HFHP will be overseen by a Project Lead who will design and execute consultative processes, work to ensure that research deployed and the materials produced reflect priorities of civil society, and incorporate learning from the research and consultative processes in the investment prospectus and the strategic framework.
|
| 19/10/2020 |
£1,382,640 |
KING'S COLLEGE LONDON |
Through SCOPE, we will produce high quality, contextual evidence and use it to design
innovations in detection and treatment, to improve the lives of people living with
psychosis in a low-income country.
Our key goals are to:
1. determine the rate of new cases of psychosis in rural and urban settings in
Ethiopia; identify possible risk factors for onset; and characterise the needs of
people with psychosis and the factors that affect early course and outcome.
2. use this evidence to co-develop innovations to improve early detection and
optimise the recovery of people with psychosis. The innovations will be
applicable to rural, urban and homeless populations in Ethiopia, with potential
generalisability to other low- and middle-income countries.
We will pilot test interventions, develop strategies to overcome implementation
challenges and identify key intervention components to inform adaptation for other
contexts. |
| 06/10/2020 |
£1,197,348 |
INSTITUT PASTEUR DE TUNIS |
We propose a different approach to antivenoms, based on recombinant nanobodies (Nbs), targeting the lethal cobra toxins, to reduce morbidity and mortality. Nbs have a high affinity for selected epitopes, allowing rapid recognition of antigens even if bound to cholinergic receptors, combined with a capacity to dislocate neurotoxin from the receptor.
This COBRA-NGaV project brings together research teams with extensive experience in venomics and antivenomics to provide the proof-of-concept (PoC) for cobra toxin-specific Nb candidates as a novel generation of antivenoms and to address the dual obstacle to neutralise cobra toxins: weak immunogenicity and fast diffusion.
Preliminary results have been obtained so far: i) strong and specific responses were elicited in dromedaries immunised against the toxic fractions of N. legionis, N. haje and N. oxiana; ii) phage display screenings were adopted to rescue strong Nb binders specific towards relevant N. l., N. h. and N. o. toxins; iii) several clusters of Nb sequences specifically binding cobra toxins have been identified.
Herein, Nb selections and combinations for optimal synergic effects and best cross-species performances will be generated. Best-in-class candidates will be tested in a pre-clinical study in mice and sheep according to GMP rules. Cost effectiveness will be established.
|
| 06/10/2020 |
£2,621,953 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
Small molecule toxin inhibitors offer great potential to rapidly deliver inexpensive, safe and efficacious oral interventions in the community soon after a snakebite, prior to subsequent admission to a healthcare facility. Despite such promise, only a handful of toxin inhibitors have been robustly explored to date. We redress this here by expanding the chemical space available for snakebite treatments by employing a comprehensive drug discovery approach. Using toxin-specific assays, we will screen diverse compound libraries ( > 50,000 molecules), including using the Human Pharmacopoeia and Phase-1 approved molecules in a repurposing approach, for hits that demonstrate broad toxin family neutralisation. Thereafter, we will rationally identify lead series by defining the toxin-specificity, kinetics, phenotypic potency and medicinal chemistry characteristics of hits, before performing murine preclinical efficacy and pharmacokinetic experiments to rationally define oral dosage regimens of lead candidates capable of achieving systemic inhibitory concentrations throughout a snakebite treatment period. Finally, we will evaluate therapeutic combinations of lead candidates by performing dose optimisation via PK/PD modelling, and preclinical efficacy and drug-drug interactions studies. This comprehensive drug discovery pipeline will deliver a portfolio of lead candidates (and numerous backups) ready for translation into clinical studies to assess their tolerability and efficacy as next-generation snakebite therapeutics.
|
| 06/10/2020 |
£1,194,565 |
KATHOLIEKE UNIVERSITEIT LEUVEN |
One of the most common lethal snakebite pathologies is neurotoxicity, which is the result of neurotoxins blocking nerve transmission, commonly via interaction with nicotinic acetylcholine receptors (nAChRs). Here we will use molecules that mimic the structural components of nAChRs that are important for toxin binding to generically inhibit the functional activity of venom neurotoxins. Our pilot data demonstrates that such ‘decoy receptors’ offer great potential to generically neutralise venom neurotoxins irrespective of snake species (unlike antivenom).
We will use structural and informatic guided approaches to rationally design a panel of acetylcholine receptor binding proteins, nAChR ligand binding domains, and peptide mimotopes, before measuring their binding affinity to venom neurotoxins. We will then identify the toxins they capture using analytical approaches, before demonstrating that they effectively prevent binding to nAChRs. Thereafter, we will use in vivo efficacy studies to robustly assess whether mixtures of lead decoy receptors protect mice from venom lethality, as either solo or adjunct therapies.
We anticipate that our inhibitory mixtures will exhibit superiority over antivenom by neutralising neurotoxins irrespective of the snake species and at lower therapeutic doses. This project therefore has the potential to generate a single, generic, eminently translatable therapy for treating neurotoxic snakebites worldwide.
|
| 06/10/2020 |
£3,032,561 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
400,000 tropical snakebite victims require, every year, life-saving surgical debridement/amputation because there is no medicine to treat the disabling, income-depleting effects of snake venom-induced necrosis. A new therapy is urgently needed to prevent the severe health and socioeconomic consequences upon already-impoverished victims and health facilities.
Our evidence-underpinned hypothesis is that rationally-selected recombinant, humanised camelid VHH targeting necrosis-inducing venom toxins (NITs) will possess the efficacy, rapid in-tissue distribution, safety, thermostability, affordability and large scale production characteristics appropriate for future development of a community-dispensed therapy – a paradigm shift in the clinical management of venom-induced necrosis to reduce morbidity.
To achieve this for Africa and India, our partners bring new approaches, platforms and all required resources to select candidate recombinant NIT-specific monoclonal VHH from (i) B cells of NIT-immunised camels and (ii) a synthetic VHH library - complementary approaches maximising likely success.
Deploying sequential in vitro, ex vivo human skin and mouse in vivo assays of venom-induced necrosis enables down-selection of the most efficacious, thermostable recombinant VHH. ‘Humanising’ the latter donates the key safety criterion. E.coli expression enables inexpensive and large-scale production of humanised VHH. These therapy-characteristics and the vast panAfrica/India need, provide economy-of-scale production incentives for future manufacturing partners.
|
| 06/10/2020 |
£2,734,121 |
INTERNATIONAL AIDS VACCINE INITIATIVE |
This proposal aims to ultimately reduce global levels of morbidity and mortality from snakebite envenoming by discovering and developing antibodies that can neutralize the low molecular weight snake venom toxins – key contributors to the disease. These non-immunogenic toxins are poorly neutralized by currently available antivenoms produced by animal derived immunizations. This proposed project will discover neutralizing antibodies through immunization experiments using rationally designed immunogens and select for high-affinity antibodies via synthetic libraries using recombinant toxins.
|
| 06/10/2020 |
£3,081,450 |
TECHNICAL UNIVERSITY OF DENMARK |
Sub-Saharan Africa (sSA) is heavily burdened by snakebite envenoming. Existing antivenoms are scarce and many have suboptimal therapeutic properties. To improve snakebite envenoming therapy, the application of carefully designed mixtures of fully human monoclonal immunoglobulin G (IgG) antibodies for systemic and nanobodies for locally acting toxins poses as not only a therapeutically promising, but also scientifically feasible solution. Therefore, taking advantage of our well-established discovery pipelines and expertise in working with oligoclonal and broadly-neutralizing antibodies against toxins, we will develop a broad-spectrum (polyvalent) recombinant antivenom for sSA. The project will focus on the following technical goals that we believe have a potential to deliver measurable societal and humanitarian health impact: 1) The identification and isolation of all medically relevant snake venom toxins that need to be neutralized by a recombinant antivenom for sSA and 2) the discovery of a well-characterized panel of broadly-neutralizing IgGs and nanobodies that can neutralize all medically relevant systemically-acting and deep tissue penetrating toxins found in the 24 medically most relevant snake species from this region. Combined, these efforts will create a substantial shift in snakebite envenoming therapy and will enable the clinical development of improved, low-cost, and quality-assured snakebite therapeutics for victims in sSA.
|
| 06/10/2020 |
£1,768,776 |
UNIVERSITY OF CAMBRIDGE |
The main therapeutic intervention for snakebite envenomation relies on the century-old approach of injecting victims with animal-derived polyclonal antiserum. Animal immunisation generates high affinity antibodies and undoubtedly saves lives but the use of immune antiserum has a number of limitations around consistency, redundancy and immunogenicity. Recombinant antibody technology will allow the capture, sequencing and characterisation of the monoclonal antibody repertoire arising from immunisation. Furthermore, the resulting high affinity antibodies will be made more human-like by fusing animal-derived variable domains with human constant domains (chimeric antibodies).
This project will generate phage display libraries from horses and llamas immunised with venoms of 4 sub-saharan African snakes represented in the co-applicants antivenom EchiTab-Plus_ICP. We will generate antibody panels by phage selection, screening and sequencing. This resolution of the immune repertoire to a complex venom into its monoclonal components essentially transforms the problem into one of deconvolution. Affinity capture-mass spectrometry will be used to identify the target of thousands of individual antibodies based on their distinct mass-defined target. Following triage based on binding profiles, antibodies to individual targets will be expressed as chimeric antibodies and validated using in vitro and in vivo animal models of envenomation towards generation of life-saving, chimeric antibody cocktails.
|
| 05/10/2020 |
£709,662 |
UNIVERSITY OF EDINBURGH |
The application of next generation sequencing to bile duct cancers (cholangiocarcinoma) has revealed a subgroup with mutations in the Isocitrate Dehydrogenase (IDH1, IDH2) genes, which appear non-overlapping with other drivers including TP53 and KRAS and which are associated with relatively favourable, but still poor, clinical prognosis. IDH1/2 mutations result in neomorphic production of the oncometabolite 2-hydroxyglutarate (2HG), which causes cell toxicity, DNA hypermethylation, and repression of cellular differentiation. This project tests two hypotheses. First, it seeks to determine whether 2HG production can metabolically reprogramme liver cell identity, triggering a cell fate change from a hepatocyte to a biliary phenotype, thereby promoting the formation of cholangiocarcinoma. I will seek to define the cell populations in the liver in which IDH1 mutations occur in disease and use lineage tracing techniques to establish whether IDH1 mutation results in an increase in hepatic progenitor or ductal cells in vivo, as well as which cell types give rise to these ductular reactions. Second, I shall examine whether 2HG causes non-cell-autonomous local toxicity or inflammation, and determine whether this contributes to tumorigenesis. My results will elucidate fundamental mechanisms of biliary carcinogenesis and suggest the likely efficacy of targeted 2HG inhibition or, indeed, 2HG overexpression.
|
| 05/10/2020 |
£788,449 |
UNIVERSITY OF EDINBURGH |
The accumulation of intestinal macrophages (iMphis) and presence of a distinct mononuclear phagocyte gene-expression profile, predict treatment failure and adverse clinical outcomes in Crohn's disease (CD). Preliminary scRNA-seq data demonstrates that a transcriptionally distinct iMphi subtype (CD-MPhi) accumulates in human and murine colitis, which I have prospectively validated. Unbiased CD-MPhi-epithelium, ligand-receptor interaction analyses reveals CD-MPhi derived activin signals to cognate receptors on colonic epithelium. CD-MPhis are the exclusive iMphi source of activin in mouse and humans, a TGF-beta superfamily member with cell-specific cytokine, growth and hormone effects. Activin administration to human colonic epithelium inhibits proliferation with a dose-dependent effect on cytokine, chemokine and pattern recognition gene expression.
Aims
Define iMphi heterogeneity and dynamics in CD
Interrogate the functional role of a novel pathogenic subset (CD-MPhi) in regulating intestinal inflammation
Investigate CD-MPhi driven activin signalling as a therapeutic target for intestinal inflammation
Methods
Using a novel, human, biopsy-based sampling approach, I will perform scRNA-seq of iMphis in newly diagnosed, treatment naive CD patients, with longitudinal, flow cytometry-based intestinal characterisation to reveal iMphi dynamics over time. Lastly, I will manipulate cell-specific activin-signalling in transgenic animals and primary human epithelium co-culture models to probe the mechanisms of activin-mediated epithelium dysfunction in CD.
|
| 05/10/2020 |
£446,707 |
UNIVERSITY OF CAMBRIDGE |
People with progressive multiple sclerosis (P-MS) have substantial unmet clinical needs. While current therapies for MS are focused on manipulating the activity of the adaptive immune system, they have limited applicability for P-MS where a switch towards the chronic activation of innate immune cells, such as mononuclear phagocytes (MPs), occurs.
MITO_META aims to test the hypothesis that the detrimental activation of MPs in P-MS is dependent on their mitochondrial metabolism and that targeting mitochondrial complex I (CI) activity in MPs will lead to novel therapeutic approaches for P-MS.
To achieve this aim, I will adopt a combination of animal models and post-mortem biological samples obtained from MS patients. I will initially use the experimental autoimmune encephalomyelitis (EAE) mouse model of MS to study the effect of removing Complex I from MPs during neuroinflammation (Aim 1). I will then analyse how the metabolism of MPs changes during neuroinflammation, and compare these findings to those obtained from post-mortem analysis of people with progressive MS (Aim 2).
Elucidating the role of mitochondrial function in MPs during chronic neuroinflammation will advance our understanding of P-MS and lead to new therapies to interfere with the progression of disability.
|
| 05/10/2020 |
£534,185 |
UNIVERSITY OF OXFORD |
Understanding the mechanisms that underlie epileptogenesis is crucial for the development of new treatments. Recent evidence has implicated astrocytes as a key cell population in the aetiology of focal epilepsy. Astrocytic gap-junction networks perform vital functions in supporting neural activity, including the shuttling of essential metabolic fuels and the regulation of the extracellular ionic environment for neurons. The objective of this project is to understand the relationship between neuronal activity and astrocytic gap-junction coupling, and how this relationship may break down in epilepsy. This will build upon preliminary evidence that astrocytic gap-junctions can show rapid, activity-dependent changes, in a manner related to levels of neuronal activity. The work will use surgically-resected human brain tissue and mouse models in which it is possible to selectively manipulate defined cell types. There are three parallel research aims. First, glioma-associated brain tissue will be used as a test case to relate functional astrocytic gap-junction coupling and neuronal hyperexcitability in a human context. Second, in vivo optical studies in mouse will examine how epileptiform network activity influences dynamic astrocytic gap-junction coupling. And third, optogenetic and pharmacological strategies will be used to dissect the cellular mechanisms that mediate activity-dependent changes in astrocytic coupling.
|
| 05/10/2020 |
£717,907 |
UNIVERSITY OF EAST ANGLIA |
Heart failure with preserved ejection fraction (HFpEF) is prevalent, increasing and has a poor prognosis. Left ventricular (LV) haemodynamic assessment is needed to diagnose and manage patients with HFpEF. The reference method for it is an invasive study and is rarely done due to costs and risks. Doppler-derived velocity is used as a surrogate for LV pressure. However, because it is based on a number of assumptions, Doppler remains unreliable for detecting increased LV end-diastolic pressure (LVEDP). I have validated a four-dimensional flow cardiovascular magnetic resonance (4D flow CMR) acquisition which addresses issues with Doppler. I have further developed an accurate quantification method, which uniquely, measures intra-ventricular blood flow in 4D. Other advantages are that it does not require any additional hardware and has demonstrated superior associated with LVEDP. In this Fellowship, I will develop 4D flow techniques for an accurate assessment of LVEDP and pressure-volume loop in HFpEF. In addition, I will learn from and collaborate with the world-renowned clinicians, software/hardware engineers and modelling experts in academia and industry, to improve the method’s accuracy and applicability. I will validate the method’s accuracy and generate clinical data to support future clinical trials, clinical translation and patient benefit.
|
| 05/10/2020 |
£1,271,351 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
I will improve understanding of key determinants and the incidence of cardiovascular disease in low-income sub-Saharan-Africa, capitalising on my expertise in stroke epidemiology in rural and urban Malawi and the research infrastructure across seven sub-Saharan-Africa population cohorts.
Information on the age- and sex-specific incidences of priority cardiovascular diseases is essential for health service planning in sub-Saharan-Africa. "Traditional" risk-factors (hypertension, type-2 diabetes and obesity) are highly prevalent and increasing in incidence and some, particular to low-income settings, such as chronic-infections, are not declining. The performance of diagnostic tools and risk prediction scores for cardiovascular disease developed in high-income settings need to be tested and adapted for use in low-income sub-Saharan-Africa.
I will build on the urban/rural cohort in Malawi, extending community and clinic surveillance with population-level questionnaire-screening (followed by a diagnostic pathway in those with "possible cardiovascular disease") to estimate the true incidence of various cardiovascular diseases. I will also extend the follow-up for our seven African cohorts and use this harmonised dataset to estimate the relative contributions of key drivers of cardiovascular disease and assess the performance of existing cardiovascular disease risk prediction scores.
This work will inform the planning of evidence-based, health-systems responses and context-relevant, individual, and population-level interventions.
|
| 05/10/2020 |
£1,304,625 |
UNIVERSITY OF OXFORD |
Viral fusion proteins are important targets for vaccine-induced neutralising antibody. Structure-guided design of such antigens in pre-fusion conformation has created leading vaccine candidates against viruses with Class I and II fusion proteins, such as respiratory syncytial virus and dengue virus. Use of pre-fusion stabilised Class III proteins for vaccination has not yet been reported, but these too are major vaccine targets for rabies virus and the herpesviruses (the gB proteins).
I propose to build upon preliminary data demonstrating pre-fusion stabilisation of rabies glycoprotein. I will evaluate pre-fusion-stabilised immunogens for vaccines against rabies and a chosen herpesvirus, Epstein Barr virus (EBV). By isolating monoclonal antibodies against EBV gB, I will ascertain whether herpesvirus gB proteins contain pre-fusion-specific neutralising epitopes. In healthy EBV carriers, I will explore whether salivary EBV shedding can be used as a marker of immune control of virus reactivation, to dissect mechanisms of natural immunity, and to rapidly detect efficacy in future early-phase vaccine trials.
A low-cost single-dose vaccine based on stabilised rabies glycoprotein could help reduce the 60,000 deaths due to rabies each year. An effective EBV vaccine could reduce the > 100,000 deaths per year due to EBV-driven cancers and, many believe, could also prevent multiple sclerosis.
|
| 05/10/2020 |
£590,676 |
UNIVERSITY OF OXFORD |
Kidney stones, which are a major clinical and economic health burden, are commonly recurrent, and current stone prevention strategies are relatively ineffective. The renal tubular mechanisms underlying this disease are poorly understood, thereby limiting opportunities to develop novel therapies. Via a genome-wide association study (GWAS) we identified twenty genetic loci linked to kidney stone formation. However, the genes influenced by these loci remain to be elucidated. My goals are to: identify additional stone-associated loci by X chromosome and sex-specific GWAS studies; define biologically relevant renal cell types by identifying areas of accessible chromatin at relevant loci through single cell assays for transposase accessible chromatin (ATAC)-sequencing in renal tissue; determine causal GWAS-associated SNPs by examining local epigenetic modifications in relevant cell types via chromatin immunoprecipitation (ChIP)-sequencing; link causal SNPs to effector genes by determining the 3-dimensional chromatin landscape in relevant cell types through Next Generation Chromatin Conformation Capture; validate predicted genotype-phenotype associations in relevant cohorts; and elucidate the roles of effector genes in cellular function via in vitro studies. This research will provide new insights into tubular function and the molecular pathophysiology of renal stone disease and reveal new therapeutic targets for the prevention of kidney stone recurrence.
|
| 05/10/2020 |
£698,120 |
KING'S COLLEGE LONDON |
Gamma-delta T-cells are critical for protecting against carcinogenesis in mice but clinical associations have been equivocal and human trials of gamma-delta T-cell therapy have been disappointing. Previous studies have been limited by unavailable technologies to describe these cells with sufficient granularity whilst clinical trials have largely focussed on the more numerous V-delta-2 subtype. Using contemporary methods such as TCR-sequencing and ex vivo culture systems to extract gamma-delta T-cells from human tissues, we recently demonstrated that only certain subtypes of these cells, namely the V-delta-1 subtype, are associated with survival in triple-negative breast cancers.
This proposal aims to extend our previous findings to a pan-cancer setting by mapping, with greater and necessary detail, these cells in melanoma, breast, lung and other cancers with a particular focus on V-delta subtyping, differential effector functions and cell regulatory axes. Importantly, we will also map gamma-delta T-cell interactions with alpha-beta T-cells as these cells have been established as being critical to cancer immunosurveillance. We will stratify our findings to clinical outcomes to build a novel reference human tumour gamma-delta T-cell atlas to guide ongoing translational efforts in adoptive gamma-delta T-cell therapy. Hence, this proposal may lead to rapid translation into clinical benefit.
|
| 05/10/2020 |
£844,510 |
UNIVERSITY OF EDINBURGH |
Our vision is to create a Centre that combines novel, integrative humanities and social science (HSS) research with innovative approaches to collaboration, stakeholder and public engagement. This vision is anchored through key themes, each a site of socio-technical transformation: Beyond Bodies, Beyond Disease, Beyond Global, Beyond Legal and Beyond Engagement. Each theme is evolving rich theoretical and empirical research that cross cuts substantive and disciplinary boundaries. We are building new collaborations and partnerships and increasingly appreciate the work involved in building such relationships for long term benefit. We strive to create a mutually respectful relationship with biomedicine and public health that embeds HSS ‘upstream’. In the proposed extension period, we aim to deepen our research and engagement, enabling new ideas to flourish; this includes a expanding work on ‘Beyond Data’ and an emergent programme of work on sex and reproduction ‘ Beyond Sex’. Our research and engagement are underpinned by an inclusive research environment where we strive to adopt a feminist approach to leadership. Supporting Early Career Researchers is key to this. In this next phase we will deepen our research across and within themes and support scholars in developing interdisciplinary skills and expertise and continue to engage widely.
|
| 05/10/2020 |
£975,813 |
UNIVERSITY OF DURHAM |
In 2017, we set out a vision to develop ‘a nexus for world class medical humanities research that aims to improve human health through an enhanced understanding of human experience’. As the newly formed Institute for Medical Humanities (IMH), we have refined this original vision to focus on human experience that is variously marginalised, difficult, unspeakable, unacknowledged, invisible and hidden. This focus has developed from successful research on the experience of breathlessness, voice-hearing and collective wellbeing, and through developing work on dreams, memory, drug use, interoceptive sensation and the menopause.
The extension grant will enable IMH to take forward a substantial programme of work, ‘Researching Hidden Experience’; to expand our team and embed new permanent academic staff; to develop further our capacity to influence health research policy and expertise in public engagement; and to extend our global influence. The current background of increasingly complex, intersecting, and socially embedded health problems, including the experience of inequality in its various forms, requires a fundamental questioning of structures, models and assumptions that perpetuate hidden health problems. Such research is only possible within a culture that is aware of its own hidden inequities. We address this through a ten-year strategy for diversifying medical humanities.
|
| 05/10/2020 |
£1,048,732 |
UNIVERSITY OF OXFORD |
In this proposal we seek an 18-month extension to the Wellcome Centre for Ethics and Humanities (WEH). The WEH is a vibrant and dynamic ethics and humanities research centre located at the University of Oxford’s Big Data Institute. It provides a flexible multidisciplinary research platform capable of engaging with the profoundly difficult ethical and social challenges presented by the scale, scope and societal implications of emerging research in the biosciences at a time of rapid social change. At the heart of our work is a commitment to rethinking concepts, theories, and the nature of scholarship in ethics and the humanities to enable them to be adequate to the task of engaging meaningfully with these profound developments. This focus on ‘rethinking ethics and the humanities’ has proven to be a highly productive framing for the Centre’s research collaborations, and engagement activities. In this application we seek to build on these foundations to undertake new research programmes on, ‘infection and history’, ‘rethinking ethics and history’, ‘rethinking justice and discrimination’, and ‘ethical applications and potentials of collective minds’. This research will be underpinned by a centre-wide programme on ‘rethinking research cultures’ and complemented by an ambitious programme of public engagement initiatives and events.
|
| 05/10/2020 |
£1,428,973 |
UNIVERSITY OF EXETER |
During the Centre's first three years, we have focused on establishing transformative research and engagement programmes, developing partnerships with policy-makers and creative organisations, building an open research culture, and recruiting doctoral students, early career researchers, and senior staff. Committed to engaged research that enables health and well-being, our projects have brought researchers, public partners, and health organisations together to address key health challenges, including: the health impacts of loneliness and social isolation; the value of different forms of evidence in health policy; the impact of relationships on children's health; and community access to - and involvement in - research and data governance.
Additional funding will allow us to address further the health impacts of social and environmental inequalities, specifically through projects on health across the life course, ageing and dying, co-creating healthy cities, and recovering from - or living with - the social and cultural impacts of COVID-19. These research programmes - as well as an innovative Masters course in transformative health research and practice - will enable us to fully embed engagement and impact in our work locally, nationally and internationally, build training and career pathways in transdisciplinary research, and strengthen our commitment to an inclusive research culture.
|
| 01/10/2020 |
£12,883 |
UNIVERSITY OF DURHAM |
Not available |
| 01/10/2020 |
£16,190 |
BABRAHAM INSTITUTE |
Not available |
| 01/10/2020 |
£13,151 |
THE PIRBRIGHT INSTITUTE |
Not available |
| 01/10/2020 |
£99,635 |
THE FRANCIS CRICK INSTITUTE |
Not available |
| 01/10/2020 |
£18,877 |
UNIVERSITY OF EAST ANGLIA |
Not available |
| 01/10/2020 |
£35,181 |
UNIVERSITY COLLEGE LONDON |
Not available |
| 01/10/2020 |
£25,084 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
Not available |
| 01/10/2020 |
£68,783 |
UNIVERSITY OF OXFORD |
Not available |
| 01/10/2020 |
£75,506 |
UNIVERSITY OF OXFORD |
Not available |
| 01/10/2020 |
£109,200 |
UNIVERSITY OF OXFORD |
Not available |
| 01/10/2020 |
£23,592 |
UNIVERSITY OF LEICESTER |
Not available |
| 01/10/2020 |
£29,873 |
UNIVERSITY OF SOUTHAMPTON |
Not available |
| 01/10/2020 |
£50,751 |
UNIVERSITY OF LEEDS |
Not available |
| 01/10/2020 |
£202,536 |
UNIVERSITY OF DUNDEE |
Not available |
| 01/10/2020 |
£44,293 |
UNIVERSITY OF EXETER |
Not available |
| 01/10/2020 |
£10,849 |
UNIVERSITY OF ST ANDREWS |
Not available |
| 01/10/2020 |
£10,925 |
UNIVERSITY OF STRATHCLYDE |
Not available |
| 01/10/2020 |
£13,297 |
KEELE UNIVERSITY |
Not available |
| 01/10/2020 |
£15,762 |
UNIVERSITY OF ABERDEEN |
Not available |
| 01/10/2020 |
£28,684 |
QUEEN'S UNIVERSITY BELFAST |
Not available |
| 01/10/2020 |
£31,761 |
BIRKBECK UNIVERSITY OF LONDON |
Not available |
| 01/10/2020 |
£38,763 |
UNIVERSITY OF YORK |
Not available |
| 01/10/2020 |
£41,401 |
UNIVERSITY OF WARWICK |
Not available |
| 01/10/2020 |
£41,779 |
UNIVERSITY OF NOTTINGHAM |
Not available |
| 01/10/2020 |
£49,187 |
UNIVERSITY OF SUSSEX |
Not available |
| 01/10/2020 |
£53,493 |
INSTITUTE OF CANCER RESEARCH |
Not available |
| 01/10/2020 |
£60,404 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
Not available |
| 01/10/2020 |
£64,793 |
QUEEN MARY UNIVERSITY OF LONDON |
Not available |
| 01/10/2020 |
£68,557 |
CARDIFF UNIVERSITY |
Not available |
| 01/10/2020 |
£80,459 |
UNIVERSITY OF SHEFFIELD |
Not available |
| 01/10/2020 |
£80,561 |
UNIVERSITY OF LIVERPOOL |
Not available |
| 01/10/2020 |
£94,276 |
UNIVERSITY OF BIRMINGHAM |
Not available |
| 01/10/2020 |
£111,364 |
NEWCASTLE UNIVERSITY |
Not available |
| 01/10/2020 |
£139,146 |
UNIVERSITY OF GLASGOW |
Not available |
| 01/10/2020 |
£171,317 |
UNIVERSITY OF MANCHESTER |
Not available |
| 01/10/2020 |
£183,060 |
UNIVERSITY OF BRISTOL |
Not available |
| 01/10/2020 |
£204,330 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
Not available |
| 01/10/2020 |
£345,206 |
KING'S COLLEGE LONDON |
Not available |
| 01/10/2020 |
£370,755 |
IMPERIAL COLLEGE LONDON |
Not available |
| 01/10/2020 |
£404,392 |
UNIVERSITY OF EDINBURGH |
Not available |
| 01/10/2020 |
£763,249 |
UNIVERSITY COLLEGE LONDON |
Not available |
| 01/10/2020 |
£787,552 |
UNIVERSITY OF CAMBRIDGE |
Not available |
| 01/10/2020 |
£1,043,556 |
UNIVERSITY OF OXFORD |
Not available |
| 01/10/2020 |
£486,720 |
INVISIBLE FLOCK CO |
A two year exploration of Solastalgia - mental distress specifically caused by environmental change, defined as a land disease of "place-based lived experience".
Our team is a global collective of artists, researchers, designers, conservationists, technologists and activists from fields including psychology, arts, sustainability, sociology, design and medicine. Through the Hub we will place lived experiences at the forefront of understanding Solastalgia. We will use human centred design, storytelling and creative media arts to deeply explore human experiences and relationships with the natural world as an alternative to the current dominant, data-driven discourses.
Through a network of global field stations, sited in critical landscapes, we will work closely with local and indegnous communities to understand and communicate their connection to land and their lived experiences of climate change. Looking at Solastalgia through the lens of these communities we will together explore the complex, fragile relationship of psyche and land.
Through the Hub we will open up this urgent and timely discussion to multiple audiences. Incorporating diverse knowledge and perspectives, lived experiences that are complex and layered through storytelling and artistic approaches we will identify context-specific pathways towards a sustainable future.
|
| 30/09/2020 |
£6,920,135 |
UNIVERSITY OF OXFORD |
There is no proven treatment, chemoprophylaxis or vaccine for COVID-19. This is the most serious pandemic emergency for 100 years. Healthcare workers are being affected disproportionately in the continuing epidemic threatening an imminent breakdown of health services. Chloroquine and hydroxychloroquine are safe and well-tolerated medications which can be taken for years without adverse effects.Both have significant antiviral activity against SARS-CoV-2 and there is emerging evidence from China and Europe of efficacy in treatment. Unfortunately there is also premature recommendation from countries such as India which now recommends low dose hydroxychloroquine for prophylaxis in health care workers.
We propose conducting a multi-centre, multi-country randomised, double blind, placebo controlled assessment of the prophylactic efficacy of chloroquine (Asia) or hydroxychloroquine (Europe) in preventing COVID-19 illness in at-risk healthcare workers and other frontline staff. At least 40,000 participants in Asia and Europe will be randomised 1:1 to receive chloroquine or hydroxychloroquine or a matched film coated placebo as daily prophylaxis for three months. The study’s objectives are the prevention of symptomatic coronavirus disease (COVID-19) and the attenuation of the clinical severity.
|
| 30/09/2020 |
£224,392 |
UNIVERSITY OF SHEFFIELD |
Not available |
| 30/09/2020 |
£823,390 |
NATIONAL UNIVERSITY OF SINGAPORE |
We propose a prospective serological study to investigate the incidence of SARS-CoV-2 infection in the general population in three Asian settings: Singapore, Hong Kong and Thailand. The study will aim to measure the age-specific seroprevalence and incidence of SARS-CoV-2 infection at 3 time points, each 6 months apart. Age-specific incidence estimates will be applied to the census population to obtain numbers of infections in the population at each time point. These estimates will be compared with external data on COVID-19 hospitalisations and deaths in each setting, to calculate age-specific infection-hospitalisation and infection-fatality ratios. SARS-CoV-2 antibody kinetics will be defined by studying changes in antibody titres over time. Risk factors for infection will be studied by comparing SARS-CoV-2 seroconverters and non-seroconverters with respect to epidemiological exposures. This study will provide crucial information regarding population exposure and SARS-CoV-2 transmission dynamics, and will provide a complete picture of the relationship between clinically apparent and asymptomatic infections.
|
| 30/09/2020 |
£1,416,424 |
KWAME NKRUMAH UNIVERSITY OF SCIENCE AND TECHNOLOGY |
As part of the response to the emergence of COVID-19, the World Health Organization Africa Regional Office is organizing various Infection Prevention and Control (IPC) and critical care training activities targeted at Low and Middle-Income countries (LMICs) in Africa. While the initiatives taken by WHO/AFRO are critical, training for research into the disease also needs to be targeted at the same LMICs, because being an Emerging Infectious Disease, we need to "learn-as-we-go". Clinical research on COVID-19 will have to be closely integrated with the IPC, clinical care, and epidemiological training activities, including use of the WHO First Few X (FFX) Cases and contact investigation protocol for COVID-19. ALERRT proposes to work closely with the WHO/AFRO and Africa CDC and existing networks and structures across Africa and globally to provide the fore-mentioned clinical research training and support. ALERRT is a member of the Global Federation - ISARIC, which has developed a Clinical Characterization protocol for COVID-19. This protocol been endorsed by the WHO and is currently being used in China and across the UK and Europe.Being already established and conducting activities in sub-Sahara Africa, the ALERRT network has the capacity to effectively implement the proposed project.
|
| 30/09/2020 |
£2,003,681 |
WITS HEALTH CONSORTIUM (PTY) LTD |
Factors prevalent in Africa such as malnutrition, HIV, tuberculosis and limited access to healthcare, among others, may impact both transmission dynamics and disease progression associated with SARS-CoV-2 infection as well as the burden on the healthcare system and society.We aim to characterize key transmissibility and clinical features of and the antibody response to SARS-CoV-2 as well as to enhance surveillance for COVID-19, identify groups at increased risk of severe illness, estimate the disease burden of medically- and non-medically attended mild, severe-non-fatal and fatal illness and forecast the impact of the outbreak on the healthcare system and the society in South Africa. Particular emphasis will be given to HIV-infected individuals. The aims will be achieved through the implementation of shedding and household transmission studies, collection of sequential serum samples, enhanced facility-based (hospitals and clinics) surveillance among patients with mild and severerespiratory illness in well-established population-based surveillance sites where incidence can be calculated, and healthcare utilization and serological surveys in selected communities. In addition, digital surveillance (based on Google searches) will be used to complement virological surveillance and nowcasting and short-term forecasting (up to 4 weeks) will be implemented over the duration of the epidemic.
|
| 30/09/2020 |
£1,217,834 |
UNIVERSITY OF OXFORD |
Background; It is unknown how prior exposure to commonly circulating human coronaviruses (HCoV) impacts immunity against highly-pathogenic species (SARS, SARS-CoV-2 & MERS). There are limited data, across Europe, Asia and Africa, on the prevalence of infection and seroconversion against widely circulating and mildly symptomatic HCoVs (229E, NL63, OC43, and HKU1). There is a current supposition that antibody-dependent-enhancement (ADE) may play a role in the pathophysiology of COVID-19. ADE occurs when non-neutralizing antiviral proteins facilitate virus entry into host cells, leading to increased infectivity in the cells. In such cases, higher viremia has been measured and the clinical course of disease can be more severe. In preclinical animal models, immunopathology was observed after challenge following vaccination with some SARS vaccines. Therefore, concerns have been raised regarding the impact of immunopathology and ADE on prophylactic vaccination against SARS and possibly SARS-CoV-2.
Goals: to perform detailed systems serology of pre-existing immunity, in children and adults, from the UK and Africa, towards novel and commonly circulating coronaviruses.
Impact: These studies highlight the limited knowledge in the field and a need for a systematic approach to investigate cross-reactive humoral immunity against HCoV to inform the immunopathology and pathophysiology of COVID-19.
|
| 30/09/2020 |
£1,030,349 |
UNIVERSITY OF WARWICK |
COVID-19 is a global threat to health, with many countries reporting extended outbreaks. To date 9 countries in Africa have recorded infection and it seems imminent that East Africa will have introductions and onward transmission. The SARS-CoV-2 virus (the aetiological agent of COVID-19) spreads rapidly (R0~2, serial interval about 1 week), and hence control will be difficult. National plans for dealing with this public health emergency will benefit from predictions of the expected rate, distribution and extent of spread in countries throughout the region, and on the likely impact and feasibility of isolation and contact tracing interventions. We will support the emergency preparations through bespoke modelling, incorporating known demographic population structure, age-related contact patterns and existing mobile phone population movement data. In Uganda and Kenya we will collect epidemiological, genomic and behavioural data through health facility surveillance, household follow-up and contact studies to quantify uncertainties of SARS-CoV-2 virus epidemiology and contact patterns in well and unwell individuals. Results from the study will be rapidly communicated to the relevant authorities, and modelling code and analysis, and data including sequences, placed in the public domain in near real-time. This project could have lasting impact on the role of research in policy decisions.
|
| 30/09/2020 |
£864,564 |
IMPERIAL COLLEGE LONDON |
Since December 2019 the emergence of severe acute respiratory infections (COVID-19) in China, caused by the new coronavirus SARS-CoV-2, has posed a huge threat to global health with fatality rates up to 10% in elderly patients. Almost 100% of patients showed bilateral patchy shadows or ground glass opacity in their lungs by chest CT scans indicating acute lung injury (ALI). Therefore, understanding the underlying mechanism(s) of ALI induced by SARS-CoV-2 is very important to inform vaccine safety and immunotherapeutic strategies. In this proposal, we will investigate the host immune responses and their association with severity of ALI in patient samples and animal models. We will bring together a team of experts with complementary expertise including immunopathology in coronavirus infections, up-to-date lab technologies, and know-how to ensure the feasibility of this study with the following goals:
1) defining SARS-CoV-2 specific serum profiles (epitopes) using yeast display antigen library
2) determining antibody functions including antibody-dependent enhancement (ADE) vs neutralizing activities in vitro assays
3) studying T cell (CD4 and CD8) responses to whole SARS-CoV-2 genome
4) evaluating ALI in response to live SARS-CoV-2 infection with or without passive immunity (antibody or T cells) generated from vaccine candidates in a humanized mice model.
|
| 30/09/2020 |
£646,963 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
Our project, AFRICO19, will enhance capacity to understand SARS-CoV-2/hCoV-19 infection in three regions of Africa and globally. Building on existing infrastructures and collaborations we will create a network to share knowledge on next generation sequencing (NGS), including Oxford Nanopore Technology (MinION), coronavirus biology and COVID-19 disease control. Our consortium links three African sites combined with genomics and informatics support from the University of Glasgow to achieve the following key goals:
1. Support East and West African capacities for rapid diagnosis and sequencing of SARS-CoV-2 to help with contact tracing and quarantine measures. Novel diagnostic tools optimized for this virus will be deployed. An African COVID-19 case definition will be refined using machine learning for identification of SARS-CoV-2 infections.
2. Surveillance of SARS-CoV-2 will be performed in one cohort at each African site. This will use established cohorts to ensure that sampling begins quickly. A sampling plan optimized to detect initial moderate and severe cases followed by household contact tracing will be employed to obtain both mild to severe COVID-19 cases.
3. Provide improved understanding of SARS-CoV-2 biology/evolution using machine learning and novel bioinformatics analyses. Our results will be shared via a real-time analysis platform using the newly developed CoV-GLUE resource.
|
| 30/09/2020 |
£782,901 |
WELLCOME LEAP INC. |
In early February 2020 Wellcome’s BoG approved the appointment of Regina Dugan as CEO of the Wellcome Leap Fund (WLF), the relocation of the WLF’s primary place of business to the U.S. and the creation of a U.S. not-for-profit entity within the Wellcome group (Leap US). This grant is a mobilisation fund to support the initial activities required for Leap US’ set up and strategy development, prior to the awarding of full grant which will be administered upon BoG approving the CEO’s strategy and business plan for the WLF. |
| 30/09/2020 |
£50,000 |
GENETIC ALLIANCE UK |
Not available |
| 30/09/2020 |
£888,104 |
MOLOGIC LTD |
Rapid diagnostics have been identified by the WHO R & D Blueprint as a critical unmet need for the control of COVID-19 - particularly in the absence of a vaccine and proven antiviral agents. Our primary objective is to develop a low cost, high performance rapid test for the detection and exclusion of SARS-CoV-2, the causative virus of coronavirus disease 2019 (COVID-19).
The technology will be made available in line with the Global Access Policy for Gavi-eligible countries that are most vulnerable to onward transmission of COVID-19 and of limited detection due to insufficient laboratory capacity. The RDT will be appropriate for assembly and manufacture with multiple quality-assured partners to meet demand.
|
| 30/09/2020 |
£249,926 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
Malawi is at high risk of COVID-19 epidemic spread, the healthcare system is fragile and the population vulnerable to severe disease. This application proposes Malawi Liverpool Wellcome Trust Clinical Research Programme preparedness activities for epidemic COVID-19 disease. These are split into three work packages: 1) Diagnostic capacity and genomics surveillance; 2) Secondary care; 3) Epidemiology and control. Strategically, we have designed our activities to develop a platform for MLW to rapidly pivot into response mode to both support the healthcare system and deliver excellent research for current and future epidemic disease threats.
Key goals for this proposal are:
Provide diagnostic capability in Malawi for the COVID-19 epidemic
Develop clinical and epidemiological tools to manage epidemic disease in Malawi
|
| 30/09/2020 |
£79,890 |
SCHWARZKOPF STIFTUNG JUNGES EUROPA |
The European Youth Parliament (EYP) is based on the idea that the great challenges of our time cannot be tackled on a national level alone, but need to be addressed multilaterally. Moreover, the EYP leverages a new generation of young changemakers to be part of the solution.
As the umbrella organisation of the EYP, the Schwarzkopf Foundation Young Europe is proposing a project that will bring various interconnections between "Health" and "Politics" to the forefront of debate among young people across Europe. The project will bring together young people from across Europe with decision-makers and experts, to debate today’s pressing topics in the field of health, and to develop positions that will be shared with decision-makers and the public. Discussions will take place in a variety of formats and settings, constituting a broad consultation process that will aggregate "young opinions" from across Europe, which are then to be shared in close-up debates with decision-makers (especially in the context of Germany’s EU Council presidency) - as well as with young peers, and the broader public.
|
| 30/09/2020 |
£6,275 |
GREATER MANCHESTER COALITION OF DISABLED PEOPLE |
GMCDP’s archive collection reveals the changing perspectives, language and attitudes towards disabled people that have occurred over recent decades. It highlights changes in medical practices, discussions and debates around bio-ethics and end of life issues, campaigns for independent living, the self-organisation of disabled people, development of disability culture, and the significant impact of wider health determinants.
Following on from feedback on a previous application to Wellcome Trust, GMCDP recognises the need to have a more detailed, specialist assessment of our collection in order to be able to move forwarded to the next stage. GMCDP are therefore seeking to carry out an archivist assessment and collections appraisal of our archives, and will commission Janice Tullock Associates (archivist) and Sharon Oldale (conservator) to provide the following outcomes:
Survey the collection to assess its needs.
Assess the level of cataloguing the collection requires.
Develop a statement of the significance of the collection.
Provide a detailed report on findings, with recommendations.
Develop a project plan for the cataloguing of the archive.
Assess the level of archivist and specialist input required throughout the duration of the project.
Conservation assessment and recommendations.
|
| 30/09/2020 |
£176,431 |
SHEFFIELD HALLAM UNIVERSITY |
Not available |
| 30/09/2020 |
£30,000 |
KNIGHT HALL AGENCY LIMITED |
This is a prize for a Screenwriting Fellowship, awarded in collaboration with the BFI and Film4 in 2019 |
| 30/09/2020 |
£50,000 |
ARTS & HEALTH SOUTH WEST |
Contribution to the establishment of a national Centre for Creative Health as recommended by the APPG report into Creative Health: Arts , Health and Wellbeing (2017). |
| 30/09/2020 |
£125,000 |
BUREAU OF INVESTIGATIVE JOURNALISM |
This 12-month pilot project would test how we can use our innovative journalistic approach to find more effective, scalable ways to engage diverse audiences around health issues and research. The opportunity for collaboration with Wellcome will bring together our expertise in local engagement and community-led investigations across the UK with our global health track record of fact-based reporting and expert, external networks. A new Bureau Local health team will explore and test issues that impact nationally and globally with local communities to find connections.
If successful, an immediate outcome would be that we’d improved relevance and relatability around a critical health topic (and research around it) for affected communities and the wider public across the UK. For the longer term, our project would strengthen understanding of how engaged journalism can support a two-way flow of communication from and to affected communities. We would hope the findings from this project could support a collaborative framework for journalists, communities and researchers to use local investigative journalism to connect and engage people more effectively with health issues.
|
| 30/09/2020 |
£49,836 |
WORLD HEALTH ORGANIZATION, SWITZERLAND |
Background Information:
The research and development (R & D) Blueprint is a global strategy and preparedness plan to address highly infectious diseases and strengthen the emergency response by bringing medical technologies to patients during epidemics. For each of these priority diseases, WHO is coordinating the elaboration of R & D roadmaps, to serve as collaborative frameworks underpinning strategic goals and research priority areas to accelerate the development of diagnostics, therapeutics and vaccines to prevent and control severe emerging diseases. R & D roadmaps have been developed for 4 priority diseases with epidemic potential: Crimean-Congo hemorrhagic fever and Ebola/Marburg virus diseases, Lassa Fever and Nipah virus disease.
Key Goals:
Effective publication and dissemination of these roadmaps, together with communication and advocacy, will help to achieve the R & D blueprint and roadmaps goals.
How the funds will be used:
To support the publishing costs of 4 of the Research and Development (R & D) Blueprint Roadmaps. |
| 30/09/2020 |
£120,000 |
ASSOCIATION OF RESEARCH MANAGERS AND ADMINISTRATORS |
This project is based on an invitation by the African Academy of Sciences (AAS) to the Association of Research Managers and Administrators (ARMA) in the UK, to contribute to their ongoing ReMPro programme. Drawing on their expertise and strengths as an association of research managers and administrators, ARMA will support ReMPro's strand on developing individual capacity of research management staff through various activities like, needs analysis and mapping workshops and implementation of an International Research Management Staff Development programme. ARMA is seeking funding to reinforce existing support to the project, specifically towards the International Research Management Staff Development Programme and personnel costs for the second phase.
1. International Research Management Staff Development Programme - aimed at strengthening capacity of research management staff in Africa, this will be an exchange programme between African and UK institutions. Participants will be drawn from diverse institutions through a competitive application process.
2. Personnel costs - to implement and oversee the activities, ARMA has employed a programme manager with a projected budget covering 12 months. However, their is a clear need to develop and implement outcomes from the mapping workshops. This will be carried out in the second phase of the programme.
|
| 30/09/2020 |
£75,000 |
UNDERSTANDING ANIMAL RESEARCH |
Support for UAR activities as per uploaded document
|
| 30/09/2020 |
£96,402 |
UNIVERSITY OF CAMBRIDGE |
This application is for support to develop a proposal for The Cambridge History of Medicine in six volumes. As General Editor, I will meet with a team of a dozen volume editors at a series of workshops to ask fundamental questions about what the history of medicine is, what it should be, and how best to represent it in these books.
|
| 30/09/2020 |
£200,000 |
EAT FOUNDATION |
With the support from Wellcome Trust during the years 2016-2019, EAT achieved important results. The EAT SFF is globally recognized as a meeting place for stakeholders to shape the future of food. The EAT-Lancet Commission changed the debate around food, environmental sustainability and health, and the scientific targets set by the Commission for healthy diets within safe planetary boundaries are guiding action by a wide range of actors across policy, business and civil society. EAT is catalyzing action through a number of collaborations, such as with C40, influencing food system policy agendas in 50 cities around the world. The GBP200,000 contribution from Wellcome Trust for 2019 will secure EAT’s ability to continue its efforts and avoid delay or disruption of its work, while working with Wellcome Trust ito develop a Phase 2 program.
EATrecognizes that there is an urgent need to undertake a proactive and strategic organizational review. This review will guide EAT in addressing weaknesses in its financial, operational, fundraising and reporting functions that have exposed risks that must be mitigated prior to the end of 2019 The review will provide a clear pathway to ensure financial and operational sustainability whilst supporting EAT’s agility within focused and strategic structures.
|
| 30/09/2020 |
£97,058 |
STEM LEARNING LIMITED |
The collaboration between Education Development Trust (EdDevTrust) and the National STEM Learning Centre (STEM Learning) will enable 60 highly trained and competent science teachers to access a unique approach (‘Test and Learn’) and set of tools to guide and support them to carry out their own rigorous classroom-based research. Teachers will test the evidence-based theories, approaches, pedagogies and policies introduced to them through STEM Learning’s CPD programme using randomised controlled trials, applying scientific method to explore science pedagogy.
|
| 30/09/2020 |
£269,680 |
ROEHAMPTON UNIVERSITY |
Spoke with Ruba Aljarf today (9 November 2019) and she said to simply upload the attachment.
|
| 30/09/2020 |
£76,800 |
COLLEGE OF TEACHING LTD |
Our project will support science teachers to engage with research through a ‘teacher journal club’ (TJC) approach, building on work in both education and in the medical sciences, where journal clubs are a well-established approach to CPD. As well as providing cost- and time-efficient CPD that adheres to the principles of effective learning for teachers, journal clubs are by their nature focused on helping teachers to engage effectively with research evidence. This project proposes to apply the principles of successful journal clubs from medicine to education. The journal clubs will exclusively be online and journal clubs facilitators and participants will receive online training before their first TJC. This online training will cover the background of TJCs and how it relates to effective teacher CPD, research appraisal and journal club facilitation skills. The project will take a 'fading scaffolding' approach where the support for TJC facilitators will fade over time with the goal for them to run TJC independently by the end of the project.
|
| 30/09/2020 |
£109,026 |
BEHAVIOURAL INSIGHTS TEAM |
Our project aims to increase teachers’ engagement with and use of research through the provision of teaching resources – a comprehensive program of work, including adaptable lesson plans – and training in their use. The lesson plans will be designed based on research evidence and will also contain annotated summaries of relevant research evidence with links to the underlying research. The training will help teachers understand how and why to engage with research evidence by using the lesson plans, and will be participatory in nature. Training will occur three times throughout delivery to remind teachers to engage with evidence. The intervention will pertain to a particular unit of year 8/9 physics e.g. forces. We will recruit physics teachers at a diverse mix of UK state-funded schools to test our resources.
In our approach, engaging with research and learning how to embed it in practice will be made extremely easy for teachers, which is the most effective way to increase the prevalence of desired behaviour (and is especially important in the context of an already overburdened workforce). In particular, this approach will address potential intention-action gaps between teachers engaging with research evidence and actually applying it in their teaching practice.
|
| 30/09/2020 |
£757,562 |
BRITISH ACADEMY |
The British Academy is submitting a funding proposal to the Wellcome Trust which will provide support for researchers in the humanities and social sciences working in areas related to health and wellbeing. Taking a broad definition of health, the proposal will provide a portfolio of support for academics, at all stages of their careers, working in the humanities and social sciences by providing funding for Small Research Grants, academic conferences and policy workshops. The proposal follows discussions with the Trust over a number of months and is valued at £3.97 million including: funding of £2.76 million for Small Research grants; £1.12 million for conferences; and £84,000 for policy workshops (over 3 years). Funding is proposed to begin in early 2020 and to finish in 2026. The collaboration is designed to demonstrate the relevance of humanities and social science research in relation to health and wellbeing through the scale and breadth of funding options for researchers and the potential for long term impact.
|
| 30/09/2020 |
£6,525 |
SHEFFIELD HALLAM UNIVERSITY |
This grant will support both Sheffield Hallam University and the National Foundation for Educational Research (NFER) to work with the four grantees of the Teacher Research Scoping Grants and to undertake the writing and costing of the proposal for the research and evaluation study of this programme. |
| 30/09/2020 |
£72,206 |
INTERNATIONAL AIDS VACCINE INITIATIVE |
Through this project, IAVI and WHO Immunizations, Vaccines, and Biologicals (IVB) will harness input from a broad network of stakeholders to produce a Preferred Product Characteristics (PPC) technical document for forthcoming monoclonal antibodies (mAbs) for HIV prevention. Created early in clinical development and with attentiveness to end-user and health systems perspectives, this PPC document will provide strategic guidance as to preferences for new HIV preventative antibodies to inform clinical development and support eventual integration into WHO policy. While the focus of this effort will be on articulating optimal product attributes for antibodies for HIV prophylaxis, it is anticipated that acceptability, suitability and feasibility criteria identified through this process can inform product design, clinical development, and access considerations for a broader array of antibody-based products for infectious and neglected diseases in the pipeline. |
| 30/09/2020 |
£510,000 |
UNIVERSITY OF OXFORD |
lvermectin is a very safe and beneficial drug which is used for the treatment of more than a
dozen different neglected tropical diseases (NTDs), many of which are associated with
important public health problems. Current label indications for ivermectin prevent use in
small children weighing less than 15kg, due to limited safety data in this group. Many of the
NTD treatment options for small children rely on compounds that are less safe and/or
efficacious compared to oral ivermectin. Our proposal will establish the safety and
pharmacokinetics of escalating doses of ivermectin to treat scabies infected children weighing less than 15kg. The safety assessment will provide crucial evidence on the use of
ivermectin for numerous diseases in children weighing less than 15kg. The information from
measuring drug concentrations in the patients will inform the optimal dosing of this drug in
small children. Assessment of the efficacy of ivermectin, compared to permethrin cream, for
the treatment of scabies in small children can provide an important alternative treatment for
this widespread disease. |
| 30/09/2020 |
£201,914 |
UNIVERSITY OF OXFORD |
Do political institutions influence the health of populations? Political institutions once seemed fixed and stable, but now appear to be flexible and open to change. This project seeks to uncover whether changing political institutions could affect health. Political institutions are the rules that govern who participates and how they participate in decision-making processes within societies; for example, they dictate who gets to vote and how votes are counted. Political institutions potentially affect health because they make governments more (less) responsive to what citizens want. However, this straightforward view of how political institutions affect health overlooks how democracies can privilege some voices over others (e.g., party donors may matter more than voters) and so universal suffrage may not necessarily deliver better health. This project will shed light on these questions through a series of empirical case studies. For example, I propose to examine whether political incorporation improves the health of formerly excluded groups, and whether their influence on policy decisions is weaker in majoritarian political systems than proportional representation systems because votes are counted differently. This project speaks to the sustainable development agenda by illuminating whether inclusive and representative decision-making institutions may accelerate progress toward ensuring healthy lives for all.
|
| 30/09/2020 |
£1,961,880 |
WORLD HEALTH ORGANIZATION, SWITZERLAND |
There is strong evidence that climate change presents severe health risks, while addressing the drivers of climate change can bring large health gains. Nationally Determined Contributions (NDCs) reflect countries' self-defined efforts to reduce greenhouse gas emissions, and adapt to climate change impacts, to meet the goals of the 2015 Paris Climate Agreement. They are renewed every five years, beginning in 2020. The first round of submitted NDCs are neither sufficient to limit warming below the global goal of 2C (aiming at 1.5C) nor to adequately strengthen resilience to climate risks. While 65% cite health, less than 25% include health cobenefits of mitigation, only 3% of proposed NDC actions connect to health, and only 50% of surveyed countries have a health adaptation strategy or plan.
The project will address barriers that currently hinder governments in systematically considering health in NDC design and implementation. It will provide national health and development actors with evidence, analytical and capacity building tools to support them in integrating health risks, and the health co-benefits of climate change mitigation, into NDCs. It will thereby contribute to protecting and promoting health, and to a more coherent and synergistic approach to climate action, health and sustainable development.
|
| 30/09/2020 |
£4,502,682 |
BRITISH SCIENCE ASSOCIATION |
The British Science Association is proposing a new funding scheme to support public engagement with health in the UK. This new fund will: take a more outcomes-focussed and targeted approach to working with applicants; support and foster innovation; and encourage the sector to diversify its approaches and audiences.
We are proposing a three in one scheme: an ‘Incubator Fund’ will provide smaller grants to support innovation and diversity, the ‘Main Fund’ will establish and expand proven links and approaches, while a ‘Discretionary Fund’ will allow us to invest in organisations or approaches that show particular promise.
As a result, the public engagement with health sector will benefit from a grants scheme that’s more flexible and easier to navigate. This will help support and diversify the applicant pool, and hence benefit the public who will be more empowered to engage in research and better equipped to interact with health researchers, or people in allied careers, on topics they’re interested in. Ultimately more people in the UK will be engaged with - and trusting of - health research, and be able to access its benefits.
|
| 30/09/2020 |
£542,290 |
INSTITUT PASTEUR DE DAKAR |
Ebola virus disease has been declared a Public Health Emergency of International Concern in Democratic Republic of the Congo.
In the short term, our consortium plans to optimise, manufacture, and validate a novel Ebola rapid diagnostic test (RDT) for deployment at the point of need — that is low cost and high performance. A simple, 5 minute, high performance test, that complements complex laboratory tools, is urgently needed to ensure earliest possible detection of Ebola in the heart of communities experiencing an outbreak.
Successful deployment will lead to an optimised and evaluated device for manufacture to support the current outbreak in DRC, surveillance in neighbouring regions, and in time post-DRC outbreak surveillance.
In the long term, we envision substantial impact generated by establishing a new model for sustainable delivery of high performance outbreak diagnostics, deployed at the point of need. Accordingly, diaTropix - a new manufacturing facility dedicated to epidemics and neglected diseases in Dakar, Senegal - will be set up with the capability, expertise, and reagents to produce rapid diagnostics responsively to evolving outbreaks — with Ebola demonstrating proof of concept and feasibility, and a portfolio of rapid diagnostics in the pipeline for dengue, yellow fever, measles, and malaria.
|
| 30/09/2020 |
£49,804 |
UNIVERSITY OF EXETER |
The project will bring to light the forgotten satiric traditions that accompanied the rise of experimental medicine in early modern Spain. Focusing on previously untapped archival and printed sources of Spain, the research will recover literary satires on diverse aspects of medical experimentation, including pharmacological trials, blood transfusions, and surgical experiments. These novel experiments prompted questions regarding the choice of patients, which frequently came from the dispossessed social groups, such as prisoners, soldiers, foreigners, servants, the poor, hospital patients, and asylum in-mates. Satire is inextricable from its public function and can therefore provide a valuable contribution to the understanding of the early modern medical experimental practices. The project aims to answer the following questions: How did satirists react to the choice of experimental bodies? What were their main concerns and how did they express them via the available satiric models? In what ways did physicians themselves use satire to discredit their rivals’ methods? Apart from yielding self-standing results in the form of two research articles and an online database, the research in Spain will prepare the ground for the investigation of satires of experimental medicine in Germany and the Netherlands.
|
| 30/09/2020 |
£20,000 |
UNIVERSITY COLLEGE LONDON |
Not available |
| 30/09/2020 |
£50,000 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
Not available |
| 30/09/2020 |
£85,000 |
UNIVERSITY OF OXFORD |
Not available |
| 30/09/2020 |
£200,000 |
UNIVERSITY OF OXFORD |
Not available |
| 30/09/2020 |
£255,939 |
WORLD HEALTH ORGANIZATION, SWITZERLAND |
Strengthening research ethics systems in Latin America and the Caribbean
This proposal of the Regional Program on Bioethics of the Pan American Health Organization (PAHO) aims at significantly improving the regional research ethics landscape and, specifically, at strengthening research ethics systems and enhancing ethics preparedness to conduct research during emergencies. In response to a 2018 explicit request from the countries in the Americas to advance research ethics with a systemic approach, PAHO’s Regional Program on Bioethics developed indicators and a strategy to address the regional challenges. While this action has already triggered progress rapidly in few countries (e.g. Peru), PAHO’s resources to scale up these efforts as requested by the countries are very limited. This grant would allow PAHO to (a) assess the current situation using indicators, (b) advance change in several countries in Latin America and the Caribbean using national research ethics policies as a strategy, (c) support the implementation of such policies through an online tool for ethics review, and (d) share this model so it can be replicated by other regions. PAHO is uniquely positioned to achieve these outcomes due to its ongoing work supporting national health authorities on bioethics.
|
| 30/09/2020 |
£56,936 |
UNIVERSITY OF YORK |
Not available |
| 30/09/2020 |
£101,427 |
UNIVERSITY OF SOUTHAMPTON |
Not available |
| 30/09/2020 |
£51,295 |
UNIVERSITY OF LEICESTER |
Not available |
| 30/09/2020 |
£187,697 |
UNIVERSITY OF DUNDEE |
Not available |
| 30/09/2020 |
£4,970 |
ROYAL VETERINARY COLLEGE |
Not available |
| 30/09/2020 |
£5,851 |
UNIVERSITY OF BATH |
Not available |
| 30/09/2020 |
£33,735 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
Not available |
| 30/09/2020 |
£51,368 |
UNIVERSITY OF WARWICK |
Not available |
| 30/09/2020 |
£813,243 |
UNIVERSITY COLLEGE LONDON |
Not available |
| 30/09/2020 |
£62,339 |
UNIVERSITY OF SUSSEX |
Not available |
| 30/09/2020 |
£23,319 |
UNIVERSITY OF STRATHCLYDE |
Not available |
| 30/09/2020 |
£13,694 |
ST GEORGE'S UNIVERSITY OF LONDON |
Not available |
| 30/09/2020 |
£16,582 |
UNIVERSITY OF ST ANDREWS |
Not available |
| 30/09/2020 |
£82,190 |
UNIVERSITY OF SHEFFIELD |
Not available |
| 30/09/2020 |
£53,976 |
QUEEN'S UNIVERSITY BELFAST |
Not available |
| 30/09/2020 |
£170,540 |
QUEEN MARY UNIVERSITY OF LONDON |
Not available |
| 30/09/2020 |
£1,157,238 |
UNIVERSITY OF OXFORD |
Not available |
| 30/09/2020 |
£51,844 |
UNIVERSITY OF NOTTINGHAM |
Not available |
| 30/09/2020 |
£154,673 |
NEWCASTLE UNIVERSITY |
Not available |
| 30/09/2020 |
£292,856 |
UNIVERSITY OF MANCHESTER |
Not available |
| 30/09/2020 |
£150,329 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
Not available |
| 30/09/2020 |
£77,795 |
UNIVERSITY OF LIVERPOOL |
Not available |
| 30/09/2020 |
£120,337 |
UNIVERSITY OF LEEDS |
Not available |
| 30/09/2020 |
£341,763 |
KING'S COLLEGE LONDON |
Not available |
| 30/09/2020 |
£20,964 |
KEELE UNIVERSITY |
Not available |
| 30/09/2020 |
£220,862 |
UNIVERSITY OF GLASGOW |
Not available |
| 30/09/2020 |
£34,749 |
UNIVERSITY OF EXETER |
Not available |
| 30/09/2020 |
£449,124 |
UNIVERSITY OF EDINBURGH |
Not available |
| 30/09/2020 |
£297,213 |
INSTITUTE OF CANCER RESEARCH |
Not available |
| 30/09/2020 |
£457,088 |
IMPERIAL COLLEGE LONDON |
Not available |
| 30/09/2020 |
£112,683 |
CARDIFF UNIVERSITY |
Not available |
| 30/09/2020 |
£33,015 |
UNIVERSITY OF ABERDEEN |
Not available |
| 30/09/2020 |
£1,029,579 |
UNIVERSITY OF CAMBRIDGE |
Not available |
| 30/09/2020 |
£174,907 |
UNIVERSITY OF BRISTOL |
Not available |
| 30/09/2020 |
£192,922 |
UNIVERSITY OF BIRMINGHAM |
Not available |
| 30/09/2020 |
£23,303 |
BIRKBECK UNIVERSITY OF LONDON |
Not available |
| 30/09/2020 |
£46,123 |
UNIVERSITY OF WARWICK |
For much of the twentieth century, children in Britain interacted with speech therapists in hospitals, private practice and the local school medical services. Emerging from the end of the eighteenth century and forming a recognised College in 1945, speech therapists became a medically-allied profession over the course of the period between 1900 and 2000. To date, however, there has been no dedicated historiographical study of speech therapy provision – either from the perspective of the therapists or their young patients. The proposed research undertaken during this grant will provide an opportunity to scope a variety of manuscript, published and oral history sources that may be used to tell the story of this profession and those who used it. By allowing a preliminary engagement with the evidence base, this initial scoping will also contribute to the development of a sound theoretical and analytic framework for a project that has the capacity to speak to on-going debates across several historiographies as well as concerns within the medical humanities - addressing the nature of children’s experiences (as ‘patients’ or recipients of therapy), the socio-cultural construction of disability, and the porous boundaries between medicine and the world of arts and theatre.
|
| 30/09/2020 |
£27,020 |
CENTRE FOR INFECTIOUS DISEASE RESEARCH IN ZAMBIA |
We aim to contribute to strengthening capacity of ethical and regulatory bodies in governing Human Infection Studies (HIS) and developing an ethical and regulatory framework applicable to Zambia and other low middle income countries (LMICs). Being new to Zambia, there is no ethical/regulatory precedence to guide conduct of HIS which are in the pipeline. Recent introduction to other LMICs have highlighted ethical dilemmas related to HIS implementation. Hence, we propose an engagement workshop to: 1) understand views, expectations, and experiences of ethical and regulatory bodies, and other stakeholders involved in HIS, 2) identify core ethical issues and their implications for HIS implementation in Zambia drawn from other LMICs' experience, and 3) develop modalities to address these and other issues as encapsulated in consultation reports from Malawi (Gordon SB et al (2017) Wellcome Open Research) and the World Health Organization (Jamrozik E & Selgelid MJ.) to be used in Zambia and the region. Through the work described in this proposal, we aim to inform ethical guidance to build a national platform for the conduct of current and future HIS at CIDRZ, Zambia and the wider region. This will accelerate development of next generation vaccines that can end preventable deaths globally.
|
| 30/09/2020 |
£1,544,321 |
HARVARD T.H. CHAN SCHOOL OF PUBLIC HEALTH |
The Planetary Health Alliance (PHA) is a consortium of over 160 universities, NGOs, and other partners from 40 countries all committed to supporting the rapid growth of a robust, global field of planetary health. The PHA has become a nerve center for the international planetary health community, forging a network that bridges the culture and language of the expansive disciplines, organizations, and individuals involved in the field. The PHA’s strength lies in its leadership in addressing the global needs to advance the field as identified by the broader planetary health community, as well as its role of raising up and supporting the needs of its individual members. The PHA’s coalition of members has identified a common vision for the next critical needs to advance the planetary health field: 1) a global community of practice with strong regional leadership that supports robust interdisciplinary research, education, and policy translation efforts; 2) transformative planetary health education at every level; and 3) broad public outreach to mainstream planetary health messages. Support from the Wellcome Trust would allow the Planetary Health Alliance to continue driving forward its work in these three crucial areas to ensure the health of our most vulnerable populations and future generations.
|
| 30/09/2020 |
£56,842 |
UNIVERSITY OF KWAZULU NATAL |
This application requests funds from the Wellcome Trust to support the refinement of a research proposal that formed part of a recent fellowship application. In response to recommendations levelled by the panel, one year of activities will undertaken towards strengthening the proposal. Three activities will feed into this objective, namely round table discussions with local health system actors in South Africa, interviews with key academics, and interviews with policymakers and researchers in global health. Round table discussions will be held in the cities of Pretoria, Cape Town and Durban, with participants from different sectors. The revised proposal will be discussed with academic experts from different disciplines and geographical regions. Participants will be targeted from different disciplines, geographies, and levels of expertise in relevant theory and research. Revisions will be discussed with participants attending the 6th Global Symposium on Health Systems Research. The revised research proposal will be discussed with the proposed study supervisor and study sponsor, during meetings at Stellenbosch University. Following this work plan will no doubt result in a more focused, coherent research project that will yield important scholarship in an increasingly important area of work.
|
| 30/09/2020 |
£29,938 |
UNIVERSITY OF DURHAM |
What might be gained by ‘doing’ medical humanities through objects and images? This grant will support an innovative programme of activities designed to stimulate interdisciplinary dialogue around the holdings of the Wellcome Collection. By bringing together ECRs and other professional participants, including creative practitioners and museums/archives staff, the Collection will be activated to appeal to a range of stakeholders beyond those who usually carry out archival work. By approaching selected objects in the Collection as ‘provocations to thought’ and ‘companions to our emotional lives’ (Turkle, 2011), the proposed activities will investigate how thinking and feeling ‘through things’ can generate new understandings of health.
Activities will centre around two workshops, the first at the Wellcome Collection, and the second at Leeds/Durham. Outputs will include a series of linked podcasts, essays and interviews, showcasing the project’s findings; a Working Knowledge Project Short outlining best practice for ‘doing’ medical humanities with objects; and a sustainable network of collaborators for further projects. Additionally, the programme will support ECRs in acquiring the necessary skills for working with objects for research and engagement purposes, and will enable ECRs to form professional connections outside of the academy, laying the groundwork for future research, outreach, and engagement activities.
|
| 30/09/2020 |
£344,340 |
UNIVERSITY OF HONG KONG |
AMR has long been of concern to scientists and health professionals because of its adverse implications for healthcare, but many others including countries initially paid little attention. In essence, AMR-related policies across many governments and non-health sectors (in particular), are developing slower than desirable because many groups within non-health sectors do not believe they are contributing to the development of AMR. In this context, many groups are reluctant to commit to taking responsibility or actions because of this uncertainty. ACES aims squarely to reduce this uncertainty as a barrier to better policies. Normally, scientific findings are published and they may, or may not, come to the attention of policy makers. ACES plans, by contrast to use a more direct, guided and multi-pronged approach to influence policy directions from the start.
Under the following aims, ACES is intended to confirm that multiple sectors (health and non-health) contribute towards the development of AMR affecting people.
Aim#1: Determine what proportion of human AMR bacterial infections are attributable to antibiotic related practices, conditions or outcomes in human, plants, food-producing animals, food and the environment.
Aim#2: Determine the main pathways and mechanisms by which such practices, conditions or outcomes result in human AMR bacterial infections.
|
| 30/09/2020 |
£1,955,607 |
OPHIREX |
Ophirex seeks funding from the Wellcome Trust to cover a portion of costs associated with developing U.S. FDA approved and W.H.O pre-certified oral and IV broad-spectrum antidotes to snakebite.
The program will advance affordable, time-of-bite, heat-stable, easy-to-use, broad-spectrum treatments for snakebite based upon Ophirex’s privately developed toxin-targeting portfolio.
This new treatment strategy will provide superior care, rescue life and limb, and be easily administered in any environment. Not only will this antidote be easily used in unsupported environments in an oral form, it will also be effective in an IV formulation when needed, such as in pediatric care, rapid infusion for rescue/emergency treatment, and traditional intensive care.
Key attributes of this First-In-Class antidote are:
1) Broad spectrum efficacy for first-line treatment of snakebite
2) Excellent safety profile
3) Ease of use, easily administered anywhere
4) shelf-stability in Zone IV conditions with at least one-year shelf life.
All tasks support submission for FDA licensure and file transfers to other regulatory authorities (such as WHO precertification). Key goals include:
Goal 1: Complete GMP API manufacturing and begin stability testing of oral and IV formulations for use in clinical trials.
Goal 2: Support Clinical Trial for registration submission for FDA and WHO precertification.
|
| 30/09/2020 |
£1,179,736 |
RADBOUD UNIVERSITY MEDICAL CENTRE |
Resistance to commonly used antibiotics for common bacterial infections is a major health threat for the 21st century. The problem is particularly pressing in low- and middle-income countries (LMICs). This proposal builds on the work from a previous program (ABACUS I) that studied the access to and use of antibiotics in the communities of 3 African and 3 Asian countries. We propose to build the case for an international system that harmonizes the appearance and thus improves identification of oral solid formulations of antibiotics both for consumers and providers. We will consider the potential negative effects as well. We have formulated the following key goals:
Assess the potential impact of and obstacles to standardising the physical appearance of commonly used oral antibiotics on formal and informal suppliers as well as consumers in six LMICs.
Design, with key stakeholders and experts, an approach and prototypes that improves (for both suppliers and consumers) the appropriate identification of oral antibiotics
Perform a health economics analysis related to inappropriate identification of oral antibiotics and the potential impact of introducing the standardized designs
Assess the proportion of substandard and falsified oral antibiotics among three commonly sold antibiotics in four LMICs (Mozambique, Bangladesh, Ghana, Vietnam
|
| 30/09/2020 |
£2,063,517 |
INSTITUTE OF DEVELOPMENT STUDIES |
With the world facing repeated threats from disease outbreaks and with significant health and humanitarian crises engulfing regions, there is increasing recognition from humanitarian agencies of the value of social science knowledge and perspectives in contributing to operational preparedness and response efforts. In addition, there is a growing need for social scientists to assist with critical reflection on past responses and contribute to future learning, across all pillars of the emergency response. More targeted engagement with both agency staff involved in on-the-ground responses, as well as advocacy directed towards social scientists in order to improve their capacity to translate knowledge into actionable recommendations, could assist in mobilising a diverse and engaged community of practice. IDS, in collaboration with Anthrologica, has been a leader in such activities through the work of the Social Science in Humanitarian Action Platform, which has received acclaim for advocacy efforts and the production of synthesis briefings, such as for the current DRC Ebola outbreak. We are seeking funding to expand the work of the Platform in order to respond to an increasing demand for written and verbal briefings, for round table events in relation to crises, and for a fellowship scheme for practitioners and social scientists.
|
| 30/09/2020 |
£7,441,507 |
AFRICAN ACADEMY OF SCIENCES |
The African Academy of Sciences (AAS) established the AESA platform in 2015 in partnership with the Africa Union Development Agency (AUDA, formerly NEPAD Agency), the Wellcome Trust, the Bill and Melinda Gates Foundation (BMGF), and the UK Department for International Development (DFID).
The initial phase has been characterized by a growing portfolio of programme activities, aligned to the AAS STI strategies, and focused on achieving the four goals outlined in the AESA Partners’ Group - approved AESA Business Plan to develop scientific excellence, leadership, innovation and improve the research landscape in Africa.
The existence of the CORE grant has been an enabler to AAS with many benefits including:
Ability to receive and disburse complex grant funds after investing in world class financial and grants management systems and policies.
Ability to flexibly recruit and retain a high calibre multinational African team.
Ability to develop and deliver robust evaluation and risk management mechanisms
Resources to renovate and refurbish the AAS offices to provide more space and better work environment
Resources for team building and leadership coaching interventions
Ability to conduct internal audits and other due diligence exercises
Improved AAS competitiveness in the employment market in terms of staff benefits and welfare
|
| 30/09/2020 |
£52,480,377 |
AFRICAN ACADEMY OF SCIENCES |
The African Academy of Sciences (AAS) is submitting this application for renewal of the Developing Excellence in Leadership Training and Science in Africa (DELTAS) Africa programme in line with Wellcome’s strategy to strengthen Africa’s research outputs and capacity developments. The first 5-year funding cycle of DELTAS Africa I concludes in 2020 and has successfully laid a firm foundation on which to accelerate health research excellence and productivity. DELTAS Africa I has been successful in achieving its core objectives of scientific productivity and quality, building a critical mass in leadership through training and mentorship, gender parity particularly in onboarding more women in science and scientific impact including policy influence. Further, DELTAS Africa I has been vital in strengthening R & D infrastructure and providing significant investment for key disease priority areas. The DELTAS Africa programme requires a new cycle of funding as building a critical mass in research leadership for scientific impact is inherently long term. This application requests for an additional DELTAS Africa II 5-year grant (2021-2025) to build and expand on DELTAS Africa I with a deeper focus on scientific priorities, governance and impact measurement. The AAS is therefore requesting Wellcome to fund DELTAS Africa II to the level of £64,264,417.
|
| 30/09/2020 |
£38,701 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
The proposed project is a joint effort put forth by eleven comprehensive universities across China (including Hong Kong) and three regional partners in Japan, Korea and Vietnam, and supported by government agencies at local, national and regional levels. Following the World Health Organisation (WHO) "Operationalizing Emergency Preparedness" cycle, the proposed project aims to systematically engage researchers from various fields of social science to (a) build a mechanism that informs evidence-based response, (b) strengthen the social science research capacities in infectious disease emergency, and (c) create a strong network of social scientists for timely and effective deployment for outbreak response. A three-phase Scoping-Development-Evaluation working framework will be followed to match response needs with critical data derived through social science methods. We will review and synthesize successful strategies throughout different regions of East Asia and create a database with case studies. The ultimate product of this proposed project will be a protocol and associated tools (including training materials), and a strong regional research network that will effectively integrate social science research in the responses to local, national and multinational outbreaks. This newfound network will be better able to inform the preparedness partners on the social and behavioral determinants of effective epidemic control.
|
| 30/09/2020 |
£113,733 |
UNIVERSITY COLLEGE LONDON |
Sex education can positively impact upon sexual behaviour and reduce the likelihood of adverse sexual health outcomes, but the quality of provision and coverage of topics is variable. There is a need for evidence-based ways to improve knowledge of sex and relationships that speak to people across the lifecourse and from all walks-of-life. Uniting internationally-recognised scientists in sexology, epidemiology, and education, with the UK’s leading charities (Brook and the Sex Education Forum) promoting young people’s sexual health and the delivery of quality life-long relationship and sex education (RSE), we will use creative arts and online technologies to produce innovative resources that meet this need.
Evidence from Britain’s nationally-representative sexual health survey (the National Survey of Sexual Attitudes and Lifestyles, ‘Natsal’) and our previous public engagement will be used:
(i) to create a free-to-use interactive online resource for the general public, allowing exploration as to what is ‘normal’, the factors that shape sexual lifestyles, and the underpinning scientific research;
(ii) as a catalyst to facilitate dialogue with and between young people on issues around sex that matter to them. This young people-centred learning will be translated into resources to better equip teachers to deliver RSE, crucially coinciding with the introduction of mandatory RSE in schools in England (2020) and Wales (2022).
These evidence-based tools will empower people of all ages to improve their knowledge of sex and relationships, their sexual health and wellbeing. They will also demonstrate proof-of-concept around novel mechanisms for engaging the public with Natsal and science more broadly.
|
| 30/09/2020 |
£5,730,747 |
MERCK SHARP & DOHME |
Malaria is one of the world's most devastating diseases of humans and results
in over 400,000 deaths annually. Novel therapies are urgently required to
populate the antimalarial clinical portfolio, as the current therapeutics that treat
this disease are becoming less effective due to emerging resistance.
A collaboration between Dr David Olsen from Merck & Co., Kenilworth, NJ USA
(known as MSD outside the US and Canada) and Professor Alan Cowman from
the Walter and Eliza Hall Institute (WEHI}, has demonstrated that malaria
aspartyl protease enzymes are attractive drug targets, as they perform
essential functions for survival in liver, blood, and sexual stages of the parasite
life cycle.
Through screening aspartyl protease inhibitor libraries, the collaboration has
identified novel drugwfike hit compounds that are potently active against the
malaria parasite. The proposed lead optimization research aims to increase
potency against the parasite whilst maintaining selectivity, progressing to a Iab development stage clinical candidate. |
| 30/09/2020 |
£931,685 |
WALTER AND ELIZA HALL INSTITUTE OF MEDICAL RESEARCH |
Malaria is one of the world's most devastating diseases of humans and results
in over 400,000 deaths annually. Novel therapies are urgently required to
populate the antimalarial clinical portfolio, as the current therapeutics that treat
this disease are becoming less effective due to emerging resistance.
A collaboration between Dr David Olsen from Merck & Co., Kenilworth, NJ USA
(known as MSD outside the US and Canada) and Professor Alan Cowman from
the Walter and Eliza Hall Institute (WEHI}, has demonstrated that malaria
aspartyl protease enzymes are attractive drug targets, as they perform
essential functions for survival in liver, blood, and sexual stages of the parasite
life cycle.
Through screening aspartyl protease inhibitor libraries, the collaboration has
identified novel drugwfike hit compounds that are potently active against the
malaria parasite. The proposed lead optimization research aims to increase
potency against the parasite whilst maintaining selectivity, progressing to a I
development stage clinical candidate. |
| 30/09/2020 |
£248,509 |
UNIVERSITY OF OXFORD |
Not available |
| 30/09/2020 |
£245,788 |
UNIVERSITY OF CAMBRIDGE |
Not available |
| 30/09/2020 |
£243,492 |
UNIVERSITY COLLEGE LONDON |
Not available |
| 30/09/2020 |
£833,400 |
UNIVERSITY OF MANCHESTER |
The enzyme lysyl oxidase (LOX) regulates cross-linking of structural proteins in the extracellular matrix.
LOX also plays a role in stimulating the metastatic spread of cancer through the body. Its expression is increased in hypoxic cancers and is correlated with tumour metastasis and decreased patient survival. In model systems its inhibition significantly decreases cancer metastasis and increases survival. Since metastasis is responsible for over 90 per cent of cancer deaths these data validate LOX as an important therapeutic target in cancer.
Professor Caroline Springer and Professor Richard Marais from the Institute of Cancer Research have been awarded Seeding Drug Discovery funding to develop drugs that target LOX. They are applying a medicinal chemistry drug discovery approach underpinned by a strong programme in LOX biology with the aim of producing orally available, small molecular weight drugs that inhibit LOX activity for cancer treatment. |
| 30/09/2020 |
£100,000 |
INSTITUTE OF CANCER RESEARCH |
While effective treatments for many forms of cancer exist, therapies that are tailored for patients with niche forms of the disease, such as triple negative breast cancer are currently unavailable. The Trust has awarded £3.9 million over three years to Prof. Alan Ashworth, FRS, Dr. Christopher Lord, Prof. Caroline Springer and Prof. Laurence Pearl, FRS, for the development of orally available small molecules that could target specific cancer subtypes. Researchers led by Prof Alan Ashworth and Dr Christopher Lord have pioneered the exploitation of novel therapeutic approaches such as synthetic lethality and the use of PARP inhibitors in cancer treatment. PARP (Poly ADP-Ribose Polymerase) enzymes modify proteins and control cell function by catalyzing the addition of poly (ADP-ribose) polymers onto substrates. With funding from the Trust, Ashworth, Lord, Springer and Pearl, in collaboration with Domainex, will develop novel small molecule inhibitors that target additional PARP superfamily members. These inhibitors will be assessed in specific tumour models and then progressed into clinical candidates that could be ultimately assessed in drug trials that target cancer subtypes for which there is significant unmet clinical need. |
| 30/09/2020 |
£1,444,200 |
SAVE THE CHILDREN |
Not available |
| 30/09/2020 |
£555,800 |
SAVE THE CHILDREN |
Not available |
| 30/09/2020 |
£143,272 |
WORLD HEALTH ORGANIZATION, SWITZERLAND |
The project supports activities in the Immunization, Vaccines and biologicals
department of the WHO that aim to advance the product development and use of
monoclonal antibodies (mAbs) for infectious diseases, with a focus on meeting the
needs of Low and Middle Income Countries (LMICs). Three specific activities will be
carried out. First, a stakeholder consultation on monoclonal antibody technologies will
be held to discuss which would best support affordability and accessibility in LMICs.
Second, an application to establish rabies mAbs on the WHO model list of essential
medicines (EML) would set the precedent for inclusion of additional infectious diseases
mAbs in the future. Thirdly, an assessment of diphtheria immunoglobulin supply and
potential demand for mAb-based products will be carried out which could serve as a
methodology to be used to assess other mAb based products." |
| 30/09/2020 |
£50,000 |
UNIVERSITY COLLEGE LONDON |
We are launching a Lancet Commission on Gender and Global Health that intends to ensure that global health take gender into consideration. A continued failure to consider and act on gender in public health policies, programmes and practices results in lost opportunities to improve health outcomes across society, equitably and sustainably.
We have drawn together a cross- and inter-disciplinary Commission that benefits from the expertise and experience of around 20 Commissioners from different backgrounds, geographical settings and genders. The Commission will be guided by Dr Richard Horton and Dr Jocalyn Clark from The Lancet, and will be co-Chaired by Professor Pascale Allotey from UNU-IIGH, Professor Sarah Hawkes from UCL and Mr Elhadj As Sy, Chair of the Board of the Kofi Annan Foundation.
We plan to launch the Commission in October 2020 after the Berlin World Health Summit (WHS). We will organise a 2-day meeting bringing Commissioners together for the first time, to discuss the direction and content of the Commission and establish a workplan covering the next 2-3 years. Funding is required to host the launch in Berlin, and to follow up with post-launch co-ordination and communication activities.
|
| 30/09/2020 |
£240,730 |
GLOBAL POLICY REPORTING |
Reliable, evidence-based media remains a key means of advancing public health literacy and bringing news, views and opinions from diverse regions of the world into the corridors of power. The vision driving Health Policy Watch, launched in 2019 as an open-access, non-profit health news service, is to create a new "network paradigm" that connects the dots between policy trends and realities in the global North and South. We provide coverage across 5 key themes, including: infectious diseases; non-communicable diseases; antimicrobial resistance; climate and environmental health; and health emergencies.
The key objective of this proposal is to foster a more balanced- and "solutions"-oriented approach to health policy dialogue around issues and choices that are critical to effective response to the COVID-19 pandemic - and to the broader global health agenda in light of COVID-19 realities.
Institutional sustainability is a second key objective. To realize its public service mission, Health Policy Watch is committed to ensuring that all potential readers can access our content free of charge. As we work, with modest resources, to build a diverse array of donors and collaborations to advance that mission, Wellcome Trust support would empower us to develop a more sustainable and robust funding portfolio.
|
| 30/09/2020 |
£250,000 |
UNIVERSITY OF OXFORD |
In low-income countries there remains a lack of internationally competitive research leaders. The Global Health Network has analysed the barriers and enablers to health research and show that typical approaches to capability building have not delivered long-term capabilities that foster internationally competitive teams. The Network has built a novel mechanism to address this which works across all types of study, disease areas and organisations to share know-how and deliver training, guidance and methods using a digital platform alongside local programmes. The success and impact that arise from this combination of cross-cutting knowledge exchange and research capability building together provide a strong research enabling platform. This active exchange of knowledge, tools and processes is increasing quality and driving efficiency in health research. The Network is driving better methods, new skills and supporting career development through the creation of active communities of practice. These capacity building, methodology research activities and delivery costs cannot be met by our project-specific funding for knowledge exchange, yet these elements deliver success and impact by bringing the research community together. This application is part of our long-term strategic development plan that sets out to further develop our unique and impactful approach for which we require consortia funding.
|
| 30/09/2020 |
£4,483,010 |
UKRI-MRC |
Not available |
| 30/09/2020 |
£230,048 |
WORLD HEALTH SUMMIT |
The most pressing global health challenges of our time require strong partnerships for multi-stakeholder exchange and appropriate policy responses. Against this background, the World Health Summit would like to strengthen its collaboration with expert organizations such as Wellcome Trust, to make a greater contribution to policy-making in the field of global health research and strengthen scientific and political activity in Berlin and beyond in the spirit of the sustainable development goals.
|
| 30/09/2020 |
£341,655 |
MUNICH SECURITY CONFERENCE |
Building on the expertise and support provided by the Wellcome Trust in recent years, the MSC wishes to create a direct continuation of existing work, sustainably strengthen its global health dimension and expand its reach with additional activities in response to COVID-19 and beyond.
During the MSC fiscal year 2020-2021 activities will include two follow-up Digital Conversations and various roundtables and side events within the scope of the 2021 Munich Security Conference, a 2021 Health Security Roundtable in Berlin and potentially a Health Security Roundtable on the sidelines of the MSC Core Group Meeting 2021 in Washington D.C.
Additionally, a Special Edition of the Munich Security Report, the "Stability Report" will address many current issues and challenges in global health security. As part of the grant proposal, the MSC will facilitate Wellcome Trust participation at the report launch and will give updates on report progress.
Events similar in number and design will take place in the fiscal years 2021-2022 and 2022-2023. Due to COVID-19, detailed plans will only be made at a later stage. The MSC will keep the Wellcome Trust up to date on its plans for new MSC health security activities as soon as they become available.
|
| 30/09/2020 |
£419,410 |
ACCESS TO MEDICINE FOUNDATION |
Equitable access is critical for maximising the impact of innovation and heavily depends on proactive actions by pharmaceutical companies, during and after the COVID-19 pandemic. In order to bring the pandemic to an end, achieve universal health coverage and protect the gains made on Sustainable Development Goal 3, the pharmaceutical industry will need to ensure that all scientific advancements benefit the maximum number of people, independent of the place they live or their ability to pay. The Access to Medicine Foundation (ATMF) has incentivised pharmaceutical company action to improve access to new innovations for more than a decade. By rewarding positive action, sharing best practices, and highlighting opportunities for change, the ATMF encourages companies to become willing partners to improve global access to their products. The ATMF will support Wellcome Trust’s approach to equitable access to healthcare interventions through a combination of research and policy initiatives that will (a) incentivise pharmaceutical company action on COVID-19, (b) support global efforts to mainstream access principles during product development and (c) untap the potential of generic medicine manufacturers in expanding access to innovations in low- and middle-income countries. The request from the ATMF is for €471,750 (£425,000) from October 2020 to September 2021.
|
| 30/09/2020 |
£2,277,389 |
UNIVERSITY OF OXFORD |
OpenSAFELY is a new secure analytics platform for electronic health records in the NHS, created to deliver urgent results during the global COVID-19 emergency. It is now successfully delivering analyses across more than 24 million patients’ full pseudonymised primary care NHS records, with more to follow shortly. All our analytic software is open for security review, scientific review, and re-use. OpenSAFELY uses a new model for enhanced security and timely access to data: we don’t transport large volumes of potentially disclosive pseudonymised patient data outside of the secure environments managed by the electronic health record software company; instead, trusted analysts can run large scale computation across live pseudonymised patient records inside the data centre of the electronic health records software company. This pragmatic and secure approach has allowed us to deliver our first analyses in just five weeks from project start.
|
| 30/09/2020 |
£2,758,611 |
OPENING KNOWLEDGE ACROSS RESEARCH AND ENTERTAINMENT (OKRE) |
The proposal outlines the request for funding to support the set-up, operation and activities of OKRE: Opening Knowledge across Research and Entertainment over five years.
OKRE is a high-profile strategic initiative for working with the entertainment industries that has been developed in partnership with UKRI. OKRE enables Wellcome to build on the work it has done so far, to scale its impact and create a more sustainable transformation in the engagement of research with mass media.
A gap was identified between research and entertainment sectors for a body akin to the Science Media Centre but designed to address the particular challenges of working with the entertainment industries. OKRE's business model has now been developed and the organisation has been registered with Companies House and the Charity Commission.
Wellcome is uniquely positioned to establish such a body. Funding enables OKRE to deliver core services in line with Wellcome's new strategic vision. OKRE's objects include promoting research, advancing education of the public and advancing the arts in social, scientific and health-related issues, as well as promoting the efficiency and effectiveness of charities. By sharing infrastructure costs with other funders, OKRE will enable Wellcome to scale the impact of its funding.
|
| 30/09/2020 |
£248,240,718 |
WELLCOME LEAP INC. |
Wellcome Leap Inc. has been established by Wellcome as a US, wholly owned not for profit entity with the aim of delivering breakthroughs in human health and demonstrate seemingly impossible results on seemingly impossible timescales. This will be achieved through the creation of a small portfolio of goal focused Programmes selected based upon their potential to improve health globally rather than by their potential financial or commercial return.
Wellcome provides initial funding of $306.9M to Leap to cover their first 10 years of operation (although further funding may be provided over this 10 years). This funding will support Leap’s operational costs and ‘Programmatic costs’ which will include (but not be limited to) the employment of Programme Directors to build and orchestrate large research programmes, subject matter advice and support to formulate a programme and the funding of sub-awardees to carry out research in pursuit of a programme goal.
Wellcome may provide further funding to Leap after 3 years of operation and it is anticipated that Leap will in time attract funding from third parties. |
| 30/09/2020 |
£1,800,000 |
UNIVERSITY OF BRISTOL |
This University of Bristol-Wellcome Trust Translational Partnership Award (TPA) will build on the successes and insights gained from the past three years of our partnership to deliver a sustained, impactful change in our translational research and culture. Our ambition is to turn University research into real world solutions which transform our society, economy and health. In this award we will continue to try new things, disrupt the status quo and advance the way we support and accelerate translation by taking a bespoke, personalised approach, driving culture change to maximise the impact of our research. We will use this funding to work with researchers at all stages of the career pathway (PhD to Professor) to develop and realise their ambitions to translate their research through: - A Translational Research Hub to enable straightforward access to expertise and funding and facilitate engagement with non-academic partners - Proof of Concept and Translation Accelerator project funding to meet gaps in the translational funding pathway - Early Career Translational Fellowships to provide bespoke support for the most promising individuals and projects - Developing Innovation Networks with partner organisations in priority modalities and areas - Exploiting the translational platforms developed from our cutting-edge synthetic biology and informatics technologies in TPA1 and 2 - Providing training to researchers that embeds learning into practice through follow-up support and individualised action plans |
| 30/09/2020 |
£2,250,000 |
UNIVERSITY OF CAMBRIDGE |
The University of Cambridge will use the TPA funding to bridge the gap between discovery science and early stage translation of projects. The aim is to encourage and support basic scientists to realise the translational potential of their research by providing integrated facilitation for training, expert advice, funding and projects through creation of a virtual Therapeutic Hub, which supports the TPA within CATS. Our objectives are:
- To provide a gateway for translation into the therapeutics sciences pipeline through the creation of a virtual therapeutic hub;
- To facilitate early stage drug discovery and translational research
- To develop a community of Translational Champions across the University who will provide opportunities for Departments/Institutes to develop their own translational strategies
- To deliver training in early translation for research scientists and early career academics. |
| 30/09/2020 |
£2,397,523 |
UNIVERSITY OF MANCHESTER |
The University of Manchester will use the three-year Wellcome Translational Partnership
Award (TPA) renewal to build on the successful initiatives launched and delivered through the
first TPA and continue to grow the translational research culture and develop the translational
ecosystem in Manchester. The TPA funding will be used to address four aims: 1) support
translational research; 2) connect across disciplines; 3) innovate with industry; and 4) change
the culture by embedding translational research across the University. The Translational
Research Facilitators will continue to bring together a network of support, facilities and
expertise to build better links between science, technology and innovation, by removing
barriers between disciplines to make the pathway to translation quicker and easier. The TPA
will support translational research across all the stages of the translational pathway through
pump-priming funding schemes, training (particularly informatics), symposiums and
workshops, with a particular emphasis on new initiatives to support early career researchers.
The Translation Manchester Research Network (TMRN), established under the initial TPA,
brings together groups and organisations that exist to facilitate translational research across
the One Manchester health innovation ecosystem, making it the ‘one-stop-shop’ for
translational research support. The TMRN will continue to play a key role in the delivery of the
initiatives set out in the TPA renewal. In addition, Innovation Labs will connect academics with
industry partners, and pump-prime new collaborations and innovation through seed corn
funding. The Research Connections Tool will enable researchers and clinicians to easily find
appropriate collaborators across the University and our partner NHS trusts. To support
delivery of these new initiatives a Translational Research Support Officer and a Translational
Research Bioinformatician will be recruited into the Translation Manchester team. |
| 30/09/2020 |
£2,401,000 |
UNIVERSITY OF EDINBURGH |
Since 2018, the University of Edinburgh has been in receipt of a Wellcome Institutional
Translation Partnership Award which has now been renewed for a further three years. The
ambition of the partnership is to engage Wellcome Trust funded researchers and all of those
working within the Wellcome Trust scientific remit, to identify and develop early stage
translational opportunities within their research. Edinburgh embedded its scheme within
Edinburgh Innovations building a small focused team, including two Entrepreneurs-in-
Residence with a successful commercial/translational background to nurture projects towards
translation through leveraging future funding, industry collaborations or commercialisation plus
a dedicated Project Manager. Since inception, the program has engaged with hundreds of
researchers, providing mentoring and support.
Renewal of the award will allow access to translational support and funding across the
University at scale. This will make beginning and navigating the translational journey for all
researchers easier and increase the diversity of the translational portfolio both in terms of
thematic area and forms of impact. |
| 30/09/2020 |
£32,419 |
CODE FOR SCIENCE AND SOCIETY |
The coronavirus pandemic has led to an unprecedented uptake of preprints, with researchers from all over the globe collaborating and sharing information at record speeds. The Wellcome Trust-funded open source platform Outbreak Science Rapid PREreview (https://outbreaksci.prereview.org) launched by our team on January 1, 2020, is well-positioned to help provide rapid feedback and a help filter the high number of COVID-19 preprints for quality and potential impact.
In just a few months, the platform has reached about 500 users, 80 rapid reviews, and more than 230 requests for reviews, the majority of which are for COVID-19-related preprints. These numbers grow every day, and so do opportunities for collaborations with third-party sites and efforts that can increase the discoverability of the content and accessibility to the tool.
To leverage our platform and aid in tackling this pandemic, our team asks for financial support for the following activities and positions:
Feature implementation and customization of our open API to make COVID-19-related content more discoverable via integration with third-party sites, such as preprint servers and research platforms;
A full-time project manager to lead and coordinate the work.
|
| 30/09/2020 |
£240,000 |
ZINC |
The early stages of health startups are science-rich environments that provide opportunities for the public to engage in health research and co-design new solutions. However, many user groups - especially those who are underserved by existing digital health solutions - are not empowered to engage with the research activities of startups. This is particularly evident for health issues considered ‘taboo’, such as incontinence, menopause, fertility, IBS, and mental ill-health. The result is a startup landscape that is overly focused on a narrow set of health issues and populations.
This project will launch a new programme of public engagement at Zinc, providing formal support and a structured programme to ~6 startups that are science-rich, dealing with taboo health issues, and committed to empowering underrepresented ‘expert users’. Working closely with specialist consultants, we will create opportunities for the public to contribute to, and learn about, health research and innovation. This work will advance the evidence-base for public engagement - in particular, our understanding of how founders and researchers can more effectively engage with publics underserved by digital health solutions. Longer-term, our aim is that this will lead to better integration of academic health research, public engagement, and commercial tech innovation.
|
| 30/09/2020 |
£27,393 |
UNIVERSITY OF LEIDEN |
Not available |
| 30/09/2020 |
£49,903 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
We will develop software building-blocks to facilitate the use of operational health data in Africa to aid the COVID-19 response. The main gap the new work addresses is the use and re-use of health data in the immediate operational response to COVID-19. The project will run under the umbrella of afrimapr, an existing Wellcome Open Research Fund project improving the use of health research data. The project philosophy is the same: firstly to develop open-source R components to assist African data scientists in creating tools to address local issues, secondly to develop training resources and thirdly to promote them within African data communities. We have already started assessing, and improving access to, open-data on African health facility locations. This extension will allow us to continue working with new collaborators; healthsites.io and OpenStreetMap communities that collate and crowdsource health facility data. We will reach out to African data communities through DFID advisers to African ministries, national statistics institutes through the Global Statistical Service, and our networks and social media. Components for working with African health zones will also be developed. Increasing the use of open-access health data has the co-benefit of incentivizing improvements to the availability of the data themselves.
|
| 30/09/2020 |
£249,544 |
UNIVERSITY OF GLASGOW |
General population serosurveillance in low-income Africa is fundamental to understanding the population exposure to SARS-CoV-2, to explain the observed epidemiology and to ensure that ongoing control measures in the region are proportionate and are not guided by observations from very different settings. Detailed longitudinal immunological studies of infected individuals will be key to determining the long-term strategy in managing COVID-19 in highly vulnerable African populations.
Utilising the longitudinal urban and rural cohorts established by the Malawi Epidemiology and Intervention Research Unit, and supported by international and national expertise, we will undertake population immunoepidemiological surveillance to understand the trends in exposure and transmission of SARS-CoV-2, risk factors for SARS-CoV-2 infection and severe disease, as well as the proportion of asymptomatic or pauci-symptomatic infection in the population to enable an accurate estimate of infection fatality rate. Furthermore, we will recruit individuals with evidence of past SARS-CoV-2 infection to a nested cohort with 3-monthly sampling, to explore the magnitude and duration of antibody response and protective immunity in the Malawian population, and at the same time creating a biorepository for further in-depth virological and immunological studies.
|
| 30/09/2020 |
£908,761 |
PATH |
Public Health Value Propositions, also called Full value Vaccine Assessments, are critical, evidence-based analyses conducted to ensure that efforts to develop new vaccines align with the needs, interests and capacity of intended beneficiaries. We are developing a Shigella vaccine Value Proposition (svvp) to assess and possible enhance the probability that appropriate vaccines targeted at the diarrhoea-causing bacterium Shigella will be developed, produced, financed, widely recommended and adapted in low-middle income countries (LMICs)where it is endemic. The SVVP will inform late stage development investments in Shigella vaccine candidates. We are assessing and synthesizing relevant epidemiological, economic, policy regulatory and manufacturing aspects to address five broad questions and inform the SVVP.
1. How strong is the evidence linking Shigella to stunting, and what would be the economic consequences of vaccine-induced reductions in stunting?
2. What would be the projected impact on and cost effectiveness of the prevention of Shigellosis by effective vaccines?
3. What is the potential demand for Shigella vaccines across different markets?
4. What would be the optimal pathogen composition of a Shigella-containing combination vaccine potentially available in the near- or medium-term?
5. From the perspectives of LMIC-level policy makers and other key stakeholder, what would be the perceived value of a shigella-containing vaccine? |
| 30/09/2020 |
£140,190 |
ALBERT B. SABIN VACCINE INSTITUTE, INC |
The COVID-19 pandemic underscores the urgency and importance of vaccines and immunization to global health. There are significant and pressing scientific, technical and policy solutions needed to tackle the enormous challenges we face in a world with COVID-19. Bold thinking across disciplines, actionable recommendations and strong advocacy are all urgently needed to advance innovative ideas, overcome these hurdles and inform future programmatic work, in particular in light of the COVID pandemic. The goal of this project is to virtually convene The Sabin-Aspen Vaccine Science & Policy Group (Vaccine Group) in September 2020 to explore how the effort to accelerate the development of COVID-19 vaccines through ACT Accelerator and other initiatives can be harnessed to bring about a "new normal" for vaccine/vaccination ecosystem and ensure that vaccines for diseases with epidemic potential or those affecting low income populations are developed. The Sabin Vaccine Institute and the Aspen Institute, co-conveners of the Vaccine Group, will draft and disseminate a meeting report on the convening with principal findings and recommendations to inform program and policy planning.
|
| 30/09/2020 |
£45,714 |
INDEXICAL FILMS LLC |
Declaring "war on disease" affects how we treat sick people, how we define the "public" in public health, and how we respond to real-world pandemics.. This was demonstrated vividly during the COVID-19 crisis, when these declarations of war initiated militarized states of emergency, prompted border lockdowns, and refreshed old fears about "foreign" pathogens. But why was this public health crisis being treated as a national security issue? What else does this metaphor do in the world? And what if it weren't a war?
To answer those questions, the feature-length documentary "Dis-Ease" retraces the origin and evolution of our "war on disease" through the history, philosophy, culture, and pop-cultural imaginaries of medicine. It is constructed around particular episodes in the history of human encounters with epidemic, endemic, and pandemic diseases, including plague, malaria, cholera, tuberculosis, influenza, HIV/AIDS, and COVID-19. By examining the cultural history that runs alongside the growing scientific understanding of these diseases over time, DIS-EASE looks to understand how pandemic preparedness became framed as biodefense, and how that has contributed to the present crisis. And it proposes alternatives for the future.
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| 30/09/2020 |
£239,027 |
UNICEF UK |
Aligned with Wellcome’s commitment to leveraging public partnership – throughout the cycles of response, recovery and resilience/sustainable preparedness – to inform research, create trusted research, and increase the access and use of research more equitably across communities, this project will (1) Fill a current gap in children and young people (CYP) insights around Covid-19 and other issues of health and science related research, (2) Equip young people with participatory research and multi-media production skills, and (3) Develop a scaleable participatory model of research and communication for change.
To achieve this, UNICEF C4D, a leader in using communication strategies to empower CYP as critical actors in research and development, will partner with innovative multi-media platforms -- inclusive of video, community radio, and mobile-based platforms -- to facilitate CYP-led cross-country surveying, personal stories (via video), in-depth interviews (with/by CYP), and deliberative dialogues (via community radio, video and mobile-based platforms), that will uncover CYP needs, behaviours and experiences with COVID-19 and other priority health and science challenges. UNICEF and its partners will develop a replicable model and partnership base for CYP-led research and engagement to influence social and behaviour change to support future joint research engagement to inform policy and programmatic decision making.
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| 30/09/2020 |
£149,993 |
UNIVERSITY OF MANCHESTER |
A 9-part digital comic for young adults (YA) aged 16-25 providing an alternative, character-based narrative about a pandemic. Co-created with young adults from across the globe, multidisciplinary researchers and experts, renowned comic writers and artists, PlanetDivoc91 offers audiences diverse perspectives on how to make sense of a pandemic. It connects and empowers YA - whose voices have been marginal in the COVID crisis - to be heard in current and future pandemic research and policy. This proposal builds on work already started in the UK and internationally, to extend in greater depth globally, particularly in India and South Africa (SA). |
| 30/09/2020 |
£1,999,436 |
UNIVERSITY OF OXFORD |
We seek to establish a research network and collaborative platform for rapidly identifying and analysing ethical and policy issues arising in infectious disease treatment, research, response, and preparedness, and engaging in research on the profound ethical challenges presented by infectious diseases across the globe. The platform and network will provide real-time ethics and policy support, create a mechanism for collaborative responsive research as well as forward-looking projects with longer timeframes and engaging with crucial stakeholders from across high-resource and LMICs, all focusing on the critically important area of infectious disease and global health bioethics. In addition to being responsive to the needs as identified by the network, we expect the platform and network to be available to respond to needs identified by the WHO Public Health Emergency Ethics Preparedness and Response (PHEEPR) Network and other global bioethics efforts. The Platform and Network will be structured into two related and overlapping sets of activities, which will complement and build on each other. These will comprise: an Infectious Disease Ethics Forum for discussion of emerging ethical issues, a Collaborative Network to identify important issues for policy response and research; and, a programme of global health ethics research focusing on infectious disease.
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| 30/09/2020 |
£191,745 |
UNIVERSITY OF BRISTOL |
The project will establish an interdisciplinary network of researchers with the aim of investigating and bringing to light perspectives from the Black humanities on Black health and wellbeing. Led by the Centre for Black Humanities at the University of Bristol, the project will consist of a series of video conferenced online workshops, symposiums and events, which will: a) create a community of scholars whose research concerns how Black writers, intellectuals, artists, activists and theorists have creatively and critically addressed the psychological and physiological health of black people across the twentieth and twenty-first centuries; b) explore how research in Black humanities might intervene in the current racialized landscape of medicine and health; c) train and develop a new generation of ECR scholars in the theories and methods of Black studies and the medical humanities and in how they insect.
|
| 30/09/2020 |
£2,352,590 |
GATES MEDICAL RESEARCH INSTITUTE |
The aim of this proposal is to obtain co-funding from the Wellcome Trust for a Phase 2 safety and immunogenicity trial of the M72/AS01E investigational vaccine. This Phase 2 trial in people living with HIV (PLHIV) is conducted to support inclusion of PLHIV in a following pivotal Phase 3 VE trial and to thus enable public health use of the vaccine in PLHIV should the Phase 2 and Phase 3 data support its use. PLHIV are at high risk for TB disease and deaths, and an estimated 251,000 of 1,450,000 deaths from tuberculosis in 2018 occurred in PLHIV.
The key deliverables of the full program (Phase 2 and 3) are:
Advance technical and clinical development of the M72/AS01E candidate vaccine from Phase 2b through Phase 3 (including Mtb uninfected and HIV-positive populations) and prepare for licensure
Identify a marketing authorization holder willing and capable to file the licensure application(s) and manufacture global product supply and to ensure global access to the vaccine
Aim for initial registration in South Africa to enable Phase 4 impact studies (outside the scope of this proposal) that generate robust effectiveness data for the prevention of TB in children and adults
|
| 30/09/2020 |
£1,521,343 |
JOHNS HOPKINS UNIVERSITY |
In this study co-funded by Wellcome and Gavi, the aim is to study the impact of mass
cholera vaccination in Uvira, DR Congo through a multifaceted approach aimed at estimating
changes in clinical disease incidence, infection rates, and the type and frequency of
occurrence of toxigenic V. cholerae in the environment. Successful completion of this project
will provide critical insights into the impact that mass OCV campaigns can have on human
health while at the same time providing a new understanding of the epidemiology of cholera
in this hyper-endemic setting. Our specific objectives are:
Objective 1: To enhance the cholera surveillance system in Uvira, South Kivu, DR Congo in
order to estimate the impact of mass vaccination on lab-confirmed cholera incidence and
mortality.
Objective 2: To conduct serial cross-sectional serosurveys after vaccination to estimate the
seroincidence of V. cholerae infection in Uvira over time and contextualize the primary
results based on clinical cholera cases.
Objective 3: To use phenotypic and molecular methods to describe the changes in the V.
cholerae population after vaccination in both human and environmental samples in Uvira.
Objective 4: To use phenotypic and molecular methods to describe the changes in the V.
cholerae population after vaccination in both human and environmental samples in Uvira. |
| 30/09/2020 |
£232,758 |
CLEAN AIR FUND |
Air pollution is a global health emergency. Outdoor air pollution causes 4.2 million premature deaths every year and 90% of these deaths happen in low- and middle-income countries. Additionally, air pollution has significant overlaps with climate change, both being caused in large part by the combustion of fossil fuels. While the link between air pollution and climate change isn’t always straightforward, smart solutions can ensure a win-win.
A survey commissioned by the Clean Air Fund (CAF) found that health professionals are the most trusted spokespeople on air pollution in all countries.[1] Consequently, there is an important opportunity to encourage real change if the health sector could be engaged as spokespeople to reduce air pollution, which has been further strengthened by COVID-19.
In this application we propose research on communications strategies that spur action on air pollution by healthcare practitioners. CAF is already funding such work in UK, India and at a global level. Additional support would add Bangladesh, Mexico and Ethiopia. Outputs include strategic recommendations for communicating on air pollution in the respective countries, as well as a database with existing campaigns and their effectiveness.
[1] Research carried out in May 2020 in the UK, India, Poland, Bulgaria and Nigeria.
|
| 30/09/2020 |
£30,476 |
CODE FOR SCIENCE AND SOCIETY |
Over the next 12-18 months, leading structures relied on to conduct, publish and disseminate scholarly research are at risk of collapse.
One leading use case to illustrate the current reality as it unfolds, and how it will affect scholarly research communications is the impact on university and scholar led presses, and the risks that presents to the creation of scholarly monographs.
University presses are collectively facing unprecedented deficits and sales shortfalls for print books this year. Budget constraints at the library level may well directly affect the sale of scholarly monographs as well as subsidies and subventions.
To address this potential threat to scholarship, we are launching a cross-institutional research effort to address pending infrastructure consolidation and collapse across the ecosystem, identifying the opportunities, leverage points, costs and approaches that could be employed.
The project sets out to deliver the following:
Cost-benefit analyses to enable faster, more informed decision making in support of open scholarship;
Criteria for assessing solutions in service of the academy;
Actionable recommendations and guidance for budget owners;
Actionable recommendations and models for projects to operate sustainably;
Scenario planning for 6, 12, and 18+ months outlooks;
A collective model for stewardship, cost-sharing, and risk pooling.
|
| 30/09/2020 |
£52,264 |
GLOBAL HEALTHCARE INNOVATION ALLIANCE ACCELERATOR |
GHIAA started the process of transforming its ‘paper’ Master Alliance Provisions Guide (MAPGuide) into an online resource in autumn 2019. Using Wellcome’s funding, GHIAA has made significant progress towards developing an intuitive, user-friendly tool, and a robust online platform to support future growth.
The development process began with creating a prototype MAPGuide tool and conducting initial stakeholder consultations in January and February 2020. These consultations provided vital input on adjustments needed to improve the user experience with the online tool. Driven by that input, GHIAA has recently completed significant improvements to the beta version of the MAPGuide.
During additional consultations in June 2020, stakeholders provided encouraging and constructive feedback on the improvements to the features and functionality of the MAPGuide. The next step in the development process is a public launch, targeted for early August 2020.
GHIAA is seeking further funding from Wellcome to:
Conduct additional consultations for wider stakeholder groups over the rest of 2020
Make additional improvements based on feedback identified through consultations and user surveys after rollout
Conduct targeted workshops on potential future features and improvements
Conduct a consultative process to advance the Global Health Transactions Glossary
Develop additional content, features and supporting tools for the MAPGuide
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| 30/09/2020 |
£503,102 |
CARDIFF UNIVERSITY |
After giving birth, some women have the rapid onset of a severe mental health condition, postpartum psychosis, with mood symptoms, hallucinations and delusions. Postpartum psychosis is a medical emergency due to the risk to both mother and child. During pregnancy there is an increase in circulating hormones called neurosteroids and these enter the brain and change the function of proteins called GABA-A receptors. In order to adapt, the brain reduces the amount of these proteins but following the rapid drop of neurosteroids after birth, the GABA-A receptors cannot recover to their pre-pregnancy levels quickly enough and therefore normal brain function is compromised, triggering postpartum psychosis. Our aim is to identify a synthetic neuroactive steroid that can compensate for the postpartum loss of natural neurosteroids and thereby reduce the symptoms in affected mothers and also prevent episodes in women at high risk. This will be of enormous benefit to women and their families. |
| 30/09/2020 |
£230,515 |
UNIVERSITY OF OXFORD |
To address the problem of antimicrobial resistance (AMR) in Thailand, the Thai government produced the "Thailand National Strategic Action Plan on Antimicrobial Resistance 2017-2021" (TNSAP). While public engagement sits at the heart of the TNSAP, Thai campaigns so far have predominantly focused on raising awareness through educational materials and events like the annual AMR Week, but less on patient and public involvement in shaping the national AMR response. In our project, we will bring together adult audiences (e.g. patients, consumers, young professionals), non-governmental organisation representatives, AMR researchers and national policy makers to co-create an AMR stakeholder map, an AMR engagement strategy, and context-specific solutions to reduce the burden of AMR. The project will be implemented over 18 months, employing Wellcome’s Responsive Dialogues approach to design and implement a combination of in-person regional Conversations and nation-wide virtual Conversations. Our main outcomes are (1) improved understanding and engagement with the issue of AMR among adult Thai communities (2) changes in the national AMR policy to include context-specific solutions and (3) improved understanding about the implementation of Wellcome’s ‘Responsive Dialogues’ toolkit in Thailand. Our project will be integrated into the activities implemented within the current TNSAP and inform the next TNSAP .
|
| 30/09/2020 |
£498,326 |
NEUROCENTRX PHARMA LTD |
Neurocentrx has developed oral capsule formulations of Ketamine, aiming to be new treatments for Depression. Ketamine is a synthetic drug created in the 1960’s. It is on the "essential medicine" list of the World Health Organisation (WHO), approved and licensed by health regulators worldwide as an injectable anaesthetic. More recently, and at sub-anaesthetic doses, clinical trials have shown that some patients with depression have a rapid response to injectable ketamine (hours or days). Most other anti-depressant medicines take many weeks to work. No oral ketamine products are currently available as a licensed medicine worldwide. Our project will assess oral capsules in healthy people in a clinical trial. We will assess absorption and excretion with increasing doses of drug and measure any side-effects. These data will be essential to accurately plan trials in depression patients where we will then look for benefits. Oral capsules could be used at home, and are hoped to be a cheaper treatment option, with fewer side-effects for patients. The summary above may be amended from time to time by mutual agreement of the Parties. For this clause agreement by email will be sufficient to render a valid amendment to the summary). |
| 30/09/2020 |
£398,043 |
THE BIOVAC INSTITUTE |
Group B Streptococcus (GBS) bacterial infection is a major health concern and a leading cause of sepsis and meningitis in infants, particularly in Africa. A promising prevention for GBS infection in newborns is maternal immunization with a GBS vaccine. Currently no vaccine for GBS is available. Several conjugate GBS vaccines using GBS surface-expressed polysaccharides linked to carrier proteins are under development. We are proposing a novel vaccine design using GBS polysaccharides conjugated to GBS conserved surface proteins which induce immune responses in infected individuals, making them potential candidates as carrier proteins for novel GBS vaccines. It combines two virulence factors of GBS with the potential to provide not only enhanced overall protection compared to traditional conjugate vaccines but also to potentially provide protection against those serotypes not included in the vaccine. It could lead to the development of an affordable and cost-effective vaccine that protects against all GBS serotypes. |
| 30/09/2020 |
£456,865 |
INTERNATIONAL VACCINE INSTITUTE |
Cholera is a disease of inequity that continues to disproportionately affect the world’s poorest and
most vulnerable people. An oral cholera vaccine (OCV) is available and in use around the world,
but it has lower efficacy in young children than in adults and a relatively short duration of protection
necessitating re-vaccination every few years. We are developing a new conjugate vaccine that
offers the promise of improved efficacy in all age groups, including those less than 5 years, and an
extended duration of protection, thus reducing the requirements for repetitive vaccination to sustain
population immunity. It can be implemented in place of OCV or as a complementary tool to prevent
or limit outbreaks in high risk settings, and build enduring population immunity that will costeffectively
control cholera over the decades required to build definitive public health capacities in at
risk countries. |
| 30/09/2020 |
£3,069,077 |
UNIVERSITY OF LIVERPOOL |
Conventional evaluation of new medicines is not fast enough for a pandemic. Our aim is to accelerate this process, rapidly identifying which drugs are safe and potentially effective treatments for COVID-19. AGILE is an innovative, multi-arm, multi-dose, multi-stage Phase I/IIa Bayesian adaptive platform protocol to evaluate experimental COVID-19 therapies, and to funnel plausible candidates into large Phase IIb/III trials such as RECOVERY and SOLIDARITY. We will efficiently eliminate candidates with little or no prospect of clinical success.
AGILE will recruit COVID-19 patients into very early phase clinical studies, including first-in-human. The innovative design allows us to move seamlessly from first-in-human use to finding the optimal dose for COVID-19 patients. The trial is pragmatic (requiring only small numbers of patients), adaptive (so that the right drug is tested in the right group of COVID-19 patients, either in the community or in hospital) and statistically efficient (so that several drugs can be tested in parallel, making best use of a small number of patients). Our primary focus is population-scalable antiviral drugs for early treatment of COVID-19, for which we will recruit primarily in the community. AGILE has full regulatory and ethics approvals in the UK.
|
| 30/09/2020 |
£402,298 |
UNIVERSITY OF DUNDEE |
The pathogenic bacterium Group A Streptococcus (GAS) causes a range of infections, ranging from mild tonsillitis to invasive necrotising fasciitis, sepsis and toxic shock syndrome. GAS also induces severe long-lasting autoimmune disease, including rheumatic heart disease. Annually, GAS infections kill > 500,000 people worldwide. While antibiotics are considered a reliable first line of defence against GAS infections, globally emerging antimicrobial resistance is an enormous threat. The WHO has included GAS in its vaccine priority list to finally reduce the high mortality and morbidity. We will use our developed novel modular system to produce the first dual-acting and lowcost GAS vaccine candidates targeting all > 150 GAS strains. Our approach provides the first robust and affordable solution to target and prevent GAS infections, urgently required for the global population and in particular the people in low-income countries. |
| 30/09/2020 |
£1,130,853 |
UNIVERSITY OF GOTHENBURG |
"The Project aims at completion of the preclinical development of a new, improved oral cholera vaccine (OCV), DuoChol. This is a proposed thermostable OCV consisting of a lyophilized mixture of formalin-killed V. cholerae O1 Ogawa and Inaba strain whole-cells and cholera toxin B-subunit (rCTB) formulated in an enterocoated capsule. The two strains are isogenic except for the single serotype determining wbeT gene, and this allows them to be co-cultured to high density, which together with inexpensive high-yield rCTB production ensures low-cost manufacturing. The Project will build a solid platform for the subsequent clinical development of DuoChol, whose affordable cost, practical formulation and higher efficacy compared with current OCVs will make this a very attractive OCV for use in national cholera control programs and ideal for use in cholera outbreaks where rapid deployment and maximal early efficacy is of the essence. |
| 30/09/2020 |
£347,602 |
KING'S COLLEGE LONDON |
Responses to psychological interventions for anxiety vary greatly. Clients and clinicians want better ways to predict outcomes. One contender is fear extinction, the process through which exposure, the "behavioural" part of Cognitive Behavioural Therapy (CBT) is thought to work. Whilst there are robust differences in fear extinction between individuals with anxiety disorders versus controls, evidence that extinction predicts CBT response is modest.
We first became interested in fear extinction as a mechanistic tool to help understand how CBT works. In order to build algorithms from numerous potential predictors, including fear extinction, we needed to undertake fear conditioning at a scale. We developed a smartphone App FLARe, that remotely delivers a fear conditioning paradigm. Our validation studies showed that fear extinction data from our App mirror that from gold-standard in-lab delivery.
We now want to test the extent to which App-delivered fear extinction data predicts CBT response. We will assess young adults with high anxiety using our App before enrolling them in CBT. We will test the strength of correlation between fear extinction and treatment outcome. We will also explore the extent to which this association is stronger in specific sub-groups (e.g. those who completed more exposure homework during treatment).
|
| 30/09/2020 |
£765,283 |
UNIVERSITY OF OXFORD |
This study aims to address the following questions through a global network of hospitals:
Is there evidence for a reduction in the total number or rates (per 1,000 inpatients) of blood cultures taken over twelve months?
Has there been changes in antimicrobial usage (quantitative and qualitative)?
Are there major changes in antibiotic resistance profiles from major pathogens?
Have there been changes in antimicrobial stewardship and why?
What is the overall change in the management of these patients?
What is the impact of COVID-19 on infection control practices during the pandemic?
Is there any evidence of reduction in nosocomial infections and bacterial outbreaks during the COVID-19 pandemic?
We will collect clinical (patient-based [severe pneumonia, ARDS, sepsis patients], hospital and microbiological data from 11 countries (UK, Switzerland, Italy, Brazil, Nigeria, Malawi, Turkey, Iran, India, Bangladesh and South Korea).
Our primary outcome will be to determine if there has been a reduction in blood cultures taken. Secondary outcomes include whether 1. changes in antimicrobial usage 2. major changes in antibiotic resistance profiles from major pathogens in hospitals during COVID-19 and correlate resistance profiles with antibiotic usage. 3. changes in infection control practices and other aspects of sepsis management behaviour during the COVID-19 pandemic.
|
| 30/09/2020 |
£48,135 |
ADDIS ABABA UNIVERSITY |
This proposal outlines the establishment of a pilot Unit for Health Evidence and Policy within CDT-Africa, a World Bank African Centre for Excellence based at Addis Ababa University, Ethiopia. Building on strong operational research into Neglected Tropical Diseases, and existing relationships within Ethiopia’s Ministry of Health, the Unit for Health Policy and Evidence will identify challenges to research uptake, pilot and evaluate an approach to improving research uptake, and produce a framework to guide future research uptake in this setting and possibly more broadly.
The pilot Unit for Health Policy and Evidence will be a 12-month project, divided into two Periods. Period 1 will comprise stakeholder consultation through two Theory of Change workshops and other interviews as necessary. During Period 2, research uptake in an NTD area defined in Period 1 will be evaluated using the Diversity Approach (see below). A Research Uptake Framework will be developed and a dissemination workshop held with key national and international stakeholders.
|
| 30/09/2020 |
£1,495,762 |
UNIVERSITY OF OXFORD |
While the first wave of COVID-19 is passing, we have yet to identify effective treatments. Most treatments have been used late in the illness. There is a pressing need to identify treatments delivered in community settings that avoid hospital admission. Novel immunomodulatory treatments have a well understood safety profile but are not suitable for studies such as Principle which rely on remote assessment. Hospital at home is a developing networ; teams of consultant physicians and nurses deliver high intensity care in community settings, commonly using point of care diagnostics. This provides a suitable framework for evaluation of novel therapies. This approach has parallels with healthcare systems employed in low and middle income countries and so the results will directly inform the delivery of interventions in these settings.
Multiple strands of evidence identify TNFa as an important mediator of the hyperinflammatory state that is associated with poor outcome. Early intervention with anti-TNF therapy has the potential to substantially mitigate its effects and improve outcomes. Adalimumab is an established subcutaneous anti-TNF therapy. We propose a randomised dose ranging study in community settings to establish whether it can mitigate progression to respiratory failure (requirement for oxygen, non invasive and invasive ventilation) or death.
|
| 30/09/2020 |
£120,585 |
UNIVERSITY OF BRISTOL |
Our objective is to provide an efficient coordinating body ("secretariat") for the continued development, deployment, collection and analysis of a shared COVID-19 questionnaire across UK cohorts.
The value of undertaking this in multiple longitudinal UK cohorts is that data can be collected in extremely well characterised members of the population across a wide demographic range who are already engaged in research, who have had data and biological samples collected on them, who have an established collection of record linked data already record linked and who sit behind supported infrastructure able to undertake novel data collection and research. Each of these cohorts is research active and collectively offers a depth or domain expertise not available within any one cohort, including that of UK Biobank. In this first coordination of COVID-19 research in deeply characterised UK cohorts, we identified the added value of a core questionnaire prospectively aligned to capture data pertinent to understanding COVID-19, as well as the direct and indirect consequences of the pandemic on health, wellbeing, social and economic outcomes.
|
| 30/09/2020 |
£504,745 |
UNIVERSITY OF OXFORD |
Ischaemic heart disease remains a major cause of disability and death world-wide. When a
major blood vessel in the heart suddenly becomes blocked, the muscle that it supplies dies
and is replaced with scar tissue. This is what happens in a heart attack. The scarred heart
no longer pumps blood properly and 40% of patients who develop heart failure die within 5
years. There is currently no treatment to help make new heart muscle after a heart attack.
We have identified a protein already present in the body, a single injection of which within a
few hours after injury can dramatically improve heart function by limiting damage and
promoting repair. We will now engineer this protein molecule to retain only the regenerative
properties, whilst eliminating potential unwanted effects. We anticipate the engineered
product to be safe, limit the damage after a heart attack and also promote regeneration of
heart muscle. |
| 30/09/2020 |
£498,656 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
As COVID-19 lacks a definitive treatment, critical care is the primary therapeutic means for
reducing mortality. How the world effectively scales up critical care will be a fundamental
determinant of the overall impact of the pandemic. Advanced critical care may be difficult or
impossible to scale-up in many settings and instead, essential, life-saving treatments should
be provided to all who need. Essential Emergency and Critical Care (EECC) is the basic,
low-cost care required by critically ill patients, such as oxygen and intravenous fluids, and
the system-wide requirements for their provision. The project will assess the costeffectiveness
of EECC and advanced critical care in Tanzania and Kenya, and analyse the
impact of the global and national response strategies to COVID-19 on critical care services.
The project aims to guide COVID-19 responses in LMICs towards scalable strategies with
the greatest potential for increased survival of critically ill patients, both in the pandemic and
beyond. |
| 30/09/2020 |
£248,385 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
The diminishing effectiveness of antimicrobials is a public health challenge of major global importance. In the Global South, where health systems are weaker and the burden of severe bacterial infection greater, the impact is already being acutely felt. In Malawi, a Ministerial AMR Unit has been established to coordinate Malawi’s response, culminating in a National Action Plan. However, the implementation of the Action Plan needs key stakeholders – including affected community members – to develop and implement interventions. This project will undertake facilitated dialogues with stakeholders in two different contexts: rural Chikwawa and urban Blantyre. Through four Responsive Dialogues events per area, participants from national, district and community levels will share their understandings, experiences and perspectives on AMR, leading to the co-creation of concrete policy asks and actions. Conversations will be carefully designed and facilitated to enable evidence about AMR to be shared, understood and used to generate ideas, as well as to inform policies governing how AMR is addressed. Through this approach the project will work closely with the AMR unit to cocreate local actions, that communities themselves can carry out to reduce the burden of AMR as well as policies and interventions that reflect people’s lived realities.
|
| 30/09/2020 |
£50,000 |
UNIVERSITY OF OXFORD |
There is a need to build capacity and improve evidence-informed decision-making concerning resource allocation and priority-setting in health in low- and middle-income countries, such as Laos. This kind of capacity building and institutional strengthening is all the more important in an era of aid transitions and uncertainty related to the current COVID-19 pandemic, to enable Laos to continue progressing towards Universal Health Coverage.
We propose the creation of a Unit for Health Evidence and Policy (UHEP) based in the University of Health Sciences in Vientiane, to enhance the use of research evidence to inform policy. UHEP will focus on health technology assessment (HTA) as a tool to enable priority-setting.
We aim to complete four main activities for this pilot project over one year.
Situational analysis of the Lao health policy context including stakeholder mapping
Training of Lao researchers and policy makers in HTA and on synthesis and use of research evidence (includes funding for one MSc student)
Development of a roadmap for institutionalisation of rational priority setting in health policy development in Laos
Selection and implementation of a pilot HTA project
At the end of this year UHEP will be established as a government technical partner for HTA in Laos
|
| 30/09/2020 |
£22,524 |
OPEN ACCESS SCHOLARLY PUBLISHERS ASSOCIATION (OASPA) |
Throughout 2020, a project is run to prepare for the OA Switchboard (a collaboratively developed and community run open source solution) to go live as an operational solution. The OA Switchboard provides essential infrastructure and back office services to facilitate the fulfilment of open access strategies across business models, policies and agreements via: 1. communication standards (‘metadata’); 2. technical solutions (‘hub’); 3. standardised real-time monitoring and reporting.
The essence of the problems it aims to address as a priority:
It is complicated/cumbersome to find out how to get the service charges for a certain OA publication settled, and to prepare for (enable) such financial settlement
It is a challenge to monitor funds and track spending in real time
In the current situation, enabling open access to scholarship has never been more pressing. Supporting the OA Switchboard is investing in open source infrastructure that will ensure that transformational change to open access can be achieved by all publishers, whilst reducing complexity for funders, institutions and researchers. It will also work alongside and strengthen other initiatives that the Wellcome Trust is supporting in this space, specifically in realising the synergies of interlinking the Journal Checker Tool and the OA Switchboard.
|
| 30/09/2020 |
£222,683 |
UNIVERSITY OF OXFORD |
Meat Your Persona will further the public’s understanding of the connection between their meat consumption and its environmental and health impacts and will empower them with accessible information and tools to make better informed choices about their consumption.
Building on the successful pilot (https://www.youtube.com/watch?v=QbHb4ap39nw), we propose a national tour, taking Meat Your Persona to audiences at urban and suburban shopping centres and community hubs. Our goal is to reach those with low science capital who are disconnected from the current conversation. In particular we will target Brexit-voting men outside London who are the most likely to eat the most meat and to not connect meat consumption with health and environmental impacts.
We will capitalise on renewed public interest in evidence, using creative design methods to convey key facts from the LEAP research so that people are able to make better informed choices. We will actively signpost people to a purpose-built website where they can receive evidence-based support to reduce their meat consumption. The project will be evaluated independently to see if we have achieved our three goals: to drive behaviour change, build public trust in science and inform research through advancing the public conversation.
|
| 30/09/2020 |
£800,000 |
GLOBAL POVERTY PROJECT INC |
Global Citizen and the European Commission ran a campaign, Global Goal: Unite for Our Future, with the aim of ensuring that everywhere in the world, those who need them have access to COVID-19 tests, treatments, and vaccines. The campaign also sought to lessen the impact of COVID-19 on the world’s most vulnerable people, ensuring they still have access to education, clean water, and more.
The campaign, launched under the patronage of European Commission President Ursula von der Leyen, focused on the development of tools to tackle COVID-19, and ensuring that these tools are available to all communities equally, as well as mitigating the impacts of COVID-19 on those living in poverty. |
| 30/09/2020 |
£283,840 |
UNIVERSITY OF OXFORD |
With this proposal we seek to establish a global community of bioethicists (to be known as 'Epidemics Ethics') combined with a range of online resources and activities together capable of providing real-time, contextually appropriate support to assist researchers, policy-makers, communities, and responders in identifying, analysing and addressing ethical issues arising in the context of global health emergencies. Epidemics Ethics will complement the newly established Public Health Emergency Preparedness and Response Ethics Network (PHEPREN) by providing: timely responses to ethical problems, access to networks of experts, an array of online resources including seminars, workshops, blogs, and ethics briefings on issues of current concern. A key aim of Epidemics Ethics will be to support the establishment of fair, collaborative partnerships to enable ethics research to be conducted by ethics scholars in low and middle-income countries in the context of broader supportive international collaborations. With this in mind, capacity building will be a key focus.
|
| 30/09/2020 |
£324,364 |
EUROPEAN BIOINFORMATICS INSTITUTE |
In this pandemic, researchers have responded by publishing results rapidly, often through preprints. In fact, about half of the publications in Europe PMC on COVID-19 are preprints rather than peer-reviewed journal articles. Currently, the full text of these preprints are scattered as PDFs on preprint servers, or, available as a non-standard set of documents for machine learning purposes. This proposal is about making the full text of COVID-19 preprints available on Europe PMC, a large and sustainable life sciences archive, for reading and reuse via a standard XML format, alongside peer-reviewed full text articles. Being able to easily search and read preprint full text on a site already frequented by millions of users a month, means that they will be significantly more discoverable by people, and will be able to make use of existing infrastructure to integrate into the typical ecosystem of publications - for example, linking to related data - as well as being more open to scrutiny. This will accelerate scientific research on COVID-19, provide an opportunity to build new open and rapid publication systems, and form a corpus for future history of science research.
|
| 30/09/2020 |
£198,817 |
JOHNS HOPKINS UNIVERSITY |
With the rapid development of candidate vaccines for COVID-19, this project will identify and provide guidance on a range ethical issues arising in the development and deployment of COVID-19 vaccines. Over the next six months, the COVER project will concentrate on the ethics of vaccine research and development—including phase 3 trial design and equitable inclusion of special populations in the research agenda, with a particular focus on pregnant women as well as population groups that have or likely will experience disproportionate burden from COVID-19. This project will also conduct formative landscaping work on the ethical challenges and tradeoffs in the allocation and deployment of vaccines, both globally and within nations. This work will lay the groundwork for normative guidance and mathematical models to best inform policymaking once efficacious vaccines become available for wider use, with explicit consideration and assessment of how various approaches will not only impact the trajectory of the COVID-19 pandemic overall, but also how the benefits of vaccination will be fairly distributed across different population subgroups. In addition, the COVER project will begin to address ethical issues of COVID-19 vaccine development and deployment specific to Africa, with a concentrated body of work in Nigeria.
|
| 30/09/2020 |
£233,652 |
C40 CITIES |
While prior national level and regional studies have evaluated the contribution of coal combustion on air quality-related health impacts at the national or regional level, a concrete understanding of how coal combustion impacts urban populations can make a strong case for the rapid phase-out of coal-fired electricity generation in cities around the world.
Project aims:
(1) demonstrate a strong urban case for a rapid-phase out of coal-fired electricity generation; and (2) utilise the research results for an effective advocacy and communications campaign at COP26. In the research project, C40 will estimate the contribution of coal combustion for C40 city electricity generation to global GHG emissions, to air quality-related health burdens in C40 cities, to COVID-19-related health impacts as well as analyse the economic benefits of different coal phase-out scenarios by looking at: (1) the economic value of improved health associated with reduced coal combustion for electricity generation in C40 cities; and (2) the number of net jobs that are generated with a switch from coal combustion to clean energy.
|
| 30/09/2020 |
£602,803 |
THE UNITED NATIONS FOUNDATION |
Global action to tackle AMR is insufficient because public engagement on AMR is limited[1]. CGD[2] can help close this gap and help communities and decision-makers take collective action on AMR.
This project will apply CGD methods in three Kenyan counties over 14 months to empower communities, health-workers, researchers and policymakers to generate and use data on AMR. A robust scoping phase will involve stakeholder consultations to tailor CGD methods and engagement mechanisms to the local contexts. The project will have three tracks:
Data to Empower: engaging citizens to better understand AMR related behavior and perceptions, and empowering citizens with objective and contextually relevant information
Data to Give Direction: using CGD to empower citizens to change behaviors, fill evidence gaps for the research community, and support health policy decision-making,
Advocacy on CGD: encouraging researchers and policymakers to incorporate CGD as an important source of evidence for more holistic AMR policies
[1] https://wellcome.ac.uk/reports/reframing-antimicrobial-resistance-antibiotic-resistance
[2] CGD is ‘data that people or their organisations produce to directly monitor, demand or drive change on issues that affect them. It is actively given by citizens, providing direct representations of their perspectives and an alternative to datasets collected by governments or international institutions’
|
| 30/09/2020 |
£245,691 |
UNIVERSITY OF OXFORD |
This project will undertake large scale data linkage between critical and primary care and
Public Health England to investigate the effects of routine medications and patient
comorbidities on the outcomes from COVID-19 disease.
Assessing the effects of routine medications on COVID-19 disease is important for two
reasons. Firstly, some medications have been suggested to make the disease worse. As a
result, patients and clinicians are unclear about whether they should be continued. Secondly,
some routine drugs may treat or lessen the effects of infection. Establishing whether peopleon particular drugs are less likely to get severe infection will help researchers find treatments
for the disease.
Identifying what types of patient are prone to get severe disease and how long term conditions
affect outcomes will help provide advice and target interventions to the right people.
Undertaking these objectives will allow us to develop a platform linking all the patients in the
primary care database to all the Public Health England COVID-19 tests undertaken and all the
patients admitted to an Intensive Care Unit. This platform will allow detailed assessment of the
course of patients during the COVID-19 outbreak, including assessment of the effects on health
for patients without COVID-19 disease.
This platform will also enable studies investigating health, medication and health resource use
before and after critical illness, accelerating development of a long term rich research resource. |
| 30/09/2020 |
£57,800 |
NHS CONFEDERATION |
Make a clear case for and facilitate UK involvement in the joint action with UK and EU stakeholders.
Act as a secretariat to support the UK partner in the joint action.
Prepare contingency plans for maintaining an influence in the absence of UK representation in the Joint Action.
Gather a body of evidence of NHS and UK expertise on data processing in the health sector to contribute to the European Code of Conduct
Maintain regular updates and briefings on the scope and objectives of the GPDR code of conduct, to maximise UK preparedness.
Follow progress of Europe’s data strategy, the European health data space and the development of a legislative proposal on Artificial Intelligence, using the same UK stakeholder group to feed in expertise where possible and provide intelligence and updates on possible implications for the health sector.
|
| 30/09/2020 |
£77,068 |
UNIVERSITY OF OXFORD |
This proposal will address the intersection of mental health and Equality, Diversity & Inclusion (EDI) within Oxford’s three Wellcome Centres. Mental health concerns permeate a broad range of challenges relevant to EDI, including social exclusion, chronic illness and disability, and minoritised populations (detailed below) that are disproportionately affected by mental ill-health.
By identifying specific mental health challenges that different groups face, we can improve equality. Through normalisation of discussions around mental health in the workplace, and building an appreciation for how these issues affect people differently, we foster inclusion. If we can recruit and retain a broader range of researchers further into their careers, we improve diversity, and therefore our science. An increasingly inclusive, fair and kind research culture will lower the risk of mental ill-health for all our team and staff members within the high-impact but high-pressure academic environment.
Our specific objectives are to:
(i) Conduct an in-depth, expert review of mental health as it relates to EDI within our Centre work environments.
(ii) Implement recommendations arising from this review relating to policies, communication and practices.
(iii) Build a broad, cross-Centre programme promoting positive research change around mental health and EDI.
|
| 30/09/2020 |
£155,243 |
REX LIFE SCIENCES LLC |
Starting February 2017, the insight from a significant amount of the Wellcome Trust-supported Expert-in-Residence work done by the applicant in support of the R & D efforts of the AMR community has been translated into a newsletter and a mirroring blogpost website. This content has come from attending key meetings (Dr. Rex is often asked to present, chair, and/or serve on program committees), authoring papers, and engagement (ad hoc email, TCs, and/or face-to-face meetings with key members of the developer community.
Wellcome Trust supported this work 2017-2019 through hourly billing and expense reimbursement. It is now proposed this support be converted to a fixed-term grant with consideration of the possibility of extensions of the grant if / as the DRI program progresses
The grant funds would be used to transformation and grow the project in 3 ways:
Website upgrade for improved analytics and visual quality.
Audience growth beyond R & D to the disciplines as finance, corporate leadership, and media relations, all of whom are key to success in this area.
Social media outreach by maintaining the core USP while making use of Twitter, Facebook, Instagram, and LinkedIn to reach more deeply into the audience of those working in antibiotic R & D.
|
| 30/09/2020 |
£327,745 |
INTERCHANGE RESEARCH LIMITED |
The Wellcome Trust 2019 PhD Programmes Call had two central criteria: scientific excellence and positive research culture. The call was unusual in the relative weight given to each of these criteria, and the open-ness to different understandings of research culture. It is important to understand the impacts of this intervention on the part of a major funder into research training. The aim of this study is to gain insights into the impact of this intervention, and into the development and implementation of measures to improve research culture. The study embraces the emergent nature of understandings of positive research that has distinguished this call from the outset. It adopts a dual approach: firstly it will support the formation of a community of practice, consisting of the funded programmes and the Wellcome Trust, as equal members; and secondly it will use the methods of participant action research to support iterative and reflective processes for understanding what positive research culture consists in, and what constitutes best practice. This dual approach serves as a framework for active observation, in which the lessons learned by the community of practice can be articulated and shared with other stakeholders, in the form of reports and publications.
|
| 30/09/2020 |
£207,999 |
YOUNG FOUNDATION |
This landmark research aims to understand in real time, and longitudinally, how Covid-19 is changing people’s experience of community and levels of social protection in society.
It will specifically focus on the ways in which:
Covid-19 is affecting and shaping the interactions between individuals in society and the effect on health, wellbeing, resilience, quality of life, and community
digital is playing a role in community responses to the virus
different measures to mitigate the virus changes the experience of community in a time of crisis
individuals and communities relate to science, research and its role with respect to Covid-19
The aim of this project is to collect real-time information to inform policy makers and practitioners about how communities are responding to the pandemic, public health measures and other mitigation measures. It will also generate early insight into the potential longer-term impacts on both individuals’ mental health and community wellbeing.
To understand how communities are experiencing Covid-19 across the UK, we will conduct a quantitative study with a nationally representative sample across the four nations. This will be supplemented by innovative digital ethnographic research which generates in-depth real time insight into the experiences of a diverse group of 100 adults.
|
| 30/09/2020 |
£955,118 |
UNIVERSITY OF MINNESOTA |
The CIDRAP Antimicrobial Stewardship Project (CIDRAP-ASP) was launched in July 2016 with the
goal of building an online international community focused on antimicrobial stewardship through
various platforms and with content and ASP tools applicable to high, middle and low income
countries. CIDRAP-ASP has offered freely available, high-quality information and educational
resources on antimicrobial stewardship practice, research, and policy. It features a dynamic,
content-rich website designed to engage a diverse, international audience. This project capitalizes
on CIDRAP’s existing internationally recognized expertise, infectious disease news and information
system, website infrastructure, and strong national and international audiences.
Through our partnerships with subject matter experts, we provide a wealth of diverse resources for
practitioners across the spectrum of human, animal, and environmental health to support their
ability to provide optimal care. CIDRAP-ASP generates deep, rich original content and aggregates
the most useful information from diverse perspectives and expertise.
CIDRAP-ASP occupies a unique niche in the ecosystem of projects addressing antimicrobial
resistance and stewardship because of the diversity of resources to which it provides access, and
the research and integrity with which it approaches nuanced and sometimes controversial topics.
|
| 30/09/2020 |
£142,915 |
UNIVERSITY OF OXFORD |
Findings from health research should be translated into recommendations that can be implemented within policy and practice if research is to deliver its maximum impact and ability to change health outcomes. Currently research ‘success’ typically concludes with the publishing of papers in high impact journals with less attention to how, and indeed whether, those findings are made visible and accessible to those tasked with decision making that should be changing their practice on the basis of these new findings. Compounding this is the current difficulty for these practice and policy decision-makers to easily be made aware, find, access and synthesise new research recommendations. The Global Health Network seeks to address this by bringing researchers and decision makers together to find new tools and mechanisms for researchers to present their outcomes as recommendations that can be readily discoverable and put into practice. This proposal will firstly, establish a community of practice for researchers and decision-makers to share knowledge and develop resources, processes and mechanisms that can support turning results into discoverable, practical and usable recommendations. Secondly, to deliver an advanced digital database which enables rapid synthesis of the available research recommendations to drive improvements in uptake.
|
| 30/09/2020 |
£349,617 |
SURGICAL SYSTEMS RESEARCH GROUP |
To respond to the COVID19 pandemic, we will be deploying community health workers, equipped with mobile technology, and accompanied by youth to visit households door to door to screen for symptoms of COVID19, isolate, test, and manage suspected cases of COVID19. The community health workers and youth will educate households about preventive measures including frequent handwashing and home management of mild cases. Simultaneously, we will work with nurses, doctors, and clinical officers, to test and treat more severe cases of COVID19 in health facilities. Our goals are to visit every household in Siaya county covering a population of close to 1 million, and to train and support health workers working in the 32 health facilities in Siaya." |
| 30/09/2020 |
£249,200 |
FIRST DRAFT |
This project will ensure as many people as possible have access to straightforward, clear information, that quickly responds to the questions and confusion people have about the coronavirus and the ways in which it is impacting their own lives and those they love. In order to reach millions of people around the world, the project will create high quality, embeddable content that newsrooms, platforms, health authorities, government bodies can all share with their audiences. It will also galvanise engaged citizens, who want to help, by creating an 'army' of 'Information Volunteers' who can take the same content and push it out to their own networks, whether that's via WhatsApp groups, Facebook communities, or family email chains. This crisis has demonstrated that there is no time or resource for duplication. By sharing efforts to monitor trending misinformation, collect real-time questions and areas of confusion from the public, and centralizing the output of shareable 'cards' that respond to these rumours and questions, it will help over-stretched newsrooms and communication departments, and provide concerned citizens with a role to play during a time where they want to help their communities.
|
| 30/09/2020 |
£411,826 |
UNIVERSITY COLLEGE LONDON |
This proposal is for the establishment of an international mental health research network for Covid-19 and the running of a UK mixed-methods mental health study.
The proposed network will have three core aims:
To support the establishment of high-quality longitudinal studies in countries internationally exploring the effects of Covid-19 on mental health
To enable international collaboration in longitudinal data analysis to understand cross-cultural differences in the mental health effects of Covid-19
To catalogue and disseminate other quantitative and qualitative mental health research on Covid-19
We will also lead a large-scale UK concurrent mixed methods study comprising a longitudinal study and a qualitative interview study to provide high quality, rigorous scientific data on the mental health impact of Covid-19 in the UK. This study is already underway and has 5 core aims:
To understand the psychological and social impact of Covid-19
To map how the psychosocial impact evolves over time as social isolation measures get stricter and once measures are relaxed
To ascertain which groups are at greatest risk of adverse effects on their mental health
To explore the interaction between psychosocial impact and adherence to healthy and protective behaviours
To identify activities during isolation that could buffer against adverse effects
|
| 30/09/2020 |
£1,000,000 |
INSTITUT PASTEUR DE DAKAR |
The African Union, Africa CDC, in collaboration with WHO on Febraury 22nd, 2020 convened an emergency meeting of all 55 ministers of health to discuss the COVID-19 pandemic. At the end of the meeting, they agreed on a continent-wide strategy for COVID-19 that will allow for greater coordination, collaboration, cooperation and communication. The strategy focuses on six major technical areas and is implemented through and endorsed Africa Coronavirus Task Force (AFCOR). As of 15 March 2020, over 26 countries have reported greater than 250 cases. In Africa, the primary strategy for COVID-19, therefore, is based on limiting transmission and minimizing harm. Delaying and diminishing the peak of outbreaks can help health systems better manage the surge of patients and communities better adapt to the disruption of social, cultural, and economic activities. In order to compliment WHO’s efforts to respond to COVID-19, Africa CDC is uniquely positioned to support Member States through its presence within the African Union, the highest political body in Africa, and its five Regional Collaborating Centers. The primary challenge now is executing these tactics in a continent that is large, diverse, and at high risk of social and economic disruption from a pandemic.
|
| 30/09/2020 |
£147,311 |
AFRICAN INSTITUTE FOR DEVELOPMENT POLICY |
Enhance DELTAS is a programme led by the African Institute for Development Policy (AFIDEP) to provide research uptake and policy engagement support to awardees of the Developing Excellence in Leadership, Training and Science (DELTAS) Africa initiative, led by the African Academy of Sciences. Enhance DELTAS will work with the first and second DELTAS Africa programmes to develop the capacity of individuals, support DELTAS institutions in creating enabling environments for policy engagement and research uptake, facilitate interaction between researchers and policymakers, and contribute to the field of Evidence Informed Decision-Making through peer reviewed publications. The programme will use face-to-face workshops, online self-learning materials including videos, interactive webinars, toolkits, and talks by policymakers. The programme will be underpinned by a robust monitoring, evaluation, and learning framework so that the programme can be continually improved, the changes as a result of the programme can be assessed, and the knowledge from implementing the programme can be shared with the EIDM community.
|
| 30/09/2020 |
£548,031 |
AFRICAN ACADEMY OF SCIENCES |
Success against the Covid-19 pandemic requires a transdisciplinary approach incorporating social sciences and humanities, economic research and health systems research. It also requires access to funding. The African Academy of Sciences (AAS), through its hosted AESA Platform, acts as Secretariat for this Fund for Covid-19 R & D priorities in Africa. This Fund is seeking proposals against identified priorities; coordinating a network of researchers working on Covid-19 R & D to build a clinical research and trials platform for Africa; and taking a longer-term view to address pandemic preparedness in research actions.
The Fund is open to multiple priority areas for research and development, including:
Epidemiological studies
Studies to define disease severity and susceptibility of particularly groups at high risk of severe infection; the role of different age groups in transmission; the impact of control and mitigation measures; and to predict the most effective interventions.
Clinical management
Studies to define the natural history of Covid-19 infection including the identification of prognostic factors for severe disease and the identification of vulnerable groups; and studies to improve the clinical outcome of Covid-19, including strategies to improve the processes of care.
Infection prevention and control
Studies to assess the effectiveness, in both healthcare and community settings, of movement control strategies in preventing secondary transmission and of personal protective equipment in reducing the risk of transmission.
Candidate vaccines, diagnostics and therapeutics
Clinical trials of potential treatments and preventative strategies, facilitated by the recent AESA programme launched as the Clinical Trials Community online platform.
Ethical considerations for research
Studies on culturally appropriate approaches to the ethical, social and legal issues prevalent in emergency situations, such as presented by Covid-19.
Social sciences in a pandemic response
Engagement to bring community voices to decision-making processes, to understand non-intended consequences of pandemic-control decisions and to understand contextual vulnerability; and studies to mitigate impacts of the socio-economic and political externalities of Covid-19. |
| 30/09/2020 |
£4,916,005 |
OXITEC LIMITED |
Human diseases that are transmitted by the Aedes genus of mosquitoes are
increasing rapidly, diseases such as Zika, dengue, chikungunya and yellow fever.
Recent estimates suggest that today around half the world’s population are at daily
risk of infection, the vast majority by a single mosquito species, Aedes aegypti.
Oxitec’s have developed a ground-breaking biological approach to control this vector
using safe, non-biting male mosquitoes ("OX5034-E"). Our male-only mosquitoes
carry a self-limiting gene, which means that when they mate with wild females,
offspring inherit a copy of this gene that prevents females from surviving to
adulthood. The genetic mechanism that prevents females from surviving also enables
deployment of our safe, non-toxic, non-biting male Aedes aegypti via egg packets in
small recyclable boxes filled with water.
This project will fund the final stages of tailoring Oxitec’s "just-add-water" vectorcontrol
device into a sustainable and scalable Aedes aegypti control solution. We
will be optimising the OX5034-E device and developing customised digital tools to
support the wide-spread deployment of this technology, particularly in low-income
communities that so often require it most.
The project’s three primary goals to accomplish this are:
- Developing new methods for scalable and rapid deployment of OX5034-E
devices in dengue-prone settings.
- Demonstrating OX5034-E’s ability to integrate with traditional Aedes aegypti
control programs used by resource-limited governments and communities.
- Completing the supporting online and mobile platform to help future end-users
manage the planning and deployment of OX5034-E.
We will provide immediate benefits by delivering a two-year Aedes control program
in a dengue-impacted city in Brazil, but importantly our project is destined to deliver
impact at a global scale. In the years to come we anticipate saving thousands of lives,
and positively impacting the livelihoods of many millions of people who currently live
under the near constant threat of this invasive and dangerous vector. |
| 30/09/2020 |
£1,001,596 |
EAT FOUNDATION |
Summary
EAT is pleased to submit this request for a continuation of Wellcome’s support for EAT knowledge engagement and communications activities. A critical assessment of the economics of food and land used systems was identified as a critical knowledge gap to further progress on transitions to healthy and sustainable food and land use system. In collaboration with SISTEMIQ, FOLU, and PIK, we are pleased to share our comprehensive proposal for the Food System Economics Commission building on the foundational work of the EAT-Lancet Commission, and FOLU’s Growing Better report.
Second, while EAT has had to cancel the 2020 version of the EAT Stockholm Food Forum, the Communications team has very rapidly pivoted and begun to develop an online version of the Forum, EAT at Home. This virtual forum is a multi-month digital food festival experience, designed to spotlight leading science, planetary health chefs, business solutions, dynamic dialogs and debates, cooking demos and more in an interactive and accessible format that will build and continue momentum on food transition, while greatly increasing the diversity of voices that EAT is able to feature and engage.
Third, EAT thanks Wellcome for its continued support, including to core institutional functions.
|
| 30/09/2020 |
£2,158,322 |
UNIVERSITY OF OXFORD |
This study will: assess the change of medium-term efficacy of the new Typhoid Conju-gate Vaccine (TCV) in children, by comparing the relative risk of typhoid in those initially vaccinated in 2017/2018 with later cohorts vaccinated in 2020 and 2021; assess the de-cline in individual-level immunity 3-5 years after vaccination; measure ongoing popula-tion-level impact against typhoid fever in the community. The data collected will help identify correlates of medium-term protection; inform the need for, timing of and potential cost-effectiveness of adding booster doses to vaccine schedules; permit the develop-ment of a mathematical model to predict future impact of typhoid vaccination in two en-demic settings. |
| 30/09/2020 |
£55,300 |
ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE |
For Wellcome Trust to contribute to the established RSTMH small grants programme to enable those early in their careers to conduct small research projects into the topic of snakebite. Our small grants are awards of up to £5,000 including VAT and available to those early in their careers who are working in a field relevant to tropical medicine or global health e.g. doctors, nurses, academic researchers, NGO workers, health economists, social scientists. These grants typically represent the very first time someone has received funding in their own name, the first application form they have written, and the first time they have managed their own project,including a budget and reporting. The grant process is designed to be as straightforward as possible, for many applicants English is not often their first language. The application is made through our online portal and 2 referees, including their supervisor, must be provided. Snakebite is a topic of great importance to RSTMH given its high levels of death and disability. Though funding has increased in the topic there is a need to encourage early career interest and we feel the small grants present a way to do this, which is easy for Wellcome to benefit from.
|
| 30/09/2020 |
£21,115 |
WELLCOME TRUST/DBT INDIA ALLIANCE |
The DBT/Wellcome Trust India Alliance will shortly be organizing the first Conference for Indian Research Managers and Administrators (RMAs), as part of the ongoing India Research Management Initiative (IRMI). IRMI activities represent the foundational steps towards strengthening research ecosystems in India. The IRMI Annual Conference series is intended as a platform for Indian RMAs to share their work and perspectives with peers, for institutional and funder representatives to engage with the possibilities of Research Management in India, and for Indian RMAs to work together as a community of professionals. Work has begun on creating a structure for the 2020 Conference, which will include 60-80 RMAs, researchers and funder representatives from India. As the current pool of RMAs in India is small and relatively inexperienced, it will be beneficial to additionally include a small group of international RMAs, for presentations and interactions at the Conference. This is a request to the Wellcome Trust for funding the costs of attendance of international experts at the IRMI Annual Conference 2020.
|
| 30/09/2020 |
£2,636,462 |
UNIVERSITY OF CAMBRIDGE |
We previously proposed to generate a complete connectome for the adult male Drosophila central nervous system (CNS), comprising both brain and nerve cord. Capitalising on that investment, this discretionary award would allow us to deliver a second, high-quality, female connectome just one year later, at a fraction of the cost.
This would be the first full CNS connectome, bilaterally complete and with sensorimotor circuits intact, of an adult female animal with complex behaviours. It would immediately allow comparisons of neuronal number, morphology, and connectivity across 1) hemispheres (this animal), 2) sexes (with the male CNS), and 3) three same-sex individuals (with partial datasets FAFB and the hemibrain) and global estimates of intra-individual, inter-sex, and inter-individual variation.
The PIs will use this joint resource to investigate circuitry underlying sexually dimorphic behaviours such as decision-making (e.g., mating receptivity and egg-laying), aggression, sensory integration and descending control of motor programmes, memory formation and recall, and sleep. We will make both datasets available with a range of analytic tools for use by the > 200 labs studying Drosophila neurobiology worldwide. Moreover, we expect the technology and pipelines developed for obtaining and comparing these connectomes to facilitate future studies in other organisms, ultimately including humans.
|
| 30/09/2020 |
£52,000 |
JISC |
The core aim of this proposal is to further increase the number of transformative open access agreements in place with Society and smaller publishers to ensure that Wellcome Trust funded authors have maximum opportunity and ability to publish in compliance with the 2021 Wellcome Trust Open Access policy.
The proposal seeks funding for a one year extension to the negotiation and licensing activity currently led by licensing manager, Kathryn Spiller. This role is dedicated to achieving agreements that meet the requirements of Wellcome Trust's policy and targets the society publishers that over the last 3 years have received the most revenue via Wellcome Trust funding grants.
|
| 30/09/2020 |
£1,412,289 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
We propose a global Commission to quantify evidence for national, regional and global actions that will be positive for health, the environment and the economy. It will draw on knowledge generated by other initiatives where relevant but will fill a major gap that is not currently addressed, namely the focus on human health as well as decarbonising economies. This will require identifying and assessing policies, technologies and interventions across a range of sectors including transport, food systems, cities, energy, industry and health systems. The Commission will fill a number of knowledge gaps that are impeding progress towards a healthy zero-carbon economy – namely which actions will have the largest multiple benefits for health, the environment and prosperity in particular contexts, and which implementation strategies should be employed for effective scale-up.
In addition to synthesising and grading the evidence, the Commission will generate a framework for action in the form of practical guidelines targeted towards national and city governments, NGOs, civil society and the private sector. These guidelines will indicate how to assess which actions should be prioritised in particular contexts. It will also include a comprehensive influence strategy to be developed with partner organisations and a leading creative agency.
|
| 30/09/2020 |
£91,887 |
JAMAL EDWARDS DELVE |
Through workshops with mental health researchers, at our youth centres, young people will deconstruct hip-hop lyrics understanding how to link them to wider mental health issues and research. The project will focus on empowering young people to investigate mental health experiences in the community and gather evidence on the mechanisms others have relied on to overcome their struggles with the aim of reinforcing young people’s resilience and discovering, through peer-led research, accessible prosocial tools to combat deterioration in mental health.
|
| 30/09/2020 |
£1,899,321 |
MRC LABORATORY OF MOLECULAR BIOLOGY |
The ability to make any human genome would transform hypothesis driven investigations in diverse areas of biology, genetic-archaeology and biotechnologies. However, there are currently no technologies for building human genomes. Moreover, there is a technological void between the state of the art in the creation of synthetic genomes and what will be required to enable the synthesis of human genomes. The current challenge is therefore to bridge this void. The goal of this proposal is to bridge the technological void between the state of the art, which has enabled the synthesis of Mbp-scale microbial genomes, and the technologies that will be required to build a human genome, which is 3 orders of magnitude larger than any synthetic genome that has been created to date. We will establish key technologies for human genome synthesis and exemplify these technologies through the synthesis of a recoded human chromosome.
|
| 30/09/2020 |
£599,245 |
UNIVERSITY OF LIVERPOOL |
Invasive non-typhoidal
Salmonella (iNTS) is estimated to cause 535,000 illnesses, 77,500 deaths, and the loss of
4,263,500 disability-adjusted life years (DALY’s) every year, with 86.7% of the global burden
falling in sub-Saharan Africa (sSA). The proposed SAiNTS study will work with the EU-funded
Vacc-iNTS consortium, and will complete a comprehensive rural community-based seroepidemiological
study in a malarial area, measuring age-stratified exposure, susceptibility and
natural immunity to NTS, and leveraging multiple additional cohort datasets, with the
overarching goals of:
- Accelerating the clinical development of 3 new iNTS vaccines in early clinical
development through phase 1 and phase 2a immunogenicity studies
- Providing a model contributing to realistic assessments of the impact of iNTS
vaccination in varying epidemiological settings across Africa.
The SAiNTS study, accordingly, has the following specific aims:
Aim 1: Develop a regression model for age-dependant, naturally acquired immunity against
iNTS disease (alphaLPS-IgG antibody and SBA) and compare to the age-stratified incidence of
Salmonella enteric infections (eNTS).
Aim 2: Estimate a Correlate of Protection for invasive NTS, based on naturally acquired
antibody levels and known age-stratified disease incidence.
Aim 3: Assess the effect of different iNTS risk factors on the age-dependent acquisition of
natural immunity, and how they might impact on estimated correlates of protection and iNTS
vaccine impact in different scenarios. |
| 30/09/2020 |
£876,884 |
NEWCASTLE UNIVERSITY |
We propose to generate an in-depth single cell and spatial atlas of embryos during late organogenesis, at 6/7 post conception weeks (PCW). This project will form a blueprint for a complete HCA development cell atlas, which will ultimately cover all accessible developmental stages week by week. We will leverage genomics technologies to profile single cells from dissociated tissues and within intact tissue sections, and deploy cutting-edge computational methods to reconstruct, in silico, a three-dimensional atlas of the whole human embryo. This work will significantly extend our existing WSSS-funded Development Cell Atlas research programme, which is focused on organ-based profiling. Our reconstruction of a complete human embryo atlas will provide a blueprint for establishing high resolution molecular-based anatomical landmarks during human development, harmonizing developmental knowledge across species, and establishing a foundational resource with significant implications for developmental and childhood disorders, regenerative medicine and tissue engineering.
|
| 30/09/2020 |
£2,164,882 |
WELLCOME TRUST SANGER INSTITUTE |
We propose to generate an in-depth single cell and spatial atlas of embryos during late organogenesis, at 6/7 post conception weeks (PCW). This project will form a blueprint for a complete HCA development cell atlas, which will ultimately cover all accessible developmental stages week by week. We will leverage genomics technologies to profile single cells from dissociated tissues and within intact tissue sections, and deploy cutting-edge computational methods to reconstruct, in silico, a three-dimensional atlas of the whole human embryo. This work will significantly extend our existing WSSS-funded Development Cell Atlas research programme, which is focused on organ-based profiling. Our reconstruction of a complete human embryo atlas will provide a blueprint for establishing high resolution molecular-based anatomical landmarks during human development, harmonizing developmental knowledge across species, and establishing a foundational resource with significant implications for developmental and childhood disorders, regenerative medicine and tissue engineering.
|
| 30/09/2020 |
£119,697 |
UNIVERSITY OF CAMBRIDGE |
We propose to generate an in-depth single cell and spatial atlas of embryos during late organogenesis, at 6/7 post conception weeks (PCW). This project will form a blueprint for a complete HCA development cell atlas, which will ultimately cover all accessible developmental stages week by week. We will leverage genomics technologies to profile single cells from dissociated tissues and within intact tissue sections, and deploy cutting-edge computational methods to reconstruct, in silico, a three-dimensional atlas of the whole human embryo. This work will significantly extend our existing WSSS-funded Development Cell Atlas research programme, which is focused on organ-based profiling. Our reconstruction of a complete human embryo atlas will provide a blueprint for establishing high resolution molecular-based anatomical landmarks during human development, harmonizing developmental knowledge across species, and establishing a foundational resource with significant implications for developmental and childhood disorders, regenerative medicine and tissue engineering.
|
| 30/09/2020 |
£161,121 |
UNIVERSITY OF CAMBRIDGE |
We propose to generate an in-depth single cell and spatial atlas of embryos during late organogenesis, at 6/7 post conception weeks (PCW). This project will form a blueprint for a complete HCA development cell atlas, which will ultimately cover all accessible developmental stages week by week. We will leverage genomics technologies to profile single cells from dissociated tissues and within intact tissue sections, and deploy cutting-edge computational methods to reconstruct, in silico, a three-dimensional atlas of the whole human embryo. This work will significantly extend our existing WSSS-funded Development Cell Atlas research programme, which is focused on organ-based profiling. Our reconstruction of a complete human embryo atlas will provide a blueprint for establishing high resolution molecular-based anatomical landmarks during human development, harmonizing developmental knowledge across species, and establishing a foundational resource with significant implications for developmental and childhood disorders, regenerative medicine and tissue engineering.
|
| 30/09/2020 |
£121,985 |
UNIVERSITY OF CAMBRIDGE |
We propose to generate an in-depth single cell and spatial atlas of embryos during late organogenesis, at 6/7 post conception weeks (PCW). This project will form a blueprint for a complete HCA development cell atlas, which will ultimately cover all accessible developmental stages week by week. We will leverage genomics technologies to profile single cells from dissociated tissues and within intact tissue sections, and deploy cutting-edge computational methods to reconstruct, in silico, a three-dimensional atlas of the whole human embryo. This work will significantly extend our existing WSSS-funded Development Cell Atlas research programme, which is focused on organ-based profiling. Our reconstruction of a complete human embryo atlas will provide a blueprint for establishing high resolution molecular-based anatomical landmarks during human development, harmonizing developmental knowledge across species, and establishing a foundational resource with significant implications for developmental and childhood disorders, regenerative medicine and tissue engineering.
|
| 30/09/2020 |
£399,144 |
GLOBAL GENOMIC MEDICINE COLLABORATIVE (G2MC) |
This proposal is for partial funding of the IHCC as it transitions from a nascent organization to a mature and sustainable one. The IHCC’s inaugural summit was funded by the Wellcome Trust, the NIH, and the Medical Research Council of the UK. Since, the NIH has provided support for both administration of the IHCC, its second and third summit and pilot work on the Atlas and scientific projects. The funding period from June 2020-2021 will be one of organizational maturing, strategic planning, demonstration of feasibility of prioritized cross cohort projects and the development of a business plan. Funding from new industry members and from HIROs is anticipated for growth and sustainability. The Wellcome Trusts’ investment will be highly levered with NIH’s investment and is key to allowing the IHCC to launch itself with a robust charter and organizational structure, a scientific plan an Atlas and data structure that will make the IHCC’s assets accessible. Deliverables from this funding will be a) a strategic plan, b) a 4th ICS, c) completion of 3-5 pilot cross- cohort demonstration projects, and d) a compendium of opportunities for research across the globe, and e) formal engagement of funders toward a sustainable funding model.
|
| 30/09/2020 |
£150,000 |
MQ TRANSFORMING MENTAL HEALTH |
This grant will enable MQ to deliver two key activities in 2020/21: the implementation of our income generation strategy, and the development and delivery of the MQ Annual Mental Health Science Meeting 2021.
MQ exists to ‘create a world where mental illness is understood, effectively treated and one-day prevented’. In 2019, MQ worked with the agency Open Creates to develop a new income generation strategy to deliver these ambitions - bringing the public and scientists together to fund ground-breaking mental health research, more quickly.
With the support of this grant, MQ will work with Open Creates to define and test priority research themes that align with the views of target audiences. Following identification of priority theme(s), MQ will then roll out activity to build public awareness, engage and grow a base of supporters, and raise funds for mental health research against a compelling research and organisational strategy.
This grant will also support MQ to work with the mental health science community and key supporters to develop and deliver a successful Mental Health Science Meeting in 2021, championing collaboration and knowledge sharing amongst researchers, and showcasing the potential of mental health science to excite and motivate our supporters and stakeholders.
|
| 30/09/2020 |
£1,499,800 |
GUY’S AND ST THOMAS’ CHARITY |
We are applying to Wellcome for a £1.5M investment as match towards an overall £3M+ programme that will test new ways of working to embed health research in our practice.
This will be split between two priority portfolio areas; Adolescent Mental Health (AMH) and Multiple Long-term Conditions (MLTCs)
We will explore 3 opportunity areas, these are:
1. New models for generating and using public insight in research
2. New models for creating impact through investment partnerships
3. Accelerating our evidence
The work will be supported by research partnerships, a network of public engagement expertise and a partnership advisory group. We already have an existing relationship with KCL, with whom we currently run a £1m+ MLTC research challenge fund in the MLTC programme, as well as our cornerstone investment into the Science Gallery London https://london.sciencegallery.com/. We would also like to deepen our relationships with other academic institutions as part of this work.
Please see Partnership Plan for details.
Please see Partnership Slide Deck
|
| 30/09/2020 |
£1,957,254 |
FOUNDATION FOR THE NATIONAL INSTITUTES OF HEALTH |
Not Available |
| 30/09/2020 |
£3,914,507 |
FOUNDATION FOR THE NATIONAL INSTITUTES OF HEALTH |
Not Available |
| 30/09/2020 |
£250,190 |
UNITED FOR GLOBAL MENTAL HEALTH |
This proposal aims to sustain lasting activity on mental health advocacy. The United GMH team will leverage support from Wellcome to mobilise partners, and the wider global mental health community, to maintain the momentum built since 2018 to raise mental health further up the global political agenda in 2020. We are requesting £250,000 from Wellcome to further this work.
This proposal plans activities covering four streams:
Sustaining the work of the BluePrint Group including delivery of the Kenya face to face meeting and a second meeting later in the year (TBC Sept/Oct)
Leading the BluePrint Group and the wider mental health community to design and undertake a comprehensive multi-stakeholder consultation and create and finalise an action plan to ensure the Global Mental Health Roadmap is delivered; starting with the engagement with key stakeholders at Davos and at the Speak Your Mind and BPG meetings in February
Working with WHO to develop the advocacy strategy, consultation process and finalisation of their WHO Mental Health Action Plan
Working to incorporate messaging around the need for more mental health research as part of UnitedGMH’s research on broader advocacy
|
| 30/09/2020 |
£100,546 |
UNIVERSITY OF OXFORD |
Blood culture (BC), the core sample for antimicrobial resistance surveillance, is recommended to be sampled from all sepsis patients prior to administration of antibiotics. However, BC sampling rates are lower than recommended in both high-income countries (HICs) and low and middle-income countries (LMICs). Various barriers and enablers have been identified that impeded the adoption of BC sampling recommendations using different theories; however, a systematic review on this topic is not currently available.
We propose to conduct a systematic review to identify known barriers and enablers to the adoption of local and international BC sampling recommendations. We will use the theoretical domain framework (TDF), which has been developed by refining a wide range of theories, as a framework for synthesizing evidence on barriers and enablers. Findings will be stratified by HICs and LMICs. We will then conduct a survey study among medical doctors using face-to-face interviews and electronic questionnaires to explore generalizability of systematic review findings among medical doctors in Thailand, Viet Nam and Indonesia. All questionnaires (in Thai, Vietnamese, Indonesian and English) will also be made available online, and open for public participation.
A systematic summary of the existing evidence can inform the development of interventions.
|
| 30/09/2020 |
£2,499,432 |
EUROPEAN BIOINFORMATICS INSTITUTE |
The decreasing cost of genomic sequencing will yield millions of samples in the coming years from both research and healthcare. To make the most use of these data, the community must agree on common methods for collecting, storing, transferring, accessing, and analyzing data.
This proposal will support the Global Alliance for Genomics and Health (GA4GH; www.ga4gh.org) as it develops the standards and policies necessary for effective and responsible data sharing. With more than 1,000 active contributors working across more than 30 countries in the areas of healthcare, research, patient advocacy, life science, and information technology, this diverse organization enables broad sharing that transcends the boundaries of any single institution or country.
We envision a future in which the full suite of GA4GH standards enables all clinicians, geneticists, and researchers to search across the world’s collective genomic data to reveal unanticipated gene-disease associations, make otherwise impossible drug-response predictions, and generally participate in genomics at a competitive pace—regardless of their means or location.
The promise of genomic medicine lies at a crossroads that depends on community harmonization and will significantly enhance human health and medicine if we succeed. We believe GA4GH is necessary to that success.
|
| 30/09/2020 |
£19,231,767 |
ROSALIND FRANKLIN INSTITUTE |
The ability to image life lies at the heart of biology and medicine. Imaging the molecules of life leads directly to discoveries since they can then be understood in atomic detail. For molecular imaging, electrons give more signal for less damage than X-rays, as demonstrated by the current success of single-particle electron cryomicroscopy. The key recent breakthrough underpinning this technology was the development of direct electron detectors for cryoEM, based on silicon computer chip technology from the 1990s. The promise of using electrons in structural biology more broadly is still held back by several technological hurdles. Here we propose a major cross disciplinary effort to develop new technologies that use electrons to revolutionise biology. There are three components: AMPLUS – using electrons to visualise proteins inside cells, (electron cryotomography) at unprecedented resolution, cryoEM100 – a ten-fold cheaper purpose-built cryomicroscope that will democratise single particle imaging, and HEXI – a project that will create a world-leading combined X-ray and electron beamline, enabling structure determination from crystals ranging from the smallest that exhibit Bragg diffraction up to those useable at a microfocus X-ray beamline.
|
| 30/09/2020 |
£1,783,532 |
UKRI-MRC |
The ability to image life lies at the heart of biology and medicine. Imaging the molecules of life leads directly to discoveries since they can then be understood in atomic detail. For molecular imaging, electrons give more signal for less damage than X-rays, as demonstrated by the current success of single-particle electron cryomicroscopy. The key recent breakthrough underpinning this technology was the development of direct electron detectors for cryoEM, based on silicon computer chip technology from the 1990s. The promise of using electrons in structural biology more broadly is still held back by several technological hurdles. Here we propose a major cross disciplinary effort to develop new technologies that use electrons to revolutionise biology. There are three components: AMPLUS – using electrons to visualise proteins inside cells, (electron cryotomography) at unprecedented resolution, cryoEM100 – a ten-fold cheaper purpose-built cryomicroscope that will democratise single particle imaging, and HEXI – a project that will create a world-leading combined X-ray and electron beamline, enabling structure determination from crystals ranging from the smallest that exhibit Bragg diffraction up to those useable at a microfocus X-ray beamline.
|
| 30/09/2020 |
£3,916,135 |
DIAMOND LIGHT SOURCE LTD |
The ability to image life lies at the heart of biology and medicine. Imaging the molecules of life leads directly to discoveries since they can then be understood in atomic detail. For molecular imaging, electrons give more signal for less damage than X-rays, as demonstrated by the current success of single-particle electron cryomicroscopy. The key recent breakthrough underpinning this technology was the development of direct electron detectors for cryoEM, based on silicon computer chip technology from the 1990s. The promise of using electrons in structural biology more broadly is still held back by several technological hurdles. Here we propose a major cross disciplinary effort to develop new technologies that use electrons to revolutionise biology. There are three components: AMPLUS – using electrons to visualise proteins inside cells, (electron cryotomography) at unprecedented resolution, cryoEM100 – a ten-fold cheaper purpose-built cryomicroscope that will democratise single particle imaging, and HEXI – a project that will create a world-leading combined X-ray and electron beamline, enabling structure determination from crystals ranging from the smallest that exhibit Bragg diffraction up to those useable at a microfocus X-ray beamline.
|
| 30/09/2020 |
£1,987,486 |
FUNDACIó UCR |
Animal-derived antivenoms are the mainstay in the therapy of snakebite envenoming. There is an urgent need to develop knowledge-based protocols for the immunization of horses, as this key aspect of production has lacked research and innovation. This project is aimed at developing protocols for the management of horses used for immunization with venoms in a pilot farm. The following aspects will be investigated: (1) Evaluation of feeding protocols; (2) veterinary care and management aimed at minimizing the deleterious effects of venoms; (3) selection of the most appropriate adjuvants for immunization and development of new immunization schemes for generating high antibody titers; (4) design of bleeding protocols providing a high yield of plasma while not affecting the overall condition of horses. The project is also aimed at selecting the best combination of venoms from African snakes in order to generate a polyspecific antivenom of wide neutralizing coverage, as well as to device ways to improve the antibody titers against poorly immunogenic low molecular mass neurotoxins from snake venoms. In order to apply the principle of 3Rs (Replacement, Reduction and Refinement) in the assessment of antivenom potency, in vitro tests will be evaluated for their correlation with in vivo toxicity assays.
|
| 30/09/2020 |
£500,971 |
CARDIFF UNIVERSITY |
Recent evidence suggests that a part of the brain called the hippocampus is responsible for
the increase in dopamine in a different part of the brain, the striatum, known to cause
psychosis. Our hypothesis is that by attenuating activity within the hippocampus, we will then
be able to reduce the increase in dopamine associated with psychosis. In order to do this,
we plan to target the GABA chemical signalling pathway which inhibits nerve cell excitability.
More specifically, we aim to increase the inhibitory actions of the so-called alpha5-GABAAR
protein, which is highly expressed within the hippocampus and is therefore ideally placed to
control overall hippocampal activity. In this proposal, we will identify molecules that
selectively enhance the function of GABA at alpha5-GABAARs and then test representative
compounds in an animal model of schizophrenia to see if they do indeed attenuate
increased dopamine activity. |
| 30/09/2020 |
£497,900 |
BRINK |
Over 30m days are lost to work-related ill health annually in the UK. Of all employers’ health-related investments, only 5.6% are being used by employees and under 15% are evidence-based.
Our aim?
Develop, test, and scale an ‘Evidence Accelerator’ that bridges the gap between science, research and the workplace. Using design methods to translate evidence into action, with employers as the bridge, it’ll provide ways marginalised employees can access, use and respond to scientific health research and improve their health.
We will
narrow in on key mission areas where under-utilised EVIDENCE shows most promise to positively impact marginalised workers’ health, (e.g. mental, musculoskeletal)
ENGAGE cohorts of employers across industries with marginalised workers most susceptible to those health issues
prototype and test a wide range of design-led and evidence-based workplace interventions to ACCELERATE the flow of evidence into the workplace
explore which offer demonstrable positive impact on workers and organisations as a result of their involvement, and which show most promise of a model that can SUSTAIN
Success means:
Marginalised workers are accessing, using, responding to health research and truly improving their health and wellbeing
More researchers and employers engaged in informing evidence-based, design-led workplace interventions
Sustainable operating and business model
|
| 30/09/2020 |
£388,023 |
THINKSONO LTD |
Deep vein thrombosis (DVT) is a condition where blood clots form in the veins
of the body, most frequently the leg. It is a serious condition and if left untreated
clots can move to the lungs, which can be fatal. Early diagnosis is vital. Normally
three steps are needed for a DVT diagnosis: a GP appointment; a hospital DVT
clinic appointment and a leg ultrasound scan. This process should take only 4
hours, but it often takes longer and therefore a precautionary anticoagulant
(blood-thinning) drug is given. Nearly 90% of people investigated for a DVT have
no clot. |
| 30/09/2020 |
£285,881 |
UNIVERSITY OF CAMBRIDGE |
Salmonella are bacteria that cause life-threatening infections in adults and children. These diseases co-exist in many geographical areas, especially in Low and Middle Income Countries. Therefore, a vaccine that can protect against all the major Salmonella infections would be highly desirable. The project will exploit the remarkable features of Outer Membrane Vesicles (mOMV) to deliver antigens from many species of Salmonella that cause disease in humans. mOMV are outer membrane blebs naturally shed by Gram-negative bacteria, including Salmonella. These bacteria can be genetically manipulated to increase mOMV production, to decrease adverse reactions and to include additional antigens. mOMV are easy and cheap to produce, strongly immunogenic and protective. The innovator award will therefore allow the development of a multivalent, easy to produce, low-cost, safe, effective Salmonella vaccine to be taken towards the end of preclinical experimentation. |
| 30/09/2020 |
£1,184,320 |
ROYAL COLLEGE OF SURGEONS IN IRELAND |
Mental disorders such as schizophrenia are among the most expensive disorders in
terms of quality of life and societal cost. Early identification and intervention is
associated with improved outcome and is facilitated by targeting those at clinical-highrisk-
for-psychosis (CHR) as up to 25-30% develop psychotic disorder (PD) at 6 year
follow-up. There is growing evidence for the involvement of the immune system and
inflammation in this disorder. We have added to this literature by demonstrating that
the complement pathway, the blood plasma component of the innate immune system is dysregulated in blood samples of individuals at age 11, many years before these
individuals report symptoms in keeping with psychotic disorder at age 17.
Based on our own plasma proteomic data and machine learning analyses, we now
have evidence for a set of biomarker proteins which can predict transition from the
CHR to PD with a high degree of accuracy. We now seek to refine and replicate these
findings.
Our study: Using state-of-the-art proteomic methods and machine learning approaches
we will replicate and refine this biomarker signature of transition from CHR to psychotic
disorder in three distinct international samples and one longitudinal cohort with a total
CHR sample size of over 1000 CHR subjects. We will also undertake functional assays
that measure plasma protein levels of the complement and coagulation pathway and
their activation fragments as indicators of complement and coagulation dysregulation.
Our study includes commercial diagnostic/prognostic biomarker expertise. |
| 30/09/2020 |
£2,000,000 |
UKRI-MRC |
N/A |
| 30/09/2020 |
£466,154 |
KING'S COLLEGE LONDON |
Brain-based disorders, including psychiatric and neurological illnesses, represent
10.4% of the global burden of disease. At present, there are no established imagingbased
tests for detecting these disorders, monitoring their progression over time and
optimising treatment. In a previous Wellcome Innovator Award, Prof Andrea Mechelli and team at KCL developed Neurofind - a user-friendly web-based tool, which usesdeep learning technology to quantify neuroanatomical abnormalities from structural Magnetic Resonance Imaging scans. This tool compares an individual scan against a
reference database and generates an individualised report that could support
diagnostic, prognostic and treatment decisions in individual patients. In this follow-on
award, the feasibility, acceptability, safety and clinical utility of Neurofind will now be
assessed in a real-world setting. Neurofind will be tested in patients with first episode
psychosis recruited from the South London and Maudsley NHS Foundation Trust.
The study aims to test if Neurofind is feasible, acceptable, safe and if the information
in the individualised patient reports it produces is predictive of clinical outcomes at 6-
months follow-up. If successful, the proposed trial will lead to the adoption of
Neurofind in real-world clinical services, with tangible benefits for patients, clinicians and service providers
|
| 30/09/2020 |
£501,929 |
KING'S COLLEGE LONDON |
In the UK and in many countries around the world, it is routine for women to undergo an
ultrasound (US) screening examination about halfway through pregnancy to check if their
fetus is developing normally. This is important as undiscovered fetal anomalies can have a
lifelong impact on the families affected, with huge cost to health services as well as
substantial wider societal impact. Currently, international screening detection rates are
highly variable, and are strongly dependent on the skill and experience of the sonographer
performing the examination.
This project builds on iFIND (www.ifindproject.com), a Wellcome Trust (WT) Innovative
Engineering in Health award, which has yielded powerful computerized technology that
uses artificial intelligence to simplify and enhance fetal US screening by automating many
routine tasks. This technology has been created by a fully integrated team of computer
scientists and clinicians working together using a close couple cycle of innovation and
clinical testing. It has the potential to have a significant impact on fetal screening, but to
achieve that it is necessary to transition from University developed prototype to healthcare
product. The usual strategy is to license to an existing player or spin-out a company.
However, in both cases the close coupling between technology innovation and clinical
testing that has proved so effective can get stressed or broken. We propose an innovative
approach in which the next stage of development is undertaken by an embedded team of
engineers working directly within a clinical environment. This will provide opportunities not
available by either of the conventional routes, providing an effective pathway to impact. |
| 30/09/2020 |
£120,000 |
UNIVERSITY OF OXFORD |
Not available |
| 30/09/2020 |
£4,333,936 |
INTERNATIONAL AIDS VACCINE INITIATIVE |
Long-standing global health challenges like antimicrobial resistance (AMR) require
synergistic approaches to dramatically reduce global morbidity and mortality levels.
We think that the availability of antimicrobial monoclonal antibodies (mAbs), which can
be used as a complementary strategy for vaccines, holds great promise for
ameliorating the expansion of AMR. A major challenge for the uptake of such antibody
interventions by those most vulnerable to AMR in low- and middle-income countries
(LMICs) is the associated costs of mAbs. This proposal is focused on two major
themes. First, we are proposing a portfolio approach to Ab discovery and development
for enteric bacteria with a focus on cross-reactive mAbs that enable broad spectrum
use to obviate the need for an accompanying diagnostic. This portfolio approach
includes the optimization and development of an existing lead mAb as well as
screening cohorts to discover new antibodies for different enteric bacteria. The second
theme is to set up a pipeline for Ab optimization to improve antibody bactericidal
potency, cross-reactivity to different enteric bacteria, Ab half-life, and manufacturability
to reduce cost of goods associated with an Ab intervention. These approaches are
meant to, respectively, reduce dosage requirements, enable broad spectrum use,
reduce administration frequency, and increase the probability of success of advancing
lead Abs through manufacturing and process development. IAVI and partners think
that investing in these two themes will greatly expedite the likelihood of advancing an
effective Ab intervention to address AMR and the burden of diarrheal disease caused
by enteric bacteria. |
| 30/09/2020 |
£3,532,625 |
FONDAZIONE TOSCANA LIFE SCIENCES |
Shigella, a gram-negative bacterium with more than 50 different serotypes, is a
major global health problem in low income countries. A recent estimate reported
more than 93 million episodes of shigellosis associated with diarrhoea and 238,000
deaths per year, 92,700 of which are in children under 5. The problem is
exacerbated by widespread antimicrobial resistance (AMR) which makes the
bacterium increasingly difficult to treat. There are several vaccines in development,
however they face the challenging need to cover a vast number of serotypes and
the absence of correlates of protection. This project aims to accelerate the
development of an ultimate remedy for shigellosis. We will isolate human
monoclonal antibodies (mAbs) from B cells collected from people previously
exposed to Shigella or vaccinated with experimental vaccines with the overarching
goal to provide new therapeutic solutions to Shigella infections. Shigella-specific
mAbs will be selected and engineered to have high potency and low cost to make
them affordable to low- and middle-income countries. The project will attempt to
establish correlates of protection that will facilitate vaccine development and
licensure and the identification of antigens common to all or to most of the
serotypes to underpin the development of universal vaccines.?? |
| 30/09/2020 |
£9,238,794 |
NOVARTIS INSTITUTE FOR BIOMEDICAL RESEARCH |
Since its launch in 2003, the Novartis Institute for Tropical Diseases has become
a world-leading drug discovery center of transformative medicines for neglected
tropical diseases – delivering a robust pipeline of drug candidates to treat
malaria, visceral leishmaniasis, sleeping sickness and dengue. In this award, we
propose to strengthen the pipeline by targeting two of the most neglected tropical
diseases, Chagas disease and cryptosporidiosis.
An estimated 8 million people are infected by the Trypanosoma cruzi parasite,
the causative agent of Chagas disease. Current therapeutics are widely
considered to be poorly effective and toxic. We aim to deliver a portfolio of highly
effective and safe new chemical entities with proven sterilising activity in Chagas
disease animal models.
Cryptosporidiosis causes an estimated 200,000 deaths in children aged under 24
months each year. With support from the Bill & Melinda Gates Foundation, and
together with our partners, we have identified drug candidates with a remarkable
safety profile, novel mechanism of action and unprecedented efficacy in
cryptosporidiosis animal models. In this award, we aim to establish a
cryptosporidium controlled human infection model for a proof-of-concept trial with
healthy adult volunteers, followed by definitive trials in the vulnerable pediatric
population. |
| 30/09/2020 |
£25,000,000 |
UNIVERSITY COLLEGE LONDON |
The Sainsbury Wellcome Centre aims to understand how computation in neural circuits generates flexible behaviour—a complex, scientific challenge that cannot be tackled by any one laboratory. The Centre is in a unique position to reveal general principles that link behaviour to neural processes across scales, by relating algorithms to neural circuits, cells and synapses. We will determine how these neural elements give rise to computations contributing to innate and learned behaviours, and develop a theoretical framework that explains how flexible, adaptive behaviour arises from neural activity. We have assembled outstanding scientific talent in an exceptional environment, with access to shared resources and state-of-the-art facilities that deliver new technologies, empowering bold research. We will exploit new models of scientific collaboration by integrating experiment, theory, data science and engineering, in close partnership with colleagues at the Gatsby Computational Neuroscience Unit. Our multi-disciplinary collaborative approach extends to the training and support of early career researchers, enhancing their success within and beyond our walls. By sharing our resources, knowledge and research culture, and through initiatives with our UCL, UK and international partners, we will collectively advance global efforts to understand the neural underpinnings of behaviour.
|
| 30/09/2020 |
£755,414 |
IMPERIAL COLLEGE LONDON |
Rapid brain imaging is central to the diagnosis and treatment of acute neurological
conditions, but existing imaging methods require large, immobile, high-power instruments
that are near-impossible to deploy outside specialized environments. We will create a device
that can be simply and rapidly applied to any patient, any time, any place, exploiting
advances that have already revolutionised imaging in geophysics. We will image the brain
using sound waves, transmitted across the head, applying advanced computer modelling to
remove the distorting effects of the skull, thereby enabling high-resolution high-contrast
imaging of the brain unachievable by conventional ultrasound. Safe, fast, universally
applicable, deployable continuously, and above all portable by paramedics, our device will
revolutionise brain imaging, in health and disease. The technology has particular relevance
to stroke – globally the second-commonest cause of premature death and a major, growing
cause of adult disability – and to brain imaging in resource-limited and inaccessible
environments. |
| 30/09/2020 |
£445,279 |
QIMR BERGHOFER MEDICAL RESEARCH INSTITUTE |
Dengue virus is an important mosquito-borne viral disease in humans. Dengue virus inflicts
390 million people annually in more than 100 countries. Currently, no specific anti-viral
treatment for dengue infection is available. This project will develop an innovative
therapeutic agent to treat dengue infection in patients. The approach is based on defective
interfering particles or DIPs, which are able to robustly inhibit dengue virus infections. DIPs
represent a novel approach for developing an anti-viral for dengue infection because they
are a specific, effective and non-toxic dengue inhibitor. DIPs are reported to co-evolve with
the infectious virus thereby potentially preventing development of viral escape mutants. This
study will evaluate the ability of DIPs to attenuate infection and disease by dengue virus in
vivo, it will determine if DIPs can block transmission of dengue virus between vertebrates
and mosquitoes and investigate co-evolution of dengue virus and DIPs. |
| 30/09/2020 |
£500,000 |
UNIVERSITY OF LEEDS |
Recent advances in cryo-electron microscopy/tomography (cryoEM/ET) are transforming structural biology, and thanks to recent investments in infrastructure the EM community has unprecedented access to high-end instrumentation. However, a severe lack of training opportunities means that the skills required to make the most of these instruments are in very short supply. This in turn is slowing progress on many existing projects within EM-focussed laboratories, and limiting access to EM by the mainstream structural and cell biology communities who are desperate to gain access to the cryoEM methodology. Effectively, there is a block on discovery, which is caused in large part by a deficit in knowledge, expertise, and training. To rectify this training shortfall, we propose a coordinated, multi-level programme of training, that complements those training opportunities that do exist, but expands upon them, significantly increasing the amount of ‘hands-on’ EM training available in the UK. This programme, which will encompass introductory "sample work up", intermediate "high resolution data collection" and advanced "Facility Placements" will provide a path for users with different expertise, and from different scientific backgrounds, to access the training they require, maximise the return on existing and new investments in EM, and drive forward new biological and biomedical discovery.
|
| 30/09/2020 |
£51,766 |
UKRI-MRC |
The UKPRP is an inter-disciplinary national initiative supported by an alliance of UK charities, Research Councils and the UK Health Departments, and established in recognition of the need for research into population-level strategies that will prevent non-communicable diseases (NCDs) and reduce inequalities in health. |
| 30/09/2020 |
£399,123 |
WELLCOME TRUST SANGER INSTITUTE |
The biodiversity of our living landscapes has never been more vital for the future health of our planet and humanity. A decade ago, Darwin 200 and the International Year of Biodiversity cast a public spotlight on evolution and biodiversity. In the subsequent decade biology has made huge advances, especially in the field of genomics where a radical new window to the natural world is being opened. The Darwin Tree of Life project is at the heart of this revolution, and will generate a library of the genomes of every complex species in Britain and Ireland, while playing a leading role in the ambitious Earth BioGenome Project - to sequence the genomes of all eukaryotic species on earth by 2030.
Just as new research questions will thrive on the new genomic datasets taking shape, the opportunities for public engagement will also evolve. Many communities passionate about nature and the environment will bring expertise to the scientific effort. Diverse themes, ranging from changing land use to pollution and climate change will resonate with particular groups. An opportunity exists to nurture a new generation of citizen genomicists, empowering people motivated by environmental challenges but new to the potential of understanding DNA and genomics.
|
| 30/09/2020 |
£499,579 |
UNIVERSITY OF GLASGOW |
High quality public engagement by Wellcome researchers will be enabled by open-call funding combined with responsive training and support - drawing on expertise and brokerage from institutional PEPs and the wider Scottish Public Engagement Network (ScotPEN). This application extends the successful collaborative ScotPEN Wellcome Enrichment Award (Phase 1) to allocate Wellcome Research Enrichment for Public Engagement funding in Scotland.
As well as increasing the quantity and quality of applications to the scheme, the activities, relationships, and resources generated across the two phases will strengthen the culture of engagement within and between Scottish institutions and extend relationships between researchers, PEPs, partner organisations, and communities within Scotland and beyond.
Building on the success of Phase 1, where 12 proposals were awarded funding of £463,670, we will:
(1) Add a new management post to support capacity building both for SWEA and ScotPEN development.
(2) Provide responsive pre- and post-award support tailored to the needs of awardees and prospective applicants.
(3) Strengthen Phase 1 partnership development with organisations including the Scottish science centres and community groups.
(4) Include Public Engagement Professionals (PEPs) more explicitly in our training offer – helping increase their visibility and capacity to progress culture change.
|
| 30/09/2020 |
£749,862 |
UNIVERSITY OF OXFORD |
This proposal is to extend the initial Oxford Enriching Engagement pilot scheme (Institutional Research Enrichment Fund award 217077/Z/19/Z, 2019-2020) for devolved Wellcome Research Enrichment: Public Engagement funding.
This extended pilot programme will build on, enhance and enrich the significant work that has already taken place to further increase the effectiveness and dynamism of this scheme to achieve the desired outcomes.
Enriching Engagement will continue to support a diverse range of Wellcome-funded researchers to apply for, and if funded deliver, high-quality PER activities that result in tangible positive changes and outcomes, drawing upon the expertise of Oxford's PE staff.
This extended pilot will also enable an increase in evidence to be gathered on outcomes, successes, challenges and lessons learnt from this approach across the whole pilot period (which, if this extension is funded, will be April 2019 - December 2021) and gather medium and longer term outcomes from the initial pilot phase.
This learning has the potential to shape future engagement funding mechanisms and inform other institutions and networks on running their own devolved funding schemes - the latter has the potential to significantly increase the effectiveness and efficiency of these institutions' plans from the get-go, therefore offering significant added-value.
|
| 30/09/2020 |
£622,407 |
WORLD ECONOMIC FORUM |
Strategic partnership with WEF, renewed annually. |
| 30/09/2020 |
£3,703,029 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
MARVELS 1
Respiratory infections are common, potentially vaccine-preventable causes of death. Despite dramatic progress in pneumococcal and influenza vaccination, much remains to be done, both to prevent mucosal disease from these pathogens and the complex effects of co-infections. As nasopharyngeal carriage provides the mode of transmission and the source of infection for pneumococcal disease, it is also an excellent point of intervention to prevent respiratory infections.
MARVELS 1 will establish respiratory infection models in the human nasopharynx in order to answer 3 main questions:
Which vaccines can prevent acquisition of pneumococcal carriage in Malawi?
Which vaccines are most effective in vulnerable populations in Malawi, particularly those with substantial exposure to household air pollution, HIV, malnutrition?
What are the critical mechanisms of respiratory tract defence that can be harnessed to develop an effective mucosal vaccine suitable for low and middle income country (LMIC) use?
This programme of work will transfer our established controlled human infection models (MRC UK Programme grant) to Malawi in order to test vaccines in populations at risk of disease, determine mucosal immune responses, including those in co-infection and in risk populations, in order to accelerate vaccine discovery.
|
| 30/09/2020 |
£1,900,000 |
WELLCOME TRUST SANGER INSTITUTE |
No Data Entered |
| 30/09/2020 |
£3,286,966 |
UNIVERSITY OF CAMBRIDGE |
Stem cell research is rich in fundamental questions and offers unparalleled translational prospects – stem cell dysfunction underlies many global health challenges and stem cell manipulations provide immense therapeutic opportunities. The Cambridge Stem Cell Institute (CSCI) is a world-leading centre for stem cell research with the largest critical mass of recognised stem cell researchers in any single institution in Europe. Its mission is to transform the prevention, diagnosis and treatment of disease through a deep understanding of the mechanisms regulating stem and progenitor cells, both normal and pathological.
In 2019 all CSCI research groups moved to the Jeffrey Cheah Biomedical Centre on the Cambridge Biomedical Campus adjacent to Addenbrookes and Royal Papworth Hospitals. The purpose-built laboratories with state-of-the-art core facilities constitute a superb setting for contemporary stem cell research. A key strategy is to embed biological, clinical and physical scientists operating across disparate tissues at multiple scales to foster cross-disciplinary innovation. A critical mass of clinician scientists facilitates synergistic interactions between basic and disease-focussed research, and a network of 35 affiliated PIs provide bridges to Departments and Institutes throughout Cambridge, placing CSCI at the heart of a vibrant stem cell community of > 700 scientists.
|
| 30/09/2020 |
£2,582,105 |
UNIVERSITY OF EDINBURGH |
The Wellcome Centre for Cell Biology (WCB) is internationally renowned for discovery of key cellular mechanisms. During the current quinquennium, WCB researchers made transformative advances, aligned with our vision of uncovering cellular epigenetic mechanisms and their impact in disease. Influential breakthroughs in fundamental genome organisation and expression, epigenetic inheritance in fungal resistance and the molecular basis of a neurological disorder provide exemplars of our accomplishments. From these exceptional foundations, we have evolved a new scientific vision for WCB: to understand transitions between cellular states in health and disease. We will determine how cells are developmentally re-programmed and respond to environmental and other stresses, how differentiation goes awry in disease, and how pathogens switch states to evade toxins. We have made recent strategic appointments aligned with these aims, in transcriptomics, cellular development, cell growth and structural epigenetics, and invested in mass spectrometry and Cryo-EM. Future appointments in epigenetic transcriptomics of infectious disease and early development will help deliver this vision. WCB will prioritise building inter-disciplinary connections and changing perceptions around translatable research. Scientific excellence will be underpinned by a strong commitment to growing an exemplary cultural environment. With this holistic vision, WCB is poised to deliver transformative scientific and cultural breakthroughs.
|
| 30/09/2020 |
£265,576 |
KING'S COLLEGE LONDON |
The Wellcome/EPSRC Centre for Medical Engineering has 3 clinical challenges: cancer, cardiovascular and neurological and psychiatric conditions. We seek to work with local partners and national charities relevant to our clinical challenges, to not just disseminate but also to engage with them to help support them and integrate into their policies. Since 2017, the Public Engagement programme has focused mainly on heart research. We have ongoing association with a local heart charity (ECHO) that we expect to lead to even stronger relationships working on newly identified, mutually beneficial priorities. Extra funding will allow us to further strengthen our partnership with ECHO and enable us to work more alongside patient groups with cancer and neurological and psychiatric conditions.
This new proposal will allow us to deliver a series of discreet projects as well as providing small seed funds for our researchers to lead on their own ideas. We hope to secure a secondment or local individual with experience of, and from, the local
community to work with us. We are approaching Wellcome for this funding, as no applicable grants are available from other funders.
|
| 30/09/2020 |
£3,732,109 |
UNIVERSITY COLLEGE LONDON |
Our overarching vision is to deliver clinically transformative applications of neuroimaging that catalyse the understanding and treatment of patients with neurological and psychiatric disorders. Cornerstone to this is the integration of paradigm-shifting neuroimaging technologies with neuronal and behavioural modelling to establish non-invasive, computationally-derived measures of neuronal function and structure. The resulting methodological innovations will be exploited to provide mechanistic explanations of how the human brain supports sensory, motor and cognitive functions in health, how these mechanisms are affected by disease, how they respond to therapeutic interventions, and how to deliver personalised prognoses.
A fundamental tenet of our vision is to conduct our science in a transparent and open manner, and to engage with stakeholders from patient groups and the wider community. Promoting this approach, in conjunction with an inclusive and positive research culture, will remain integral to our vision. Our supportive environment, highly-trained, multidisciplinary staff, innovative technological capacity, and embedded position within the Queen Square Institute of Neurology, creates a dynamic and cooperative critical mass with expertise in the use and development of computational approaches that make our neurobiological questions tractable. These factors provide the capacity to deliver our vision of clinically transformative applications of neuroimaging.
|
| 30/09/2020 |
£3,820,192 |
UNIVERSITY OF CAMBRIDGE |
Our vision is to understand the fundamental mechanisms of normal development, to determine how these mechanisms are subverted in cancer and other diseases, and to apply this knowledge to develop new therapies. Our research themes focus on: cell proliferation and genome maintenance; function and regulation of the genome and epigenome; mechanisms of cell fate determination, multipotency and plasticity; and the cell biology of organ development and function. We also emphasize two strategic directions: (i) human development and disease and (ii) quantitative analysis of cellular dynamics, to understand developmental and disease processes quantitatively at the molecular, cellular and tissue scales. We investigate both normal development and disease in a range of in vivo model systems, as well as primary human tissues, organoid systems, and patient-derived stem cells. Extension funding would allow us to further progress our overall scientific vision, our strategic areas of human development and quantitative approaches, our work on in vivo models of disease, and the translation of our research. It would also support our ambitious public engagement programme, enable continuation and development of our training activities, and underpin our efforts towards and commitment to a positive and inclusive research culture.
|
| 30/09/2020 |
£5,405,397 |
UNIVERSITY OF OXFORD |
We are a research community of basic and clinician scientists on an inter-disciplinary hospital campus with extensive outreach to Oxford’s tropical medicine units and global health challenges. Our vision is improving human health by maximising the informativeness of human genetics and disease mechanisms.
We commit to:
Responding to clinical need, making discoveries in biology to investigate genome function, translating them to molecular-cellular structures and mechanisms, and investigating impact of variation between individuals and cells, with disease and clinical outcomes.
Enabling through technology, using genetics/genomics, bioinformatics, structure determination, computing, and cell/mouse genome editing, underpinned by world-leading core facilities, to understand human physiology and pathology. Data, results, materials, software, and knowhow are made fully accessible.
Translating knowledge to the clinic and, where appropriate, filing patents and establishing partnerships, within the University and wider academic, technology, and biomedical sectors.
Promoting a positive research culture and building capacity in people and expertise, for all staff, including enabling early-career researchers to test ideas and flourish with essential support from our core facilities.
This extension will enable us to capitalize on, and extend, significant innovations since 2016, developing the next generation of innovative, game-changing technologies, approaches, and researchers, to meet still-existing and emerging threats to health.
|
| 30/09/2020 |
£3,101,188 |
UNIVERSITY OF OXFORD |
Understanding how interactions between neurons generate human behaviour, why individual brains vary from one another, or whether a patient is likely to develop a particular disease, requires explanations that span vast differences in scale. Yet such explanations are essential if insights from neuroscience are to make a meaningful impact on human health. Precise mechanisms discovered in animal models must be related to clinical phenotypes discovered through population studies; both must be combined to improve diagnosis and treatment in individual patients. Neuroimaging offers a powerful route to connect these different scales, providing measurements that are sensitive to cellular phenomena and that can be acquired in living humans.
The Wellcome Centre for Integrative Neuroimaging aims to enable novel insights into brain function that span levels of description, and therefore bridge the gap between laboratory neuroscience and human health. This requires fundamental discoveries concerning relationships between species and between scales, and major technological developments for mapping big-data discoveries onto neurobiological mechanisms. We bring together diverse investigators who can tackle different themes within this grand challenge. Within each theme, neuroimaging is used alongside complementary methodologies, ensuring that it takes inspiration from, and has impact on, areas beyond its typical reach.
|
| 30/09/2020 |
£185,420 |
UNIVERSITY OF CAPE TOWN |
The Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa) at the University of Cape Town leads research programmes on high-burden infectious diseases, particularly HIV and tuberculosis. Through this enrichment grant, we will develop our researcher community as public engagement champions, improve our research through inolvement of our local communities and stakeholders, and raise awareness of our research to maximise health outcomes.
To develop our researcher community’s involvement in PE, we will create and implement a PE communication toolkit, which will become an embedded component of study conduct at CIDRI-Africa, and enable our researchers to confidently engage the wider public.
We will continue to engage the community with whom we conduct research through health research awareness activities, and establish a community advocacy programme to extend the work of CIDRI-Africa’s Community Advisory Group. Members of the advocacy programme will bridge research and non-research communities, providing input to both and effectively advocating tuberculosis and HIV research.
We will engage young people through our school’s engagement project, drawing on methods from a previous pilot. This will follow a workshop format, and improve understanding amongst school learners and the people they connect with of tuberculosis and HIV as well as research into these conditions.
|
| 30/09/2020 |
£1,471,193 |
UNIVERSITY OF CAPE TOWN |
The Centre
1. Fosters investigator-led approaches with the overarching scientific objective of combating infection, especially HIV-1 and tuberculosis, through epidemiological, clinical and laboratory research.
2. Supports research on the interaction between communicable and non-communicable diseases, especially where the latter impact susceptibility to infection, or arise as a consequence of infection.
3. Improves understanding and management of the challenges of antiretroviral therapy (ART) such as metabolic complications and antiretroviral drug resistance.
In its first 2.5 years the Centre has been strikingly successful, with Centre facilities and expertise contributing to multiple successful investigator and fellowship submissions that already exceed the value of the Centre award itself. The Centre is a cross-cutting, dendritic organisation promoting the values and mission of Wellcome via its meetings, investigator support, platforms and provision of core services. It is an integral part of Faculty and Institute life and has disproportionately high influence in research and engagement strategy and in the development of a healthy research culture. Its brand is highly positive and prestigious. A very strong commitment to individual investigator development, University and national transformation goals and to internationalisation, particularly within the context of African science and development, will remain core to the mission.
|
| 30/09/2020 |
£1,579,167 |
UNIVERSITY OF MANCHESTER |
Matrix accounts for two-thirds of total protein mass and provides the scaffolds necessary for cell function and tissue health. Consequently, matrix dysregulation is central to ageing and the pathogenesis of major human chronic diseases affecting all organ systems. Discoveries in the Centre have shown that synthesis and degradation of matrix is under circadian clock control, we have identified immunomodulatory pathogen proteins that tether to the matrix during gut infection, and have identified specialised adhesion complexes that mediate cell migration, division and attachment to matrix. We are learning how to regulate matrix synthesis, have unravelled the disease mechanism in a chondrodysplasia, and developed a biologic for the treatment of osteoarthritis and dry eye disease. These, and other Centre discoveries described below were only possible when researchers with complementary approaches worked together in a collaborative environment underpinned by exceptional core facilities. Importantly, we have learned the value of incorporating bioinformatics and mathematics into our research programmes. We are applying for a 2-year extension to our Core Award to implement predictive mathematical modelling, machine learning, and bioinformatics throughout the Centre, maintain our Core Facilities and make ground-breaking discoveries that underpin all of biomedical research and translation combined with a strong public involvement programme.
|
| 30/09/2020 |
£2,369,302 |
NEWCASTLE UNIVERSITY |
Our mission is to transform the lives of patients with mitochondrial disease.
The key aims of our Centre are to:
1. Understand the clinical course of patients with mitochondrial disease and how this relates to the underlying disease mechanisms
2. Delineate the molecular and genetic mechanisms causing mitochondrial disease
3. Develop techniques to prevent the transmission of mtDNA disease and improve treatment for patients with mitochondrial disease.
The training aims of our Centre are to:
1. Provide the optimum training opportunities for all postgraduate students including our MRes programme in Mitochondrial Biology
2. Ensure the continued professional development of all staff in the Wellcome Trust Centre for Mitochondrial Research.
The public and policy engagement aims of our Centre are to:
1. Engage with patients and their carers to ensure that research in the Centre is responsive to their needs
2. Engage with policy makers and clinicians ensuring our research discoveries that lead to improved care are made available for all patients with mitochondrial disease.
|
| 30/09/2020 |
£52,181 |
MERCK SHARP & DOHME |
Malaria is one of the world's most devastating diseases of humans and results in over 450,000 deaths annually. Novel therapies are urgently required to populate the antimalarial clinical portfolio, as the current therapeutics that treat this disease are becoming less effective due to emerging resistance. A collaboration between Dr David Olsen from Merck & Co., Kenilworth, NJ USA (known as MSD outside the US and Canada) and Professor Alan Cowman from the Walter and Eliza Hall Institute (WEHI), has demonstrated that malaria aspartyl protease enzymes are an attractive drug target, as they perform essential functions for survival in blood, sexual and liver stages of the parasite life cycle. Through screening aspartyl protease inhibitor libraries, the collaboration has identified novel drug-/ike hit compounds that are potently active against the malaria parasite. The proposed research aims to increase potency against the parasite whilst maintaining selectivity, progressing to a lead optimisation stage discovery program. |
| 30/09/2020 |
£52,181 |
WALTER AND ELIZA HALL INSTITUTE OF MEDICAL RESEARCH |
Malaria is one of the world's most devastating diseases of humans and results in over 450,000 deaths annually. Novel therapies are urgently required to populate the antimalarial clinical portfolio, as the current therapeutics that treat this disease are becoming less effective due to emerging resistance. A collaboration between Dr David Olsen from Merck & Co., Kenilworth, NJ USA (known as MSD outside the US and Canada) and Professor Alan Cowman from the Walter and Eliza Hall Institute (WEHI), has demonstrated that malaria aspartyl protease enzymes are an attractive drug target, as they perform essential functions for survival in blood, sexual and liver stages of the parasite life cycle. Through screening aspartyl protease inhibitor libraries, the collaboration has identified novel drug-/ike hit compounds that are potently active against the malaria parasite. The proposed research aims to increase potency against the parasite whilst maintaining selectivity, progressing to a lead optimisation stage discovery program. |
| 30/09/2020 |
£69,533 |
EXONATE LIMITED |
Exudative age-related macular degeneration (wAMD) and diabetic macular oedema (DME) are the leading causes of blindness in the Western world. wAMD affects 1.3 per cent of people over 50 years old with a global incidence of 1. 5 million. Diabetes affects 382 million people worldwide, expected to increase to 592 million by 2035 and is the leading cause of severe vision loss in working age adults. Diabetic macular oedema is the major cause of visual loss in diabetic patients. Approximately 14% of diabetes patients develop DME and the prevalence increases to 29% (696, 000) for patients using insulin for more than 20 years. Current treatment options for these conditions are limited. Anti-Vascular Endothelial Growth Factor (VEGF) agents improve vision in some patients and slow its deterioration in most, but they must be administered by regular intravitreal injections and non-specifically block both pro-angiogenic and antiangiogenic isoforms of VEGF. There is therefore an incentive to develop a non-invasive therapeutic modality with efficacious and safe agents. Exonate has developed small molecules that inhibit production of proangiogenic VEGF through selective inhibition of Serine/threonine-protein kinase 1 (SRPK1)-mediated VEGF splicing. These inhibitors have already demonstrated superior efficacy as topical agents in preclinical models of wAMD. Thanks to the support of the Wei/come Trust, Exonate will take several of these inhibitors into an optimisation programme culminating in the nomination of a preclinical candidate drug with optimal characteristics for clinical development. The funded project will also involve the assessment of the candidate in regulatory toxicology and safety pharmacology studies to support an application to the regulatory authorities for clinical evaluation at the end of the funding. Exonate expects to reach this milestone and enter the clinic in early 2020. |
| 30/09/2020 |
£209,348 |
UNIVERSITY OF GLASGOW |
Not available |
| 30/09/2020 |
£218,456 |
UNIVERSITY OF CAMBRIDGE |
Not available |
| 30/09/2020 |
£196,434 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
Not available |
| 30/09/2020 |
£161,237 |
CARDIFF UNIVERSITY |
Huntington's disease is a fatal genetic disease characterised by a movement disorder that is accompanied by a decline in cognitive function and changes in mood and behaviour. The decline in cognitive function may precede the movement disorder by a decade or more and is a very important component of the functional disability associated with the disease. There is, however, no effective treatment for enhancing cognitive performance in Huntington's. Professor John Atack at the University of Sussex aims to identify novel drugs that can enhance cognitive performance in subjects with Huntington's disease to address a large unmet medical need. |
| 30/09/2020 |
£232,800,000 |
WELLCOME TRUST SANGER INSTITUTE |
Not available |
| 30/09/2020 |
£1,813,110 |
UNIVERSITY OF GLASGOW |
The Wellcome Centre for Integrative Parasitology (WCIP) has evolved through Trust support since 1987 into a world-leading and cutting-edge research hub. We now propose a further transformation to take us and the field forward through the integration of disciplines, locations and scales, to tackle disease problems in disease endemic regions (DER). Our 2014 renewal broadened our portfolio of pathogens and technologies and grew the Centre at every level. Our PI complement increased from 9 to 15, including numerous Fellowship and Investigator Award holders (6F/5M). World-leading recruits from Harvard, Oxford and Edinburgh together with young emerging (female) PIs radically extended the Centre’s activities. We have new programmes on immunology, helminths and their population structures, single cell bioinformatics, and clinical pathology of parasitic diseases. Technologically, we have expanded with dedicated technologists in both imaging and metabolomics, while internationally, fruitful engagement with Malawi has embedded Centre members in key areas such as paediatric malaria, epidemiology and enhanced training opportunities. Our strategic growth reflects the evolution of our vision from the intense, largely laboratory-based investigation of parasite biology into the integrated pursuit of WCIP-generated knowledge-based therapies positioned by informed interactions with Global Health stakeholders in Glasgow and selected partners across Europe and particularly DER.
|
| 30/09/2020 |
£94,780 |
CARDIFF UNIVERSITY |
Around 1% of the population will suffer from schizophrenia at some point in their life. Symptoms such as paranoia and/or hearing voices can be reasonably well treated by existing medications.
However, these drugs have little effect on the other symptoms (lack of motivation and impaired social function) and impaired cognition, including difficulties with attention, memory and problem-solving that result in a “brain fog”. These largely untreated symptoms remain a huge barrier to the resumption of a fully functional, “normal” life for these individuals and are associated with an annual estimated cost in the UK alone of around £12 billion.
Professor Simon Ward from the University of Sussex has received a Seeding Drug Discovery Award to identify and develop drug which is a selective modulator of the AMPA receptor which has the potential to provide an innovative new treatment for patients with schizophrenia. If successful the team expect to have a compound ready for clinical evaluation in just over three years time.
Nerve cells (neurons) communicate with each other by releasing chemicals known as neurotransmitters that interact with proteins called receptors on adjacent neurons. Levels of the neurotransmitter glutamate, which is crucial for normal cognitive function, are altered in schizophrenia. A specific subtype of glutamate receptor, the AMPA receptor, is thought to be associated with cognition and therefore increasing AMPA receptor function should improve cognitive performance in schizophrenia and thereby addressing an unmet need and revolutionizing the functional outcome of this patient population. |
| 30/09/2020 |
£149,640 |
UNIVERSITY OF MANCHESTER |
The enzyme lysyl oxidase (LOX) regulates cross-linking of structural proteins in the extracellular matrix.
LOX also plays a role in stimulating the metastatic spread of cancer through the body. Its expression is increased in hypoxic cancers and is correlated with tumour metastasis and decreased patient survival. In model systems its inhibition significantly decreases cancer metastasis and increases survival. Since metastasis is responsible for over 90 per cent of cancer deaths these data validate LOX as an important therapeutic target in cancer.
Professor Caroline Springer and Professor Richard Marais from the Institute of Cancer Research have been awarded Seeding Drug Discovery funding to develop drugs that target LOX. They are applying a medicinal chemistry drug discovery approach underpinned by a strong programme in LOX biology with the aim of producing orally available, small molecular weight drugs that inhibit LOX activity for cancer treatment. |
| 30/09/2020 |
£99,998 |
UNIVERSITY OF EDINBURGH |
Human African Trypanosomiasis (sleeping sickness) is a neglected disease which is transmitted by tsetse flies. Without treatment death is inevitable and current drugs are poorly effective.
Professor Malcolm Walkinshaw of the University of Edinburgh and colleagues are working on developing a new drug for sleeping sickness based on understanding the biology of the T. brucei parasite that causes the disease. T. brucei gets its energy from the breakdown of glucose (glycolysis) obtained from host blood for survival. The proteins used for this process (so-called glycolytic enzymes) provide the parasite with its only source of energy (ATP molecules).
The compounds already identified in this project have been shown to kill the parasite by specifically inhibiting glycolysis. High throughput screening against one of the glycolytic enzymes (PFK) identified three chemically different families of inhibitors each capable of killing T. brucei parasites. The objective of this project is to design and synthesise related compounds to improve potency so that very low (nanomolar) concentrations of compound are needed to kill parasites. |
| 30/09/2020 |
£53,847 |
MQ TRANSFORMING MENTAL HEALTH |
Interest payable to MQ |
| 30/09/2020 |
£10,000,000 |
EUROPEAN BIOINFORMATICS INSTITUTE |
Not available |
| 30/09/2020 |
£2,573,099 |
DIAMOND LIGHT SOURCE LTD |
Not available |
| 30/09/2020 |
£8,780,116 |
DIAMOND LIGHT SOURCE LTD |
Not available |
| 30/09/2020 |
£715,680 |
IMPERIAL COLLEGE LONDON |
Malaria kills half a million children each year. Despite decades of investment, there is still no efficacious vaccine. To date, the best protection achieved against malaria came from injecting volunteers with live parasites, attenuated so they don't cause disease. However, translation of this approach has performed poorly in field trials, largely because of the laborious nature of isolating pure parasites from mosquitoes, a process that requires skilled manual dissection. We have developed a revolutionary, dissection-independent process for malaria parasite isolation, extracting them from thousands of pulverised, infected mosquitoes. This scalable method produces pure, highly-infectious parasites that offer robust immune protection. Here we propose to advance this technology into a pipeline for parasite purification, vaccine formulation and vaccine production that has potential for good manufacturing production. By reducing costs and improving the effectiveness of whole-parasite vaccines we aim to reinvigorate malaria vaccinology providing a pathway for protecting children from disease. |
| 01/09/2020 |
£15,653,620 |
ACADEMY OF MEDICAL SCIENCES |
The Academy of Medical Sciences’ mission is to advance biomedical and health research and its translation into benefits for society. The vision set out in this proposal is central to our strategy to create a diverse workforce of researchers to advance scientific discovery and to generate and optimise improvements in health.
Drawing on our strengths of breadth, connectivity and unparalleled career support activities, over the next five years we will:
Support researchers’ transition to independence by enhancing our Starter Grants for Clinical Lecturers and Springboard for Biomedical Researchers schemes
Promote health innovation with new programmes that support greater cross-disciplinary and pan-sector connectivity and collaboration by researchers
This proposal will enable us deliver a platform of cohesive, innovative activities that enhance research career pathways and achieve wider positive impacts on diversity and research culture. Our proven track record in galvanising action across the sector and leveraging further funding will drive greater coordination and effort across the UK’s university, healthcare and industry sectors.
In five years’ time we will have created mechanisms and a regional infrastructure that will equip and support cohorts of excellent researchers and future leaders to work collaboratively and proactively in addressing societal health challenges.
|
| 30/07/2020 |
£1,560,998 |
UNIVERSITY OF EXETER |
The project pioneers a new history of global health that, for the first time, incorporates the socialist world - a constellation of countries in a fluctuating political, economic and military nexus distinct from the capitalist West. It identifies the particular health cultures produced by socialism (in all its variety) and explores the impact of socialist internationalism in co-producing global health in the 20th century. This project offers a radical new account that will not only transform our knowledge of historical processes, but will further our understanding of ideas, practices and processes that current global health structures have been built on.
Global health histories are framed mainly through American, colonial and liberal perspectives. The omission of socialist contexts, however, distorts our understanding of what global health is. Although there was not one socialist template, diverse framings of socialist medicine played major roles in shaping and contesting global practices.
A systematic analysis of socialist medicine and international health through global case studies integrates missing expert networks, political agendas, public health models and diplomatic agreements in global health history. This work, in turn, allows us to rethink concepts such as socialism, solidarity, development, socialist medical research and health provision.
|
| 30/07/2020 |
£599,638 |
UNIVERSITY OF EDINBURGH |
This study investigates the biosocial conditions that frame the persistence of rabies as a public health concern in India to rethink One Health approaches in post-anthropocentric directions. Dog-mediated rabies in Asia and Africa is a priority in transnational public health, and One Health approaches have scientific consensus as being key to its prevention (WHO 2019). India has the highest burden of human rabies globally despite long-standing initiatives, including One Health, on rabies elimination. Our project addresses this impasse.
Challenging the (post)colonial One Health conceptualisation of street dogs as out-of-place disease vectors, our analytical framework of multispecies cultures directs new inter-disciplinary attention to the lived experiences of human and nonhuman animal actors, and to multiple dimensions of people-street dog relations in urban and rural India. We will examine historical and contemporary transnational influences on dog-related public health agendas; public attitudes and knowledge; everyday interactions between people, dogs, and the biophysical environment; and institutional interventions to advance decolonial concepts and practices for healthy multispecies societies. Through this fresh approach to rabies, we will reframe how One Health is theorised and pursued, and reconfigure it to enable more equitable approaches to health in a world marked by multispecies risk and vulnerability.
|
| 30/07/2020 |
£238,110 |
UNIVERSITY OF TECHNOLOGY, SYDNEY |
This study investigates the biosocial conditions that frame the persistence of rabies as a public health concern in India to rethink One Health approaches in post-anthropocentric directions. Dog-mediated rabies in Asia and Africa is a priority in transnational public health, and One Health approaches have scientific consensus as being key to its prevention (WHO 2019). India has the highest burden of human rabies globally despite long-standing initiatives, including One Health, on rabies elimination. Our project addresses this impasse.
Challenging the (post)colonial One Health conceptualisation of street dogs as out-of-place disease vectors, our analytical framework of multispecies cultures directs new inter-disciplinary attention to the lived experiences of human and nonhuman animal actors, and to multiple dimensions of people-street dog relations in urban and rural India. We will examine historical and contemporary transnational influences on dog-related public health agendas; public attitudes and knowledge; everyday interactions between people, dogs, and the biophysical environment; and institutional interventions to advance decolonial concepts and practices for healthy multispecies societies. Through this fresh approach to rabies, we will reframe how One Health is theorised and pursued, and reconfigure it to enable more equitable approaches to health in a world marked by multispecies risk and vulnerability.
|
| 30/07/2020 |
£338,768 |
UNIVERSITY OF WESTERN AUSTRALIA |
This study investigates the biosocial conditions that frame the persistence of rabies as a public health concern in India to rethink One Health approaches in post-anthropocentric directions. Dog-mediated rabies in Asia and Africa is a priority in transnational public health, and One Health approaches have scientific consensus as being key to its prevention (WHO 2019). India has the highest burden of human rabies globally despite long-standing initiatives, including One Health, on rabies elimination. Our project addresses this impasse.
Challenging the (post)colonial One Health conceptualisation of street dogs as out-of-place disease vectors, our analytical framework of multispecies cultures directs new inter-disciplinary attention to the lived experiences of human and nonhuman animal actors, and to multiple dimensions of people-street dog relations in urban and rural India. We will examine historical and contemporary transnational influences on dog-related public health agendas; public attitudes and knowledge; everyday interactions between people, dogs, and the biophysical environment; and institutional interventions to advance decolonial concepts and practices for healthy multispecies societies. Through this fresh approach to rabies, we will reframe how One Health is theorised and pursued, and reconfigure it to enable more equitable approaches to health in a world marked by multispecies risk and vulnerability.
|
| 30/07/2020 |
£326,834 |
UNIVERSITY OF LIVERPOOL |
This study investigates the biosocial conditions that frame the persistence of rabies as a public health concern in India to rethink One Health approaches in post-anthropocentric directions. Dog-mediated rabies in Asia and Africa is a priority in transnational public health, and One Health approaches have scientific consensus as being key to its prevention (WHO 2019). India has the highest burden of human rabies globally despite long-standing initiatives, including One Health, on rabies elimination. Our project addresses this impasse.
Challenging the (post)colonial One Health conceptualisation of street dogs as out-of-place disease vectors, our analytical framework of multispecies cultures directs new inter-disciplinary attention to the lived experiences of human and nonhuman animal actors, and to multiple dimensions of people-street dog relations in urban and rural India. We will examine historical and contemporary transnational influences on dog-related public health agendas; public attitudes and knowledge; everyday interactions between people, dogs, and the biophysical environment; and institutional interventions to advance decolonial concepts and practices for healthy multispecies societies. Through this fresh approach to rabies, we will reframe how One Health is theorised and pursued, and reconfigure it to enable more equitable approaches to health in a world marked by multispecies risk and vulnerability.
|
| 30/07/2020 |
£398,900 |
UNIVERSITY OF WARWICK |
Around 1900 a new classificatory system appeared to eliminate puerperal insanity from the psychiatric canon. However, as this project will illuminate, far from disappearing from psychiatric practice, mental hospital admissions under this category actually increased, while maternal mental illness was frequently drawn on in constructing defence pleas in infanticide trials. Exploration of postnatal mental illness offers a superb opportunity to understand the relationship between psychiatric theory and practice across the twentieth century, how psychiatric categories were defined, understood and implemented, and how they both adapted to and helped create new service provisions and treatments. The project will also explore how broader social and cultural factors, including attitudes towards motherhood and women’s changing status, especially in relation to their alleged bodily and reproductive autonomy, was reflected in interpretations of postnatal mental illness. Existing at the ‘borderland’ of psychiatry and obstetrics, the project will investigate the energetic and on-going debates on causality, that became increasingly complex with the involvement of an expanding range of health professionals and campaign organisations in the second half of the century. Finally the project will explore how public and media responses and the experiences of sufferers can enhance our understanding of postnatal mental illness in the past.
|
| 30/07/2020 |
£701,588 |
UNIVERSITY OF OXFORD |
Despite policy changes and advocacy efforts to promote the inclusion of women as participants in research and to advance a global agenda of women’s sexual reproductive health over the past two decades, women remain significantly underrepresented in biomedical research and its translational outputs beyond reproductive health. In this empirical ethics project, we will investigate the reasons why structural barriers to women’s health improvements persist within the practices of research itself—in how research is designed, conducted, and translated. More deeply, we will interrogate the role that implicit and explicit moral attitudes, beliefs and arguments play in making the case for a focus on women’s and girl’s health needs, and in the reactions to these priority-setting appeals in academic, policy, and social media domains. Taken together this work aims to make a significant contribution to evidence-based advocacy within biomedical research practice, transforming how researchers think and do research with and for women and girls.
|
| 30/07/2020 |
£648,234 |
UNIVERSITY OF MANCHESTER |
In contemporary Kazakhstan, Kyrgyzstan and Tajikistan, involuntary childlessness is a source of immense social stigma, addressed through a heterogeneous therapeutic landscape including shrines and sacred sites, Soviet-era sanatoria, and newly-opened fertility clinics. Central Asian states are positioning themselves as international ‘reprohubs’ (Inhorn) offering fertility treatment within strict conjugal confines to growing Chinese, European and local markets for Assisted Reproductive Technologies (ARTs). This configuration has generated intense public debate about the ethics of medically assisted reproduction, specifically concerning the intensified movement of people, gametes and technologies across borders. Through a tripartite focus on sites of reproductive care, itineraries of reproductive assistance, and debates about the (bio)ethics of emergent reproductive technologies, this project will illuminate how different models and practices of reproductive care are debated and used by individuals and couples to address infertility in stratified and rapidly-marketizing medical landscapes. Immersive ethnographic fieldwork will reveal how biomedical interventions to address infertility are incorporated into wider repertoires of healing practices and will examine how ARTs appear as objects of policy intervention, legal regulation, and religious commentary in emerging reproductive markets. In so doing, it will advance our understanding of involuntary childlessness, therapeutic landscapes, and the social ramifications of both in the global South.
|
| 30/07/2020 |
£650,069 |
KING'S COLLEGE LONDON |
Epidemiological efforts to map cancer in sub-Saharan Africa have a long history, playing an important role in how the disease has been imagined in the region. In the late colonial and early postcolonial period, British and French doctors produced small-scale epidemiological maps to advance understandings of cancer aetiology and improve treatment strategies at home. More recently, global surveillance initiatives seeking to rationalise health policy and planning in Africa have generated political atlases of the continent with national cancer burdens.
This project carries out an archival and ethnographic study of these epidemiological efforts to chart malignancy in sub-Saharan Africa over the past 70 years. It takes these cartographies of diseases as its object of study, examining their scientific, political and material conditions of possibility and analysing their influence on cancer imaginaries and healthcare policies in Africa. In doing so, the project aims to draw attention to the crucial role that epidemiological maps have played in the postcolonial history of biomedicine in Africa, while developing an innovative approach to epidemiological surveillance that highlights its socio-technical infrastructure and performative power. At the same time, the project also purports to move Africa out of the margins of the global history of cancer.
|
| 30/07/2020 |
£913,683 |
NEWCASTLE UNIVERSITY |
North and South: Regional Health Inequalities in England
The ‘north-south health divide’ in England is longstanding and persistent, documented both before and after the epidemiological transition. In the mid-19th century, life expectancies in northern cities were four years lower than in southern cities, and today, there is still a two-year difference in average life expectancy between the northern and southern regions.
However, there has been no thorough academic study of regional health inequalities, so we know little about the temporality, aetiology, experience, representation or perception of the ‘north-south health divide’. This oversight is becoming even more pressing given emerging evidence that health inequalities are increasing and that the north is falling further behind.
Using a novel, mixed-method, intensive, multi-disciplinary approach, the North and South project will fill this gap by providing the definitive account of the ‘north-south health divide’ and regional inequalities in health in England – contextualised within the wider European experience.
By drawing on concepts, data and methods from geography, epidemiology, sociology, history, social policy and literary studies, the project will enhance our understanding of the ‘north-south health divide’; provide insights into how to close it; and advance the international health inequalities field empirically, methodologically, and conceptually.
|
| 21/07/2020 |
£378,655 |
UNIVERSITY OF MANCHESTER |
Prosthetic Embodiment investigates what it means to live – and live well – with prostheses. Adopting a historical approach, informed by critical medical humanities and disability studies, and focusing on artificial legs and their users, this globally sensitive project will be the first to consider how the experience of prosthetic embodiment has changed, from the 1970s through to the present. For people to use and live healthy lives with prosthetic legs, collaboration with those who make and fit them is vital. Through an innovative combination of historical approaches and visual anthropology, this study explores the agency and materiality of users, health professionals and technologies, following the relations between them in terms of prosthetic design, fitting, use, and recycling. A central question to be investigated is how practicalities of lives and bodily experiences are negotiated and renegotiated as users learn to live with new prostheses, and once again when devices are recycled through charitable organisations to new users in the global south. Exploring the diverse embodiment of people with limb difference will reveal important insights into how prostheses create both new possibilities and unexpected constraints on day-to-day living, and the experience of disability and medical technology more generally.
|
| 21/07/2020 |
£245,249 |
UNIVERSITY OF CAMBRIDGE |
High prices of new medicines have led most European countries to set up health technology assessment (HTA): evidence-based processes that evaluate whether a drug’s benefits outweigh its costs, before it receives public funding. Yet, increasingly, expensive new medicines bypass this scrutiny. Instead, they enter health systems through alternative access schemes: diverse provisions that provide patients with access to treatment that are not routinely funded – for example the English Cancer Drugs Fund or individual patient funding requests. As a result, some drugs, including notably expensive cancer medicines, are prescribed even though they never demonstrated their "value for money" in HTA, reaching up to 5% of pharmaceutical budgets in some countries. Despite evidence of their growing significance, there is little systematic research on alternative access schemes.
This project seeks to understand why alternative access schemes emerged, how decisions in these schemes are made, and what the policy implications are for patients and public finances. It systematises knowledge of this emerging phenomenon by providing an overview of alternative access schemes in Europe and a detailed analysis of their political economy in selected health systems. It will contribute to debates on affordability of new medicines.
|
| 21/07/2020 |
£174,702 |
UNIVERSITY OF OXFORD |
Patients’ 'best interests' are important in healthcare, but their use faces challenges:
Resource allocation: As well as aggregate measurements like population health, healthcare resource allocation should be sensitive to individual patients' claims. The idea of best interests provides limited guidance here, since resource constraints mean we cannot promote everyone's best interests.
Value disagreement: Caring for patients who cannot communicate preferences – including infants – often generates fundamental value disagreement between carers and medical professionals over their best interests.
My proposal explores whether a principle of sufficiency - the idea that it is particularly important to prevent people from being very badly off - can help. Sufficiency has received renewed attention in political philosophy; my research will build on recent theoretical advances, developing a theory that is responsive and applicable to practical challenges.
Goals
Systematically outline challenges to best interests and existing work on sufficiency;
Generate a novel sufficiency-based approach that can be used in healthcare decisions;
Consider challenges and develop recommendations for two related practical issues: resource allocation and the care of critically ill infants;
Publish 12 peer-reviewed journal articles;
Disseminate research findings via websites and public-engagement activity at Oxford;
Host a workshop on the role of sufficiency in healthcare.
|
| 21/07/2020 |
£236,313 |
UNIVERSITY COLLEGE LONDON |
A recent, unprecedented influx of migrants to Peru means that roughly 3% of the country’s population are now of Venezuelan origin, with an estimated 1,700+ living with HIV. The focus of this research will be the social, medical, and legal aspects of ‘belonging’ for migrants in situations of medical precarity. This will be achieved by exploring the processes whereby these refugees access HIV-related medical-care and legal-migratory status, integrate into the wider Peruvian community, and interact with a biomedical system troubled with intersections of race, racisms, and xenophobia at a transformative moment in the history of Peru with never-before-seen mass- immigration from a Caribbean to an Andean nation.
In order to address this focus, the key research goals will be to:
Investigate how HIV-positive Venezuelans negotiate ‘pharmaceutical citizenship’ (citizenship dependent on pharmaceutical compliance (Ecks,2005)) and receipt of Anti-retroviral therapy (ART).
Interrogate actual and potential integration into biosocial communities (social-kinship based upon shared bio-factors (Young,2016)) based upon HIV-positivity.
Query the intersections of racism and biomedicine when seeking HIV/AIDS-related health care for migrants.
Research for this project will involve 18-months ethnographic fieldwork in Lima, Peru with migrants and stakeholders, and will transform our understandings of migrant health, race, and ‘belonging’.
|
| 21/07/2020 |
£231,432 |
UNIVERSITY OF OXFORD |
New ‘pathogen sequencing technologies’, which have the power to identify and describe infectious disease transmission networks, are transforming public health practice. They also raise practically important ethical questions (for example regarding privacy protection), as-well-as conceptual and normative questions concerning responsibility for disease transmission, blame and the obligations of various actors.
This empirical bioethics study will combine qualitative research with normative ethical analysis to develop an account of ethical practice in the use of technologies that can identify and describe infectious disease transmission networks.
This will be achieved by answering the following research question:
What are expert and lay views on the potential social consequences and ethical risks of identifying transmission networks through the use of pathogen sequencing technologies?
What ethical norms concerning transmission of infectious disease underpin these views?
How do the concepts of personal responsibility, blame and obligation bear on the ethics of using pathogen technologies to identify and describe infectious disease transmission networks?
What contextual factors influence ethical norms and ethical practice in this area?
|
| 21/07/2020 |
£245,971 |
UNIVERSITY OF YORK |
This Fellowship will explore the intersection of contemporary marginality, ethnicity and mental health through an integrative mixed methods study of the prevalence, causes, and lived experience of food insecurity in the UK.
The goals are to:
understand variations in the prevalence and socio-demographic correlates of food insecurity, and its interaction with mental health, among UK ethnic groups
understand how different ethnic groups conceptualise ‘food insecurity’ and how this shapes its interaction with their mental health
understand ethnic variations in the lived experience of food insecurity, including food bank use, and its interaction with mental health
theorise the nexus of marginality, ethnicity and health in post-industrial Britain
provide a platform for mixed-methods, longitudinal analyses of food insecurity.
The Fellowship is composed of two interlinked studies, integrated within a new theoretical framework on contemporary marginality. Study 1 employs Qualitative Longitudinal Research methods (N=30) over two years to explore the experience of food insecurity, the contingent nature of ethnicity, and the interaction of food insecurity, ethnicity and mental health.
Study 2 will estimate the prevalence, socio-demographic correlates and mental health causes and consequences of food insecurity and food bank use among UK ethnic groups, using existing and commissioned national and local survey data.
|
| 14/07/2020 |
£4,000,000 |
UNIVERSITY OF EDINBURGH |
I propose to study how a set of key proteins (condensins I/II, cohesin, Kif4A, topo IIalpha) mold the chromatin fibre into its characteristic rod-shaped helix of loops in mitosis. Using a transformative system allowing us to obtain cultures entering mitosis with near-perfect synchrony we will adopt an interdisciplinary approach involving genomics (Hi-C, Capture-C, cut & run), proteomics, crosslinking, microscopy and molecular modelling to resolve changes in chromatin fibre and chromosomal protein organisation on a minute-by-minute basis during mitotic entry. Using non-toxic synchrony methods plus acute (and reversible) protein depletion with auxin degrons, we will determine when, where, how and with whom these proteins act to shape mitotic chromosomes. Access to the single copy chicken Z chromosome with its unique-sequence centromere allows us unprecedented mapping of the chromatin folding and protein distribution at a vertebrate centromere during this process. Following our discovery that RNAs mediate assembly of the mitotic chromosome periphery compartment (MCPC) downstream of Ki-67, we will initiate a new research direction identifying the proteins and RNAs involved, and determining their functional significance for chromosome segregation. Lastly, we will optimise methods for isolating human artificial chromosomes (HACs), avoiding unwanted DNA rearrangements that endanger future synthetic genome efforts.
|
| 14/07/2020 |
£3,640,891 |
UNIVERSITY OF CAMBRIDGE |
Programmed axon degeneration (or Wallerian degeneration; WD) is a preventable and druggable mechanism of axon loss. WD is well-characterised in animals and highly conserved. Blocking WD alleviates axon loss and symptoms in multiple disease models, suggesting a common, downstream mechanism. Human data are essential to confirm the role of WD in specific human diseases, ensuring drugs under development are tested in highly-relevant disorders and patients. We reported mutations in rare human axonopathies that aberrantly activate WD, and lifelong rescue of a related mouse model. Our programme determines the wider involvement of WD in rare and common human disorders, specifically peripheral neuropathies and ALS, where axon degeneration is important. We use online resources (100,000 Genomes, Project MinE, UK Biobank, etc.) and targeted sequencing of well-phenotyped cohorts and test roles of gene variants in causation, risk and severity. We determine their functional impact using complementary human iPSC and mouse modelling and develop specific biomarkers of WD for clinical samples. This project will provide insight into pathogenic mechanisms and a firm platform for developing and testing therapeutics. Our team, a world leader in Wallerian degeneration and leading neurogeneticists in rare and common neuropathies and human iPSC modelling, is uniquely placed to deliver this.
|
| 14/07/2020 |
£1,409,484 |
IMPERIAL COLLEGE LONDON |
The last decade has witnessed substantial declines in the global burden of malaria; however, in recent years progress has stalled. We aim to combine a mathematical modelling framework with economic analyses to gain insight into the optimal global, regional and country strategies to achieve the ultimate aim of malaria eradication. Specifically:
What is the optimal strategy to achieve malaria eradication? Should resources initially focus on high burden countries, elimination countries or a balance between these? How does this change as burden and transmission decline? How do competing aims in the short-term (e.g. the need to reduce morbidity and mortality) hamper achieving longer-term eradication aims?
What is the trade-off between country priorities and regional and global strategies? How do competing national priorities determine regional and global success? What degree of international cooperation is needed and at what scale? What are the economic benefits and costs of co-operation to countries?
How are strategies influenced by the wider political economy? How do competing priorities influencing national decision makers impact wider eradication efforts? How does weak governance and political constraints in national and international decision-making reduce the effectiveness of strategies?
|
| 14/07/2020 |
£1,555,838 |
UNIVERSITY COLLEGE LONDON |
The lymphatic vasculature is essential for health in vertebrates. Alongside roles in tissue fluid balance, cholesterol transport and immunomodulation, lymphatic vessels possess remarkable organotypicity, which underpins organ-specific lymphatic functions during embryonic development, health and disease.
Using the mammalian kidney as a model system, I will study two concepts responsible for the organotypicity of lymphatics: the cellular sources of lymphatic endothelial cells and molecular crosstalk between lymphatics and epithelia, a paradigm that may be applicable to other organs like lung and gut. I will focus on these processes in embryonic development, health and polycystic kidney disease (PKD); the most common genetic renal disorder, which features dysfunctional lymphatics. I will use several emerging technologies including high-resolution three-dimensional imaging, single-cell RNA sequencing, novel in vivo imaging modalities, targeted kidney delivery of therapeutics and computational modelling.
The insights arising from these experiments in this Investigator Award will enhance our understanding of lymphatic biology in kidney development, physiology and disease; areas in which the contribution of lymphatics is poorly understood. The findings will provide new directions and tools for understanding and manipulating lymphatic function in organogenesis, health and multiple disease processes.
|
| 14/07/2020 |
£2,276,736 |
UNIVERSITY OF OXFORD |
The goal of this proposal is to transform our understanding of both the molecular mechanisms and the pathophysiological roles of members of the rhomboid-like superfamily. At the mechanistic level, our long-term research into this group of polytopic membrane proteins has led us to the hypothesis that the core function of the rhomboid-like domain is specific TMD recognition of substrates (of the rhomboid intramembrane serine proteases) and clients (of the non-protease members of the clan). Using a structural and biochemical approach, we seek to understand the molecular details of how this specific recognition is achieved.
Biologically, rhomboid-like proteins have many functions, but we still have little understanding of their role in mammals, particularly of the rhomboid proteases. Building on our mechanistic aims, we plan to break this log-jam by pioneering systematic methods of substrate identification. We already know that iRhoms, catalytically inactive homologues of rhomboids, regulate inflammation, growth factor signalling and, as we have recently discovered, tumour growth. We plan to further elucidate these roles, both at the level of fundamental cell biology but also with a goal to reveal their potential medical significance. By the end of this work we expect to know which rhomboid-like proteins are useful therapeutic targets.
|
| 14/07/2020 |
£1,636,956 |
UNIVERSITY COLLEGE LONDON |
This proposal aims to understand how neural networks for memory emerge during post-natal development, both during normal development and following early-life brain damage.
Episodic memories (memories of events and their spatio-temporal context), and generalised learning such as semantic memories (factual world-knowledge) are supported by different brain networks. Episodic memories are thought to be encoded initially by the hippocampus, whilst general knowledge would be extracted by integrating across experiences via hippocampus-neocortical interactions.
However, the ontogenetic unfolding of memory runs counter to this framework. Early development is characterised by the rapid acquisition of general knowledge, despite amnesia for specific events. Furthermore, sustaining early-life hippocampal damage results in dense amnesia for specific episodes, but general learning is relatively preserved.
We aim to resolve this apparent paradox by studying neural circuit activity in vivo, in conjunction with behaviour, in developing rodents.
Our goals are to:
1) Understand the development of hippocampal mechanisms supporting the generation of memory traces of specific events;
2) Understand the neural mechanisms that enable the association of items with their spatio-temporal context (episodic memory processing);
3) Discover how neural coding for generalised knowledge emerges across cortical-hippocampal networks during normal development, and identify networks supporting preserved learning after early-life hippocampal damage.
|
| 14/07/2020 |
£654,391 |
IMPERIAL COLLEGE LONDON |
This proposal concerns the identification of genetic polymorphisms which alter the fitness of Human Immunodeficiency Virus (HIV-1), the robust estimation of virus fitness, and the characterization of how polymorphisms influence replicative fitness within hosts versus transmission to new hosts.
HIV evolves to evade the immune system, resist antiviral medications, and maximize its rate of replication within infected hosts. But at the epidemic level, natural selection promotes evolution of variants which are more transmissible. Natural selection within and between hosts can act in opposing directions, and evolutionary trends have been discerned from population based sampling of HIV such as a hypothetical transmission/virulence tradeoff. Because HIV evolves at multiple scales, the fitness of a particular polymorphism should be characterized along multiple dimensions including its impact on replication within hosts and transmission to new hosts. We will develop a framework for characterizing genetic fitness along multiple dimensions by building on theory developed for estimating state-dependent speciation rates. These methods will be applied to several large population-based samples of whole-genome deep sequencing (WGDS) of HIV. The outcome of this analysis will be an unprecedentedly detailed characterization of how particular genetic substitutions influence HIV pathogenesis and transmission at the epidemic level.
|
| 14/07/2020 |
£1,666,180 |
TECHNICAL UNIVERSITY OF MUNICH |
‘First contact’ between Bifidobacterium and their infant host represents a critical developmental window.
Our studies show that supplementation with Bifidobacterium isolates that metabolize breastmilk positively influences the preterm infant microbiota. We have also shown that: full-term infants have mini-bifidobacterial ecosystems that form dietary (breastmilk) cross-feeding networks; that geographically-separated infants harbour Bifidobacterium isolates with key differences in genomic content, and that particular Bifidobacterium genetic variants drive beneficial immune programming.
Building on our established findings and preliminary data, bringing together global maternal-infant cohort samples and using integrated multi-disciplinary approaches, we will:
Genetically characterise geographically distinct intra- and inter-infant Bifidobacterium populations
Profile geographically divergent maternal breastmilk samples, link them to genetic and phenotypic variation in Bifidobacterium, and define novel breastmilk metabolism pathways.
Determine how different Bifidobacterium communities influence immune responses, and how this relates to vaccine-related immunity.
We will significantly expand our fundamental knowledge by elucidating how Bifidobacterium species and genetic variants co-operate within an early-life diet (breastmilk) environment and define ‘signatures’ across different geographical regions. In a direct link to infant health, we will probe how these communities alter immune system development and vaccination responses. A fundamental understanding of these features will allow selection of Bifidobacterium-communities for next-stage translational projects.
|
| 14/07/2020 |
£2,258,810 |
UNIVERSITY OF EDINBURGH |
Atopic eczema is an itchy condition characterised by skin barrier dysfunction and inflammation. It frequently causes chronic morbidity, but a subset of cases enter long-term remission, demonstrating that resolution may be a tractable therapeutic aim.
Eczema is highly heritable. Null mutations in FLG are the strongest genetic risk and a locus on chr11q13.5, for which the nearest gene is EMSY, has a multiplicative effect. We have shown that EMSY is a transcriptional regulator in skin, controlling multiple aspect of barrier formation.
We will investigate molecular mechanisms at these two major risk loci: chr1q21.3 (FLG, FLG-AS1 and related genes) and chr11q13.5 (EMSY and LRRC32), aiming to define pathways contributing to eczema resolution. Findings will be tested in a well-characterised birth cohort (ALSPAC), to confirm clinical relevance.
Analyses of European cohorts (n > 25,000) show evidence of gene-environment interactions in eczema, but these findings require validation. We will use an optimised skin organoid model to investigate three environmental factors (tobacco smoke, wash-products and pet allergens) for which there is evidence of interaction with FLG genotype. Detailed functional and biochemical phenotyping will increase understanding of gene-environment interactions.
This work will inform eczema prevention strategies and characterise mechanisms contributing to eczema resolution, as future therapeutic targets.
|
| 14/07/2020 |
£1,374,681 |
KING'S COLLEGE LONDON |
We have identified bifurcation in human B cell development from shortly after bone marrow exit. B cells following one trajectory express high levels of IgM and have a gut-homing phenotype when in blood. They selectively migrate through gut and ultimately give rise to marginal zone B cells (MZB). The other branch expresses low levels of IgM and is systemic. All stages of the gut-homing branch are vastly depleted in the autoimmune disease lupus nephritis.
We will ask:
1. What drives the lineage split that commits a subset of developing B cells to migrate into GALT, and how does this fail in lupus nephritis?
2. What happens to MZB and their precursors in GALT?
3. Do MZB emergent from GALT enter spleen and respond to further tissue specific cues?
We will apply cutting-edge technologies to identify the epigenetic marks and transcriptomes that reflect the key events in vivo and use these to compare pseudotime developmental sequences. We will merge deep single cell phenotype in tissues with paired transcriptomes of single cells in suspension to create a multidimensional map of events in GALT, and track subsequent clone evolution across tissues.
This understudied area of basic immunology is fundamental to good human health.
|
| 14/07/2020 |
£1,776,461 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
Malaria is predominantly a rural disease in Africa and whilst urbanisation is occurring rapidly it was thought unlikely to lead to substantial increases in malaria transmission because Africa lacks an urban-adapted malaria vector. However, Anopheles stephensi, a common and efficient urban malaria vector in South Asia and the Persian Gulf, has recently been found in the Horn of Africa, including Ethiopia and Sudan and is associated with a rise in malaria in Djibouti. This prompted the WHO to call for urgent action to control the spread of the vector. This proposal brings together biologists, epidemiologists, mathematical and geostatistical modellers and medical anthropologists with the aim of preventing the spread of An. stephensi in Ethiopia and Sudan. The research will: (i) investigate the distribution, routes of introduction/reintroduction and spread of An. stephensi; (ii) quantify the importance of An. stephensi for malaria transmission and iii) evaluate multi-sectoral vector control strategies. This incredibly timely research will quantify the threat posed by An. stephensi in Ethiopia and Sudan and identify control measures to reduce populations and combat further spread in Africa. Historic examples (e.g. An. gambiae in Brazil) demonstrate that without prompt action, invasive species can become established with massive impacts on morbidity/mortality.
|
| 14/07/2020 |
£1,395,744 |
QUEEN MARY UNIVERSITY OF LONDON |
Hepatitis C infection can be cured by affordable drugs, leading to calls to expand treatment among the 70 million infected people worldwide. Many countries have initiated ‘test and treat’ programmes. e.g. India have reported treatment for ~40,000 patients in Punjab. However, 5-10% of infected people don’t respond and may develop viral resistance and go on to develop liver cancer. Salvage regimens are often unaffordable/unavailable.
We will address the remaining questions in hepatitis C therapy. We will work in Pakistan where hepatitis C is highly endemic (4.8% sero-prevalence) with regions reaching sero-prevalences of 10-20% (hot-spots). We will link with the government HCV programme to determine the most effective treatment for people who don’t respond to initial therapy. We will examine viral resistance in treatment failures to determine whether resistance dissemination is problematic and develop strategies to address it. We will determine whether some viruses are more oncogenic, allowing targeted surveillance. We will measure incident infection in the uninfected population (in hot-spot areas) and treated people, using modelling to determine what proportion of people must be cured to prevent disease recurrence. These data will inform the global elimination agenda and provide crucial data to develop optimised elimination programmes.
|
| 14/07/2020 |
£1,878,714 |
UNIVERSITY COLLEGE LONDON |
I propose a new overarching hypothesis that innate immune sensing of nucleic acids, cell cycle regulation, and a hitherto unappreciated function of endogenous viral elements, contribute to an integrated system of regulating inflammatory responses to infection. Encouraged by preliminary data we will investigate the relationship between cell cycle and innate immune sensing by manipulating cell cycle and measuring responses to infection and relating expression of endogenous viral elements to cell cycle and their activation of nucleic acid sensing. We will also study the mechanisms of lentiviral Vpx/Vpr proteins taking molecular genetic and structural approaches to examine their enhancement of viral expression, manipulation of endogenous element expression and inhibition of innate immune signaling. We will also investigate the role of G3BP1 stress granules and their role in coordinating nucleic acid sensing with regulation of translation by PKR, mediated through cyclophilins. Overall our approach is to manipulate cellular pathways, for example cell division, and test sensing responses or manipulate virus and measure activation of sensing or viral inhibition of sensing. We expect to reveal mechanisms of nucleic acid sensing that can be tractably inhibited therapeutically and provide new mechanistic knowledge of inflammatory pathways broadly relevant to infectious and inflammatory diseases.
|
| 14/07/2020 |
£1,690,786 |
KING'S COLLEGE LONDON |
In recent years, RNA dynamics in axons and dendrites have arisen as central to neuronal maturation and maintenance of healthy neuronal connectivity. However, the functional roles of transported mRNAs and their binding proteins are scarcely understood. Some of the proteins associated to local mRNAs are splicing factors and spliceosome proteins.
We recently demonstrated that their axonal role is complex, as, in developing neurons in vivo, the splicing factor SFPQ and the U1 spliceosome protein snRNP70 locally control axonal shape and connectivity, through modulation of the local transcriptome. These findings open two essential questions: how are these splicing proteins shaping the transcriptome landscape locally and what is the molecular nature of the axonal interactions between specific mRNAs and these two proteins?
Moreover, the recent findings of axonal and dendritic partially spliced mRNAs, retaining a single intron, open the additional question of the role(s) of intron-retaining transcripts in neurites and the possibility of direct functional interaction between retained introns and splicing proteins.
We propose to answer these essential questions, at cellular and molecular levels, using zebrafish developing neurons (in embryos and in culture) as experimental models.
|
| 14/07/2020 |
£2,530,384 |
UNIVERSITY OF EDINBURGH |
Despite major advances in our understanding of depression’s genetic architecture, there remain major gaps in our understanding of its environmental risk factors that impede prevention. Using studies of both related and unrelated individuals, I will identify the genetic changes and behaviours in those individuals that lead to depression in those individuals, as well as in their relatives. I will compare these changes with the genetic signatures of lifestyle factors (e.g. obesity) and behaviours, such as smoking and alcohol consumption, to identify if they are environmental risk factors for depression. In a complimentary approach, I will measure epigenetic changes in DNA methylation associated with depression and its risk factors. I will use optimise these epigenetic measures to improve the prediction of depression and the measurement of its risk factors. Finally, I will optimise the prediction of depression and its risk factors by applying these findings to prospective longitudinal dataset where depression and environmental risk factors have been measured on multiple occasions. These studies will be used to refine the accuracy of each predictor and estimate how it would behave in unseen samples of individuals, in whom it may be applied for prevention in future studies.
|
| 14/07/2020 |
£859,476 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
Our discovery of Schistosoma haematobium hybrids co-infecting Malawian children exposes critical knowledge gaps in WHO’s preventive chemotherapy (PC) strategy for schistosomiasis. Our HUGS (hybridisation in urogenital schistosomiasis) study will generate robust evidence that best informs medical, veterinary and environmental sectors in schistosomiasis control and interruption of schistosome transmission. This 4-year multidisciplinary investigation will develop new molecular assays that quantify multihost transmission dynamics and zoonotic spill-overs. We will reveal which pre- or post-zygotic drivers facilitate saltatory hybrid evolution. HUGS is set out in four objectives [% allocation] that:
Obj-1 [25%]: Test if the proportion of hybrid co-infection is (non)uniform across two representative communities where S. haematobium-mattheei or S. haematobium-bovis occur, inclusive of household GPS mapping and identification of associated risk factors by questionnaire;
Obj-2 [45%]: Verify, in a 2-year longitudinal population follow-up study with annual PC, if the above proportions and spatial patterns of hybrid co-infection hold or alter in the two communities;
Obj-3 [15%]: Ascertain if there is any increased host morbidity (e.g. anaemia or urogenital disease) in hybrid co-infection(s) as measured by point-of-contact assays and portable ultrasonography;
Obj-4 [15%]: Reveal hybrid environmental transmission by malacological inspections, livestock tracking and abattoir surveillance, with advanced molecular typing of collected schistosome material.
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| 14/07/2020 |
£1,628,077 |
UNIVERSITY OF CAMBRIDGE |
Protein synthesis is one of the most fundamental processes in all organisms. Due to the unique constraints under which RNA viruses evolve, non-canonical mechanisms are particularly prevalent in RNA virus gene expression. Thus, we are using viruses as a source for the discovery of novel gene expression strategies. We will leverage our expertise in computational biology to mine public transcriptomic datasets for 10000s of novel virus species, and use our expertise in virus comparative genomics and molecular biology to identify and characterize novel translational mechanisms. An important feature of the research strategy is close synergistic interaction between the bioinformaticians and experimentalists in my team, which allows us to efficiently investigate new discoveries.
Key goals are to:
Search ~120,000 RNA-Seq datasets for RNA virus-derived sequences from diverse host organisms from protists to mammals.
Use comparative genomics to predict novel cases of non-canonical gene expression.
Experimentally characterize the most interesting novel mechanisms.
Characterizing these exceptions to the rules of canonical translation will provide new insights into the mechanisms underlying protein synthesis, reveal new modes of cellular gene expression, and provide new tools for molecular biology research, biotechnology and synthetic biology. Thus the results will have broad applications in fundamental molecular biology.
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| 14/07/2020 |
£1,882,059 |
THE FRANCIS CRICK INSTITUTE |
To maintain unlimited proliferative capacity, cancer cells must maintain their telomeres. ~85% of cancers achieve this by up-regulating telomerase, while the remaining ~15% of cancers employ the Alternative Lengthening of telomeres (ALT) pathway. Currently, there are no targeted treatments for ALT cancers, which have a poor prognosis and are universally aggressive. Insights into the mechanisms that promote/are essential for the ALT process may reveal vulnerabilities that could be exploited therapeutically. However, the lack of a cellular model that permits the induction of ALT has severely limited our ability to interrogate the underlying mechanisms. We have recently made a key discovery that Kaposi’s Sarcoma Herpes Virus (KSHV) infection triggers the stable acquisition of ALT. In this application, we will exploit KSHV to identify the host and virally encoded factors that are critical for ALT induction. Using PICh to interrogate the proteomic composition of telomeres, we have identified 703 proteins that are specifically enriched at ALT telomeres. We will perform a "703 ALT" CRISPR dropout screens to identify genes that modulate/are essential in ALT cancer cells but are dispensable in normal cells. Our proposal will expand our understanding of the ALT process and may identify critical vulnerabilities, which could be targeted therapeutically.
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| 14/07/2020 |
£2,769,513 |
MRC LABORATORY OF MOLECULAR BIOLOGY |
Genetic code expansion enables the site-specific, incorporation of non-canonical amino acids (ncAAs) into proteins, and has enabled diverse biological discoveries. Most experiments incorporate ncAAs in response to amber stop codons. This strategy is limited to incorporating one type of ncAAs into a protein at a time, and there are no other natural blank codons that can be used for ncAA incorporation.
We synthesized a 4 Mb E. coli genome with a compressed genetic code, through the genome-wide substitution of three target codons by defined synonyms. The resulting cell, Syn61, uses 61 codons to encode the 20 canonical amino acids.
In Aim 1 we address the limitations of genetic code expansion by encoding multiple distinct ncAAs in response to blank codons in Syn61. This dramatically expands the applications of ncAA incorporation.
The recoding of Syn61 was based on the prior identification of a synonymous codon compression scheme (a rule that defines which codons to remove and which codons to replace them with). In Aim 2 and Aim 3 we systematically discover allowed synonymous codon compression schemes that we use to create deeply compressed synthetic genomes using accelerated genome synthesis methods. This creates more blank codons that may be reassigned to ncAAs.
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| 14/07/2020 |
£1,104,076 |
UNIVERSITY OF BRISTOL |
The endocannabinoid system (ECS) acts as a negative feedback mechanism to suppress excitatory and inhibitory synaptic transmission. This is critically important for a wide range of brain functions including appetite, pain, and cognition. Moreover, ECS dysfunction is implicated in multiple neuropathologies, and there is increasing scientific and public interest in drugs that target the ECS, including medical marijuana.
The molecular organisation of the ECS is highly unusual because, in reverse to other neurotransmitter systems, endocannabinoids are released from the postsynaptic membrane to activate receptors at the presynaptic membrane. Despite its importance, remarkably little is known about how the enzymes and receptors essential for ECS ‘backwards’ transmission are targeted to, and retained at, opposing sides of the synapse.
Focusing on the primary cannabinoid receptor CB1R and the major endocannabinoid synthesising enzyme diacylglycerol lipase alpha (DAGLalpha) as prototypic examples, we will investigate the protein interactions and pathways that determine the architecture and organisation of the ECS.
Our goal is to define how the differentially polarised trafficking of ECS components to synapses is orchestrated.
This mechanistic knowledge of the ECS will advance understanding of neuronal protein polarisation and inform the design of future strategies to modulate ECS signalling for therapeutic benefit.
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| 14/07/2020 |
£2,105,418 |
UNIVERSITY OF OXFORD |
Invasion of erythrocytes is one of the most critical steps in the life cycle of the malaria parasite. Prevent erythrocyte invasion, and we can prevent parasite growth, disease symptoms and transmission.
Essential for erythrocyte invasion is the PfRCR complex of Plasmodium falciparum, consisting of PfRH5, PfCyRPA and PfRIPR. This proposal will use structural insights to guide experiments to understand the function of PfRCR in erythrocyte invasion, and to guide development of future vaccines and therapeutic antibodies. Over the next five years, I will:
(i) Determine structures of PfRCR and PfRIPR and understand whether complex formation is necessary for invasion.
(ii) Understand molecular mechanisms of the most invasion-neutralising human antibodies targeting PfRH5, PfCyRPA and PfRIPR.
(iii) Determine how PfRH5 induces calcium flux in erythrocytes.
(iv) Use structural insights to design improved therapeutic monoclonal antibodies and vaccine immunogens targeting PfRCR.
These studies will deepen our understanding of this critical event in erythrocyte invasion. They will reveal the human antibody response to PfRCR vaccination and use this insight to guide design of the malaria therapeutics of the future.
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| 14/07/2020 |
£1,201,563 |
IMPERIAL COLLEGE LONDON |
For 500 million years, vertebrates have retained three distinct lymphocyte lineages bearing rearranged receptors– alphabeta T-cells, B-cells, and gammadelta T-cells - suggesting that each compartment is critical to host immunity. We have a good understanding of classical alphabeta T-cells and B-cells but our knowledge of "unconventional" gammadelta T-cells lags far behind. There has been a recent explosion of interest in the gammadelta population and considerable excitement around their therapeutic potential. This is motivated by their unique recognition capabilities, their enrichment at sites of pathogen entry, and potent antimicrobial/antiviral/antitumour activities. Previously assumed to sit at the interface of innate and adaptive immunity, recent work has shown that gammadelta T-cells can be divided into functionally-distinct innate-like and adaptive-like subsets. A knowledge of the dynamics that critically underpin such diverse populations is lacking, hindering fundamental understanding and therapeutic exploitation. We will investigate gammadelta T-cell dynamics in humans including quantification of in vivo lifespans, maintenance mechanisms (de novo production versus self-renewal), and repertoire dynamics relative to canonical adaptive (CD8) and innate-like (MAIT) populations. We will establish benchmark in vivo dynamic measurements for "innate" and "adaptive" human gammadelta T-cell subsets, and generate the first quantitative models of the human gammadelta T-cell compartment.
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| 14/07/2020 |
£1,813,347 |
KING'S COLLEGE LONDON |
Membrane function is fundamental to life. Deregulation of the membrane lipid repertoire has severe consequences for cellular and organismal fitness. Defining how lipid composition controls membrane organization and cellular physiology remains a major challenge in biology. Membrane lipid composition is subject to complex feedbacks and reflects the metabolic and regulatory capabilities of the specific experimental system. I propose to attack this problem by exploiting the natural divergence in membrane lipid composition between S. pombe and S. japonicus, two related genetically tractable fission yeasts with different lifestyles. I believe that our research program integrating comparative analyses and reverse engineering of cellular mechanisms with biophysics and systems approaches, provides an unmatched discovery platform capable of revealing the core principles that govern membrane organization and function. Our research will explain how changes in the architecture of glycerophospholipid fatty acyl tails affect membrane properties. It will provide insights into the organization and evolution of genetic networks regulating membrane homeostasis. Finally, it will test if acquisition of new lipid metabolic functionalities engenders diversification of cellular pathways and organismal physiology.
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| 14/07/2020 |
£1,243,595 |
UNIVERSITY OF CAMBRIDGE |
Genetic and transcriptional studies have demonstrated that shared aetiology between immune-mediated diseases (IMD) is reflected in shared patterns in both data types, and suggested new targets for treatment. However, the huge number of variants and genes measured mean that only a minority of potential information in these data has been harnessed, and disease prognosis and treatment success remains variable and unpredictable. My goal is to overcome this dimensional challenge by developing genomic feature engineering which exploits these shared patterns, to extract new insight from jointly analysing over a hundred existing datasets.
I will generate summary features by tailoring dimension-reduction strategies and applying them to genetic and transcriptomic data from patients and cohorts with related traits measured. I will investigate how each feature contributes to rare and common IMD risk, and prognostic variability within diseases. I will correlate features with molecular measurements and clinical data to understand the gene products they represent, and the situations (cell type, disease state/subtype) in which they are relevant. Finally, through predictive modeling, I will explore the expected impact of targeting these gene products in different diseases and subtypes, to generate, and test, hypotheses about which targets might modify specific IMD activity or progression.
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| 14/07/2020 |
£1,789,979 |
UNIVERSITY OF OXFORD |
Lymphocyte function underpins effective immunity to infection and cancer, and is adversely affected by age in a process called immune senescence, a major obstacle to having a healthy lifespan. The cellular basis of T cell senescence is largely unknown. Maintaining proteostasis, regulated by protein synthesis and degradation, in the face of intrinsic and environmental insults is a key determinant of cellular and organismal lifespan. We will address the hypothesis that modulating the conserved degradation and recycling process known as autophagy, can restore immune responses in lymphocytes in the elderly. We have shown that autophagy prevents immune aging, and demonstrated a decline in autophagic flux in lymphocytes with age, and a global age-related decline of protein translation. But it is uncertain which of the synthesized and degraded proteins are most important. It is clear, however, that the induction of specific repair pathways, including autophagy, extends life and health span. We have uncovered a novel pathway that rejuvenates lymphocyte function by regulating autophagy translationally, which we intend now to fully characterize. Our goal is to identify potential therapeutic strategies for restoring health span in the elderly. This work will also address fundamental gaps in our understanding of the aging process.
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| 14/07/2020 |
£2,345,878 |
UNIVERSITY OF EDINBURGH |
Meiosis generates gametes with half the parental genome through two consecutive chromosome segregation events, meiosis I and meiosis II. Meiotic errors are prevalent in humans, accounting for frequent miscarriages, birth defects and infertility, yet the mechanistic origins of these errors are undefined. Our vision is to discover the molecular basis of the adaptations that sort chromosomes into gametes during meiosis. We will exploit the tractability of yeast meiosis to overcome the limitations of protracted meiosis and scarcity of material in other systems, to address three complementary aims. First, we will determine the mechanism by which kinetochores suppress crossover recombination near centromeres during meiotic prophase, and the significance of this suppression for chromosome segregation. Second, we will reveal how sister kinetochores are specifically fused, and the surveillance machinery re-wired, to permit sister chromatid co-segregation only during meiosis I. Third, we will identify the modified cell cycle controls that drive two consecutive chromosome segregation events during meiosis and determine how these controls couple chromosome morphogenesis to gametogenesis. The molecular pathways we discover will provide a framework for identifying potential sources of meiotic errors in humans.
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| 14/07/2020 |
£1,567,546 |
UNIVERSITY OF OXFORD |
This proposal will investigate the mechanism of cell-to-cell transmission and spread of flaviviruses using Dengue and Zika as model systems. We will therefore address a longstanding debate on how they exit from infected cells, and preferentially spread into specific cell types. Dengue and Zika are the two most prevalent flaviviruses worldwide, sharing significant overlap in their genome architecture and biology. Dengue infects > 50 million people annually, causing severe pathologies. Zika too has emerged as a global threat with recent outbreaks linked to serious neuro-developmental complications in children and Guillain Barré syndrome in adults. No vaccines or therapeutics exist for these viruses, and our current understanding on mechanisms of their transmission and spread is severely limited.
Viral infections spread by overcoming multiple barriers to move from cell to cell. Viral progenies can move across extracellular space either as free particles via fluid phase diffusion, within vesicles, or by cell-cell contacts. To understand transmission, we will therefore address: (i) characteristics of the extracellular virus populations, (ii) whether multiple transmission routes exist (iii) whether the viral envelope is the primary determinant of transmissibility. This proposal builds on our previously published and ongoing studies on viral manipulation of autophagy for assembly and spread.
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| 14/07/2020 |
£1,900,785 |
UNIVERSITY COLLEGE LONDON |
Productive communication between T cells and B cells is vital for protective immunity, however dysregulation of this process can trigger autoimmunity. Costimulatory checkpoints limit T cell help for B cells by controlling the differentiation of follicular helper T cells (Tfh), a cellular subset overrepresented in multiple autoimmune diseases. We have found that anti-CTLA-4 antibodies can trigger spontaneous Tfh differentiation in mice. Targeting CTLA-4 with checkpoint inhibitors in cancer patients may therefore induce Tfh, potentially relevant to the autoimmune side-effects seen with these treatments. Despite their escalating clinical burden, the cellular mechanisms underpinning checkpoint-inhibitor induced autoimmunity remain poorly understood.
In this proposal I will investigate the hypothesis that induction of Tfh responses is a general feature of autoimmunity, reflecting a loss of costimulatory (checkpoint) control. I will explore how CTLA-4 and PD-1 co-operate to regulate Tfh differentiation, and establish the consequence of a Tfh response for tissue autoimmunity. Insights will be drawn from autoimmune patients treated with CTLA-4-Ig, and cancer patients treated with CTLA-4 antibodies. Building on exciting preliminary data, I will determine whether Tfh populations have value in predicting outcomes in classical autoimmunity as well as in checkpoint-inhibitor induced disease.
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| 14/07/2020 |
£64,000 |
WELLCOME TRUST SANGER INSTITUTE |
Productive communication between T cells and B cells is vital for protective immunity, however dysregulation of this process can trigger autoimmunity. Costimulatory checkpoints limit T cell help for B cells by controlling the differentiation of follicular helper T cells (Tfh), a cellular subset overrepresented in multiple autoimmune diseases. We have found that anti-CTLA-4 antibodies can trigger spontaneous Tfh differentiation in mice. Targeting CTLA-4 with checkpoint inhibitors in cancer patients may therefore induce Tfh, potentially relevant to the autoimmune side-effects seen with these treatments. Despite their escalating clinical burden, the cellular mechanisms underpinning checkpoint-inhibitor induced autoimmunity remain poorly understood.
In this proposal I will investigate the hypothesis that induction of Tfh responses is a general feature of autoimmunity, reflecting a loss of costimulatory (checkpoint) control. I will explore how CTLA-4 and PD-1 co-operate to regulate Tfh differentiation, and establish the consequence of a Tfh response for tissue autoimmunity. Insights will be drawn from autoimmune patients treated with CTLA-4-Ig, and cancer patients treated with CTLA-4 antibodies. Building on exciting preliminary data, I will determine whether Tfh populations have value in predicting outcomes in classical autoimmunity as well as in checkpoint-inhibitor induced disease.
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| 14/07/2020 |
£2,388,796 |
IMPERIAL COLLEGE LONDON |
This proposal aims to understand:
1) What circuitries sense the inexorable drive to sleep when we are sleep-deprived? We will investigate if sleep need is sensed locally in the brain by a distributed circuit network that feeds into a central hub, the lateral hypothalamus, providing global restorative sleep. We have identified neurons in the mouse prefrontal cortex, preoptic hypothalamus, and ventral tegmental area (VTA) that sense sleep need and contribute to inducing sleep after sleep deprivation. Learning how responses to sleep deprivation are embedded in distributed sleep circuitry would explain how sleep homeostasis works at the circuit level.
2) Do sedative drugs promote these restorative sleep pathways? How do two important drugs, propofol and dexmedetomidine, intervene in the sleep-homeostasis circuitry? We will search for cells that respond to sedatives to induce restorative sleep without deleterious effects (hypothermia). Understanding this circuitry may identify new drug targets.
3) What is the significance of sleep-promoting circuitry we have discovered in the basal ganglia and midbrain (globus pallidus to lateral habenula to VTA to lateral hypothalamus), which overlaps with circuitry that responds to aversive outcomes and stress? We will investigate if this basal ganglia-triggered sleep helps offline processing of negative experience.
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| 14/07/2020 |
£1,195,323 |
UNIVERSITY OF CAMBRIDGE |
Kidneys play a vital role in homeostasis. Chronic kidney disease (CKD) is characterised by kidney dysfunction and organ fibrosis, and affects millions of patients worldwide, but the underlying pathogenic mechanisms are poorly understood. Using single cell RNA sequencing, we have shown that the human kidney contains a network of tissue-resident immune cells, including macrophages and two subsets of natural killer (NK) cells. These NK subsets have distinct transcriptional signatures suggestive of differing interactions with macrophage subsets, and the potential to variably influence tissue repair/fibrosis by via production of the epidermal growth factor receptor ligand amphiregulin (AREG) and by regulating macrophage polarisation towards a wound-healing M2 phenotype.
My key goals are:
1. To determine the functional characteristics, cellular interactions, developmental relationships and lifespan of NK cell subsets in normal human kidney.
2. To understand how the global kidney immune landscape and NK cell phenotype/function/interactions change in CKD.
3. To determine if NK-cell depletion or NK cell-specific AREG-deficiency affects macrophage polarisation and kidney fibrosis in mouse models of kidney injury.
Answering these questions will provide critical information about tissue immunity in the kidney, delineate previously unappreciated aspects of NK cell biology, and will potentially identify new therapeutic targets for CKD.
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| 09/07/2020 |
£997,614 |
IMPERIAL COLLEGE LONDON |
The Centre for Structural Biology at Imperial College London includes a heavily-used electron microscopy facility on the South Kensington campus that features four electron microscopes for single particle and tomographic analysis of biological samples. A large and rapidly-growing Imperial- and London-based user community spanning molecular biology, chemical biology, and drug development, uses these instruments for sample screening, optimisation, and data collection. These instruments, however, are all based on 20+ year-old archetype, resulting in rising maintenance costs and risk become irreparable any day due to inability to source replacement parts. These machines are also bottlenecks, incapable of providing high-throughput screening, optimisation, and data collection needed to feed high-resolution data collection instruments such as Titan Krioses accessible at various UK-based facilities. Our community is in urgent need of a contemporary electron microscope such as a Talos Arctica capable of both single particle and tomography cryoEM, equipped with technology for rapid screening and optimisation and compatibility with Krios sample handling. The instrument will be embedded and managed within the CSB EM facility and accessible by all CSB users on an hourly user rate basis to guarantee full cost recovery, a company-based service contract, and long-term sustainability.
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| 09/07/2020 |
£172,500 |
IMPERIAL COLLEGE LONDON |
Multiparameter analysis of nanoscale entities such as viruses, nanoparticles and extracellular vesicles is restricted by the limited resolution of standard flow cytometers. Both the nanoparticle and extracellular vesicle fields are rapidly growing in the academic and commercial setting.
We are applying for a state-of-the-art dual-laser Flow NanoAnalyzer (model U30) from NanoFCM, as well as five years discounted servicing and support. The Flow NanoAnalyzer (FNA) is an innovative flow cytometer which has been specifically engineered to surpass the nanoparticle detection limitations of current commercial flow cytometers. In particular, the FNA enables detection of nanomaterials, nano-drug delivery systems, bacteria, viruses, cell organelles (e.g. mitochondria) and extracellular vesicles (e.g. exosomes and microvesicles) within a size range of 7-1000nm. The FNA is equipped with one highly sensitive side scatter channel, a 488 nm laser, a 638 nm laser and three single-photon counting module (SPCM) detectors (525/40 nm, 580/40 nm and > 650 nm) to enable multi-colour/parameter experiments.
The FNA only recently launched in the UK (April 2019). Therefore, if funded, Imperial will become one of the first UK (and potentially European) universities to have this machine. This will attract significant interest from UK, as well as, international academic and industrial collaborators or users.
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| 09/07/2020 |
£1,000,000 |
UNIVERSITY OF GLASGOW |
Magnetoencephalography (MEG) is an advanced technology using super-conducting quantum interference devices (SQUIDs) for measuring the tiny magnetic fields produced by the coherent electrical activity in groups of neurons. MEG is the only neuroimaging technology that enables non-invasive recordings with both excellent temporal and good anatomical resolutions. Such spatiotemporal accuracy is instrumental for discovering the mechanisms underlying mental functions and deficits in healthy and impaired brains.
We seek Wellcome Trust funding to replace our 12-year old MEG system with a state-of-the-art TRIUX-neo from MEGIN Ltd. The TRIUX-neo is an ultra-sensitive system based on new technology that combines MEG recordings with high-density EEG, online head-motion tracking and a helium recycling mechanism now essential with worldwide helium shortage.
With the TRIUX-neo, our multi-user MEG group (with significant Wellcome Trust funding, Investigator, Innovator, Seed and Sir Henry Wellcome Fellowship) will keep enhancing its cutting-edge, unique, cohesive and collaborative research and pioneer new methods and techniques across our extensive platform of in-house imaging facilities (i.e. EEG, MEG, NIRS, 3/7T fMRI).
Key MEG innovations will focus on understanding brain network dynamics and oscillations in health and disease, using information theory and advanced network analyses and unique data fusion of EEG and 3/7TfMRI and neurostimulation (TMS, tES).
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| 09/07/2020 |
£232,273 |
BIRKBECK UNIVERSITY OF LONDON |
ISMB (Birkbeck/UCL) is renowned for its research in structural biology, successfully combining X-ray crystallography and electron microscopy and supporting users from a wider scientific community. The current set up for crystallisation includes a nanoliter liquid handler (Mosquito, SPT Labtech), an old Perkin-Elmer liquid handling robot for sample optimisation and an outdated Minstrel/Rigaku automated imaging suite. Recent crystallography beamline technological developments at high-end synchrotrons have pushed the boundaries of data collection and reduced the usable size of crystals down to a few microns. However, our current instrumentation does not allow us to take full advantage of these new technologies since refinement of crystallisation conditions, and monitoring of ‘microcrystals’ growth, cannot be managed by our outdated equipment. Moreover, two of the existing instruments are no longer supported by authorized services.
Therefore, we are requesting the purchase of a new state-of-the-art ‘imaging hotel’ (UVEXps, swissci) and liquid handler (Dragonfly, SPT Labtech). Specifically, we propose to purchase a microliter liquid handler for optimisation of crystallisation conditions and a high-resolution crystal imaging system for storage, monitoring, imaging and detection of protein crystals. The two instruments will complement the existing liquid handler (Mosquito), while offering more flexibility to all users by remote access.
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| 09/07/2020 |
£162,283 |
UNIVERSITY OF LEEDS |
The Flow Cytometry & Imaging Facility, Leeds Institute of Medical Research, needs to expand capability and capacity for live cell and high content imaging (HCI) to serve the local and wider scientific community. We request part-funding of a LIPSI high content/multichannel live-cell imager with environmental control (Nikon Instruments UK Ltd). The acquisition of a state-of-the-art LIPSI will replace our obsolete Operetta and Incucyte instruments and will transform our Facility by allowing fully integrated, automated, high-throughput, and high-content/live-cell imaging. The system allows very rapid epifluorescence (six simultaneous fluorescence channels), chromogenic and DIC acquisitions whilst running multiple time-lapse assays with sampling rates up to 60fps. This allows imaging of long-term live-cell 2D/3D cell cultures, tissue sections, small model organisms or rapid HCI of fixed cells. For increased throughput, the LIPSI includes motorised stage, robotic handler and environmentally-controlled plate-holder. This enables streamlined automated processing of multiplexed long-term live cell functional assays, with complex imaging schedules in both hypoxic and normoxic environments for up to 20 plates. Standard acquisitions comprise multichannel, time-lapse, multiple-positions, z-stacks, large images and multidimensional imaging using standard plastic or glass SBS plate, dish and slide formats used within the Facility.
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| 09/07/2020 |
£189,485 |
UNIVERSITY OF LEEDS |
We request a 75% contribution to purchase two IncuCyte S3 Live-Cell Analysis Systems, together with archive data storage capacity (£189,485). These instruments are designed to acquire real-time growth, migration, morphology, phenotypic and gene expression data from virus-infected cells in microplates. They will be located in newly-opened Biological Safety Level 3 (BSL3) and BSL2 laboratories, transforming existing capacity for real-time analysis of virus-infected cells and enabling ambitious plans for expansion of virology research. The overall aims of the research supported by these instruments are: 1) to understand the molecular mechanisms by which viruses enter cells, replicate their genomes and assemble into infectious virions, and 2) to drive early-stage development of new anti-viral therapeutics (eg screening compound libraries). The IncuCyte instruments will facilitate both work streams. They will be housed in standard cell culture incubators and can be remote controlled allowing the analysis of cell parameters over time safely without disturbance. In order to effectively train users, provide technical advice, oversee usage and manage the instruments, we also request funding for 10% of the salary of the current BSL2/BSL3 laboratory manager, and 5% of the BioImaging facility support scientist over 5 years (£31,390).
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| 09/07/2020 |
£271,222 |
UNIVERSITY COLLEGE LONDON |
This application is for the purchase of a BD Aria-Fusion fluorescence activated cell sorter. The instrument performs high-speed multi-parameter sorting, allowing isolation of rare cell subsets and supporting single-cell genetic and functional analyses. It will enable scientists at the UCL Institute of Immunity and Transplantation (IIT) to be at the forefront of studies of the patho-physiology of the human immune system and responses to disease treatments.
This state-of-the-art sorter is essential to allow us to maintain a cutting edge flow-cytometry core facility in the newly constructed Pears building, which will house the IIT from late 2020. The Pears building is a £61 million joint project between UCL and the Royal Free NHS Foundation Trust to create a world-leading centre for disease-focused immunology research. The building will accommodate some 20 research groups comprising approximately 200 scientists. The translational immunology programs of the IIT include mechanistic studies in animal models, genetic and functional analyses of the human immune system, high-dimensional analysis of clinical samples and the monitoring of patients participating in novel immunotherapy trials. The technical capability of the FACS-Aria-Fusion is therefore required to support a wide variety of cutting-edge research programs in infection and immunity.
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| 09/07/2020 |
£1,000,000 |
UNIVERSITY OF LEEDS |
The Astbury Biostructure Laboratory, was established in 2015 with University of Leeds investment, and a Wellcome multi-user equipment award, allowing us to install two Titan Krios microscopes (2016). In just three years, we have established an international reputation for excellence in cryoEM, and a buoyant user base that means our facility is already operating at capacity. We request funds to upgrade our microscopes, aiming to increase data acquisition rates, whilst improving data quality, allowing us to shorten session lengths, increase sample throughput, and introduce new methodologies.
Upgrades will include:
1. A ThermoFisher Falcon-4EC camera on Krios#1
2. A Gatan Bioquantum K3 on Krios#2
3. Aberration-Free/Fringe Free Imaging Systems (both microscopes)
4. EPU-D software for electron diffraction (Krios#1)
5. Whole-system maintenance contract extensions to 5 years from installation.
We anticipate a 5-8x improvement in data acquisition, empowering users to drive more challenging biological and biomedical discovery. We will be able to determine new high-resolution structures and integrate them into their cellular/tissue context, helping us to understand the molecular basis of diseases such as infections, cardiovascular disease, degeneration and cancer.
We request £1m from Wellcome, with a University capital contribution of £325k, plus salary costs, Giving a total project cost of ~£2.13m.
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| 09/07/2020 |
£517,128 |
IMPERIAL COLLEGE LONDON |
We propose the establishment of a dedicated facility for three-photon live imaging of deep tissue. This will comprise a dedicated multiphoton microscope (Scientifica Hyperscope or similar) with optical components anti-reflectance coated for long-wavelength light (up to 1700 nm) for three photon imaging, together with a suitable laser excitation source. Funding is requested for a high power ultrafast laser (Amplitude Systems Satsuma 40/40 or similar) producing up to 40W at 1030nm, pumping an Optical Parametric Amplifier (APE/Amplitude Mango SP or similar) to produce 1150-1700 nm light at a 2 MHz repetition rate, optimised for three photon excitation of both green and red fluorophores. The microscope will be mounted on a single large antivibration table. The three-photon microscope will be installed in a Home-Office designated small animal imaging suite. A dedicated facility manager (with substantial expertise of in vivo multiphoton imaging including biomedical optics), will run the facility, ensuring continued high imaging performance, and maximising effective and collaborative use of the facility. The imaging suite will provide a unique capability for deep tissue imaging by Wellcome Trust funded researchers across a range of biomedical application areas, including neuroscience, cardiology, stem cell biology and respiratory physiology.
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| 09/07/2020 |
£674,756 |
UNIVERSITY COLLEGE LONDON |
The requested equipment is the ThermoFisher Orbitrap Eclipse Tribrid Mass Spectrometer with an Ultimate3000 LC system. This new instrument is designed for high-end proteomics, top-down protein characterisation, and crosslinking analysis and is equipped with the latest Orbitrap analyser, which offers higher resolution, sensitivity and acquisition rates compared to previous Orbitraps.
These features result in improvements to both limit of detection and quantification of peptides, ultimately leading to enhanced quantitative proteomics and crosslinking analysis.
Its atypical geometry allows multistage fragmentation of ions (MSn), which is necessary for multiplexed proteomics experiments and for advanced crosslinking analyses using cleavable crosslinkers. Combined with a novel in-built real-time search algorithm, fragment ions of interest e.g. crosslinked peptides can be preferentially selected, further increasing the depth of analysis. The Eclipse is also capable of top-down proteomics experiments which is an ideal method for the study of proteoforms and labile post-translational modifications.
We will use the Eclipse to study the biological processes underpinning viral secondary envelopment, type 2 diabetes, cell responses to protein misfolding and cell competition; these studies are challenging due to the low amounts of sample available. The sensitivity and robustness in protein quantitation provided by the requested instrument will be key for their success.
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| 09/07/2020 |
£369,413 |
UNIVERSITY OF OXFORD |
Protein crystallisation continues to play a central role in structural biology as the foundation for determining the atomic structures of macromolecules, understanding disease mechanisms, vaccine design and drug discovery. Several challenges remain, including crystallisation of multiprotein complexes, membrane proteins and time-resolved studies from systems directly engaged in catalysis, cell signalling, and ion movement. Studying different levels of structural complexity and dynamics is essential to understand protein function in health and disease. Technical developments are contributing to progress in these areas, including X-Ray Free Electron Lasers (XFELs) and Serial Synchrotron (SFX) data collection, coupled with advances in crystal imaging, which enable researchers to identify microcrystals that were previously not detectable with older instrumentation. This proposal builds on these advances through the acquisition of cutting-edge instrumentation for protein crystallisation, including advanced UV and multi fluorescence imaging optics and lipid cubic phase fluorescence after photobleaching (LCP FRAP) systems, which will provide access to, and development of, novel methods to detect and grow protein crystals of challenging multiprotein systems. A new multiuser protein crystallisation facility, centred in Oxford Biochemistry, but incorporating several stakeholders from across the wider University research community, will provide access and training.
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| 09/07/2020 |
£367,500 |
NEWCASTLE UNIVERSITY |
Multi-dimensional single cell analysis using cytometry technologies is one of the most significant contributors to our understanding of complex cellular compartments such as the immune system. In recent years we have seen an explosion of new technologies and methodologies that have expanded the number of parameters per cell such as scRNA-seq, but we have suffered from an inverse correlation with scalability and throughput due to significant associated costs. Our goal is to successfully introduce Spectral Flow Cytometry (SFC) as a new, sensitive, scalable and future proof multi-dimensional single cell phenotyping technology to the vibrant, multi-user core facility. We will use the immense capabilities of SFC to understand rare immune-deficiencies (Hambleton); decode the developing blood and immune system (Haniffa); dissect the role of macrophages in inflammatory disease through somatic mutation analysis (Collin); unravel molecular processes in host-pathogen interactions that dictate immune responses (Trost); understand more about Giant Cell Arteritis (Reynolds), anti-viral responses (Duncan), immune surveillance of liver cancer (Wilson) and the control/relapse of Rheumatoid Arthritis (Pratt). We will also address fundamental questions about the technology and methodology itself through expanding the parameter set using probes and label free measurements based on auto-fluorescence (Filby) as well as develop analytical tools (Rico).
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| 09/07/2020 |
£1,560,990 |
EUROPEAN BIOINFORMATICS INSTITUTE |
Single Cell Expression Atlas (https://www.ebi.ac.uk/gxa/sc) is an open science resource that offers powerful searches for a gene expression data in different cell types, across tissues, species and conditions. Since its launch in May 2018, the Single Cell Expression Atlas has annotated and reanalysed 132 single cell RNA-Seq (scRNA-Seq) experiments across 12 different species that can be searched and visualised through its web interfaces. The SCEA is unique in that it reprocesses raw scRNA-Seq data in a standardised way. This proposal aims to keep up with the rapid technology development, expand the resource with new data modalities, continue expanding the species coverage and cross-species mapping and expand the functionality of the resource. In particular, we will integrate single cell data sets from spatial and in-situ transcriptomics technologies, as well as emerging single cell omics protocols. Additionally, we will expand the types of analyses performed to facilitate study integration, cell type discovery and annotation. Finally, we will develop anatomograms at the organ, tissue and cell type level to enable intuitive interpretation of the experimental results and easily integrate the different types of data on the user interface.
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| 09/07/2020 |
£1,504,262 |
UNIVERSITY OF CAPE TOWN LUNG INSTITUTE |
We propose to create an African biorepository and linked comprehensive database to support cross-disciplinary research that advances child health. The biorepository will consolidate > 527,000 samples and data from three ongoing large population-based studies: (i) Drakenstein Child Health Study, a birth cohort with samples from parents, children and the environment collected antenatally through childhood; (ii) paediatric tuberculosis studies with samples longitudinally collected over 15 years; and (iii) Cape Town Adolescent Antiretroviral Cohort, a study of HIV-infected adolescents on antiretroviral-therapy and uninfected controls investigating development and determinants of chronic disease. Ongoing prospective data and sample collection for the next 5 years, in these and other child health studies, will substantially grow this facility ( > 732,000 samples). The facility will support several Wellcome Trust grantees and serve as a platform for cross-disciplinary research, linking metadata and samples to different databases (demographic, clinical, radiological, microbiological, genetic, transcriptomic, environmental, immunological, psychosocial). A key focus is on infectious exposures and development of non-communicable diseases, key priorities in African health. A web interface will be created for investigators to access samples or datasets. This resource will be invaluable for current and future collaborative research to advance child health and to provide African-specific data and samples.
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| 09/07/2020 |
£1,476,141 |
EUROPEAN BIOINFORMATICS INSTITUTE |
The Electron Microscopy Public Image Archive (EMPIAR) was developed following consultations with the cryo-EM community highlighting the pressing need for public dissemination of image data underpinning cryo-EM structures. Since 2014, EMPIAR has quickly grown in volume (286 entries; 284 terabytes as of 01/04/2020) and established its role and value for the community ( > 180 EMPIAR citations). Its remit now includes micro-crystal electron diffraction (microED), soft-X-ray tomography (SXT), and volume-EM (including Focused Ion Beam and Serial Block-Face SEM) data. The main goals of this grant are to streamline and facilitate the deposition process (encouraging deposition and improving quality and quantity of deposited information) and to enhance and facilitate data reuse. All hardware and IT infrastructure will be provided by EMBL-EBI.
Specific aims:
Fully support deposition of volume-EM data;
Support handling large (tissue- and organism-level) 3D-volumes by pump-priming EMPIAR with flagship connectomics and non-connectomics datasets;
Enable efficient and interactive reuse of large 3D-volumes by supporting multiscale imaging formats;
Facilitate potential mandatory deposition by simplifying the deposition workflow and enhancing data reuse;
Improve support for correlative imaging data, working with stakeholder communities and the EMBL-EBI BioImage Archive;
Prepare for rapid growth of data volumes by evaluating and implementing data-compression methods.
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| 09/07/2020 |
£1,132,223 |
NATURAL HISTORY MUSEUM |
Schistosomes, transmitted by freshwater snails, infect > 200 million people in low/middle-income countries, particularly sub-Saharan Africa. While substantial advances have been made in the control of human schistosomiasis, the diversity and complexity of schistosomes and their specific fresh-water snail hosts warrants fundamental research requiring lifecycles and live material. Without the availability of Schistosoma lifecycles, future research faces substantial obstacles; currently very few labs are able to maintain the parasites and/or the snail hosts and current long-term cultures lack the genetic heterogeneity observed in natural populations. Our proposal is for the creation of a Schistosome and Snail Resource (SSR), maintaining live material and lifecycles that are currently limited or that do not exist elsewhere. The SSR will provide access to 1) the "standard/model" Schistosoma and snail species; 2) key African Schistosoma species/strains; 3) cultures of diverse snail vectors, enhancing current research and capacity while enabling new research avenues. Our historical expertise in establishing and maintaining unique schistosome and snail isolates from different endemic settings, together with our state-of-the-art snail facility (NHM) and LSHTM rodent facility will facilitate the development of the resource. The SSR will add considerable value by facilitating priority research needed to support schistosomiasis control and elimination.
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| 09/07/2020 |
£1,288,017 |
UNIVERSITY COLLEGE LONDON |
We are seeking to acquire the resources to develop a unique X-ray 3D nanoscope. We will need: custom-source, isolation, manipulators, custom-detector, radiation-safe enclosure, two PDRAs (hardware- and software-focussed) and 1year system engineer for the transition to the long-term maintenance/management of the instrument.
We plan to build a nano-resolution multi-contrast 3D scanner with transformative potential across diverse disciplines, including cellular structural biology, pathology, musculoskeletal and respiratory medicine, tissue engineering and child health.
This will create a multi-user tool, benefitting researchers across multiple specialties. The simultaneous attainment of nano-scale resolution, unprecedented scale range (six orders of magnitude,5cm/50nm), multi-contrasts and a wide energy range will make the X-ray nanoscope proposed here a unique non-destructive 3D imaging tool.
Its key advancements will be ultra-high-resolution zoom-ins on intact samples, whose entire structure is measured at a lower resolution, combined with multi-contrast modes arising from phase effects. A simple analogy of this new X-ray tomography paradigm is the way we navigate digital maps. We use coarse resolution at large scales, blowing-up in precise locations of interest. Both capabilities must be concurrently present: it would not be useful to navigate large areas at highest resolution (lost in space) and having only coarse resolution would lack invaluable insights.
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| 09/07/2020 |
£845,715 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
We will establish a facility for the transmission of human malaria parasites to the mosquito vector and onwards to humanized mice that is open to all members of the research community. Owing to the difficulty in transmission of human malaria parasites in laboratory settings, only few facilities exist where this can be achieved consistently. The three UK facilities capable of this are not open facilities, and none have established the humanized mouse model for investigating the liver stage of the parasite. Notably, this facility will enable the investigation of transmission-blocking compounds, malaria vaccine development, basic research into the interaction of the parasite with the mosquito host and the mammalian liver using a humanized mouse model, the effect of insecticides on the transmission of parasites by insecticide-resistant mosquitoes, the trial of specific genetic modifications of mosquitoes, genetic crosses of malaria parasites and many other investigations. This will make available avenues of research that are currently out of reach for most members of the research community and support the acceleration of new and innovative interventions to halt the spread of malaria.
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| 09/07/2020 |
£1,282,716 |
UNIVERSITY OF DUNDEE |
Bioimaging measures the structure, constitution and dynamics of molecules, cells, tissues and organisms in biological systems. Data are often GBytes or Tbytes in size, cover space, time and other dimensions, include complex metadata that describe experimental setups, acquisition parameters and analytic outputs and are stored in 100s of different proprietary file formats. The scale and complexity of these data are a consistent, unsolved block to researchers making their bioimaging data public and FAIR, despite the fact that open data sharing and publication are mandated by the Wellcome and many other funding agencies.
OME is a globally recognised, open source bioimage data specification and software project (https://www.openmicroscopy.org). Since 2002, OME's OME-TIFF file format and Bio-Formats file translation library have served as the global de facto standard for accessing bioimage data, but the capabilities of these tools will soon be surpassed by the growing volume and complexity of bioimaging datasets. We propose to build next generation bioimage file formats, flexible data models, data linkages and transfer tools to serve the needs of the rapidly evolving bioimaging community and feed new public data repositories and databases. The software will be liberally licensed to allow adoption across the research and industrial bioimaging communities.
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| 09/07/2020 |
£635,056 |
UNIVERSITY OF SHEFFIELD |
AFM has unique capabilities for understanding life, and is able to image living systems in their native state under physiological conditions with molecular resolution. However, technologically, it is where EM was in the 1990s – far from delivering its theoretical potential when imaging biology. By understanding the physical principles of the technique and systematically optimising the instrumentation, the potential of EM has been unleashed in recent years. We aim to drive a similar "resolution revolution" in AFM, developing an instrument that can:
Image functioning biological molecules in intact systems, including living cells, without perturbing their function or structure.
Obtain these images with sufficient resolution to identify biomolecules by their topography.
Accurately measure the organisation of biological molecules in complex, native samples.
We will do this by targeting fundamental weaknesses in AFM technology:
Reducing the thermal noise of the cantilever by producing smaller and softer cantilevers, and a microscope that can use them, reducing the imaging force 10-100x compared to the current state-of-the-art.
Reducing positioning noise and drift by developing a hierarchical, interferometric closed-loop scanner that reduces noise by > 10x and drift by 100-1000x compared to the current state-of-the-art, providing traceably accurate measurements of size and position.
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| 09/07/2020 |
£983,193 |
UNIVERSITY OF YORK |
A comprehensive understanding of communication in both healthy and diseased cells requires new tools to quantify the spatial distribution, onset and rate of protein secretion. To address this challenge, we will develop an in vitro technology that maps the three-dimensional (x, y, time) distribution of multiple cell-secreted molecules, such as chemokines, hormones, and cytokines, with single cell resolution. This technology allows to better characterise the heterogeneity of cell populations in response to stimuli and to define mechanisms of inter-cellular communication. Our innovation exploits the sensitivity of optical resonances to map the secretion of specific proteins without the need for a labelled antibody. Critically, and in contrast to competing technologies, such label-free approaches enable protein detection in real time. The photonic sensor can be fabricated at low-cost and can be integrated into standard commercial microscopes rendering the technology widely applicable. We have already demonstrated the technology and will now optimise its performance, develop its capability to detect at least 3 different types of proteins in parallel and work with a commercial partner to develop a system compatible with a laboratory-standard inverted microscope. We will engage with the community through exemplar projects that span infection and immunity, cancer, haematology and vaccinology.
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| 09/07/2020 |
£851,128 |
UNIVERSITY COLLEGE LONDON |
We will significantly expand CATH, widely used by biomedical researchers, and enhance its value for disease analyses. Data on disease-associated genetic variations is vastly increasing but to fully exploit it we must understand how the resulting residue mutations impact protein functional sites and therefore functions. We will use CATH to predict the impact of variants on diseases and drug responses, enabling personalised medicine.
CATH-FunFams are functional sub-classifications of CATH evolutionary superfamilies and the only structural resource comprehensively linking variants, structure and vast sequence data for predicting functional sites accurately (FunSites). Close proximity of disease variants (residue mutations) to FunSites, in 3D, is a key indicator of pathogenicity.
Our expanded CATH-FunFams and FunSites will enhance machine learning methods to predict functional impacts and drug responses/side effects, including for different genders and ethnicities.
We will:-
1. Expand CATH-FunFams and FunSites > 5-fold by adding sequence data from metagenomes.
2. Expand CATH-FunSites further by integrating comprehensive data from PDBe-KB, PDBsum and VarSite.
3. Develop machine-learning tools that exploit data from (1) & (2) to predict impacts of genetic variations in different populations.
4. Integrate drug data into FunFams and develop tools to predict drug repurposing/side effects.
5. Develop intuitive webpages reporting functional impacts/drug repurposing/toxicity.
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| 09/07/2020 |
£1,391,682 |
EUROPEAN BIOINFORMATICS INSTITUTE |
InterPro is a core protein data resource that amalgamates 13 protein family databases (including Pfam) to provide the definitive description and classification of protein domains and families. Various scientific communities rely on the range of annotations provided by InterPro and its member databases to acquire novel insights into the vast amounts of new DNA sequence data, enabling scientists to interpret experiments and design new ones based on annotations spanning complete genomes down to single residues. The past five years have witnessed a major increase in the scale of sequences, concomitant with the emergence of AI/ML approaches for unlocking the biological signals encoded within the data. This project will exploit these innovative approaches to enhance protein annotations and refine classifications through the incorporation of additional data types, along with the application of ML methods and organisation of the protein family data. We will integrate KOfams and AMRFinder into InterPro, while continuing to scale the InterPro/Pfam/HMMER resources to tackle billions of proteins. Cumulatively, these developments will accelerate biomedical research by facilitating scientists to decipher the effect of human mutations, understand drug interactions, combat antimicrobial resistance, and tackle emerging pathogens.
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| 09/07/2020 |
£1,559,880 |
UNIVERSITY OF MANCHESTER |
Our goal is to enhance and accelerate the validation and translation of new drug targets identified by the UK academic biomedical research community. In order to achieve this we will establish a DNA-Encoded Library (DEL) screening resource that will provide cost-free and commitment-free access to high-throughput compound screening for academic research groups, by;
1) Designing and preparing DNA-encoded libraries containing 5-10 million diverse and drug-like compounds, representing a unique resource for academic researchers.
2) Utilising these libraries to undertake 40 target selections against novel protein targets for academic users, delivering validated hit compounds to > 20 research groups by 2025.
3) Developing a sustainable and expandable resource which will continue to deliver beyond the current funding period.
DELs are an established screening approach that are utilised by the majority of large pharmaceutical companies. The technology allows for the rapid identification of ligands for a target protein with a very simple protocol compared to other screening approaches. Active compounds are identified by affinity selection of protein-binding compounds from libraries containing millions of different compounds that are each linked to a unique DNA sequence. The DNA tag allows for rapid and high-throughput deconvolution of the active compounds by next-generation sequencing.
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| 09/07/2020 |
£1,062,390 |
UNIVERSITY OF EDINBURGH |
Synapses are damaged in over 130 different brain diseases and yet thus far there are no reliable ways to measure synaptic structure or function in vivo in a preclinical or clinical setting. The recent discovery of promising Positron Emission Tomography (PET) radiotracers for imaging synapses, by targeting the synaptic vesicle glycoprotein 2A (SV2A), has the potential to transform clinical diagnosis, neuropathology, drug development and treatment of multiple brain diseases. Two major bottlenecks to deliver on this promise are: (1) the unavailability of high-yield and high-molar activity [18F]MNI1126, the lead SV2A PET radiotracer; and (2) the lack of a quantitatively accurate and validated SV2A brain PET atlas during normal aging in rodent models. This project will generate synthetic routes and radiochemistry methods for efficient production of [18F]MNI1126, it will develop detailed template resources for quantitative analysis of SV2A PET signal in different brain regions over the course of natural aging in the rat and mouse, and it will validate SV2A PET in vivo outcomes at unprecedented scale and resolution using synaptome mapping technology. The development of SV2A PET technology proposed in this award will catapult the use of quantitative SV2A PET in many brain diseases in humans and model organisms.
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| 23/06/2020 |
£917,588 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
In sub-Saharan Africa, over 50 million people have chronic kidney disease (CKD) making Africa the continent with the highest burden of CKD in the world. With rapidly increasing urbanisation, trends towards unhealthy diets, obesity and increases in metabolic risk factors, the projected increase in the prevalence of CKD may be even greater in Africa than in other parts of the world.
Over the past decade, genome-wide association studies have uncovered numerous genetic determinants of CKD in European and Asian ancestry populations. These studies have led to numerous novel findings, which are helping improve our understanding of factors and pathways affecting both normal and pathologic kidney function. However, to date, there is no known published GWAS of CKD in any continental African population.
Key goals include
Conduct large-scale genomic studies of CKD in Africa which will potentially provide new opportunities to identify the biological determinants of CKD in individuals of African ancestry.
Leverage the low linkage disequilibrium between genetic markers in African populations to conduct fine-mapping of novel and previously identified signals in the trans-ethnic meta-analysis.
Develop a Polygenic Risk Score for CKD risk in Africa and assess whether cardiometabolic traits/diseases are causally related to the risk of CKD in Africans.
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| 23/06/2020 |
£613,982 |
NOGUCHI MEMORIAL INSTITUTE FOR MEDICAL RESEARCH |
Some bacteria species in the mosquito midgut demonstrate anti-Plasmodial effect independent of the mosquito immune system. Understanding this mechanism could help propose bacteria-mediated strategies for targeting and blocking transmission without producing transgenic bacteria. This project proposes to identify mosquito midgut bacteria that secrete anti-parasitic factors and investigate their variations in natural Anopheles mosquito populations. Mosquito stages of P. falciparum will be exposed to spent culture media of midgut bacteria species through in vitro and in vivo (using axenic mosquitoes) assays and developmental and functional parasite effects assessed by immunofluorescence microscopy. The biological significance of the bacteria secreted products will be confirmed by comparing with parasite exposure to bacteria cells. The natural prevalence of effective bacteria will be investigated in blood-fed field-caught Anopheles malaria vector species from areas of high and low malaria transmission using 16S sequencing. In addition, bacterial metabolites will be identified by LC MS/MS for further investigations into their mechanisms of cell activity. It is expected that results from this study will increase our knowledge in the biological role of specific bacteria in natural variations of vector competence and reveal bacterial products from mosquito microbiome that can be further explored for parasite transmission-blocking in the mosquitoes.
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| 23/06/2020 |
£695,284 |
CENTRE FOR RESEARCH IN INFECTIOUS DISEASES (CRID) |
Insecticide resistance is threatening effectiveness of insecticide-based interventions to control malaria across Africa. However, the impact of this resistance on malaria transmission remains a matter of debate. It is not yet well established whether insecticide resistance, particularly metabolic resistance, in addition to allow survival to insecticide exposure, positively or negatively affect capacity of vectors to develop and transmit malaria parasites. Taking advantage of the recent designs of the first simple DNA-based assays allowing to track cytochrome P450- and glutathione-S-transferase mediated metabolic resistance in the major malaria vector Anopheles funestus, this project aims at establishing the impact of metabolic resistance on malaria transmission in Africa, to improve resistance management. More specifically, I will: Aim1) Investigate the influence of metabolic resistance on the development of P. falciparum in An. funestus using GST and P450 markers; Aim2) Characterize the transcriptomic changes accompanying P. falciparum infection in metabolic insecticide resistant An. funestus using RNAseq; Aim3) Investigate interactions between metabolic resistance and Plasmodium immune response genes in An. funestus using functional genomics (RNAi).
This project will benefit from the expertise gained during my Wellcome Trust Training Fellowship including the successful rearing and establishment of experimental infections of field An. funestus using natural P. falciparum isolates.
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| 23/06/2020 |
£103,661 |
ABRASCO |
The 2030 Agenda for Sustainable Development highlights the need to prevent and respond to violence against women and girls. It also affirms the need to invest in early childhood care for the promotion of sustainable development in low and middle-income (LMICs). Intimate partner violence (IPV) is one of the most common and extreme manifestations of gender inequality worldwide, and has a higher prevalence and more severe consequences for women and children living in LMICs. I aim to examine the association of IPV with parenting practices and early childhood development in LMICs. This will be done using data from nationally representative household surveys (DHS) carried out since 2010 in at least 10 LMICs, and a large population-based prospective cohort study in Brazil, following over 4,000 children born in 2015. A key objective of the project is to explore whether women´s mental health mediates the proposed associations, and the role of women’s empowerment levels in the associations under study. The empirical evidence generated from this project will contribute to increasing visibility of the intergenerational consequences of IPV on children and provide guidance for the direction of global resources to prevent gender-based violence.
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| 23/06/2020 |
£241,245 |
AFRICA HEALTH RESEARCH INSTITUTE |
HIV induces B-cell defects that could impair the development of effective antibody responses, such as broadly neutralizing antibodies (bNAbs). However, some rare patients still develop anti-HIV bNAbs. Such responses can be mimicked with vaccines for protection against HIV. The B cells that develop breadth despite the ongoing HIV-induced immune defects could have unique profiles that enable their survival and functionality. The aim of this work is to characterize the transcriptional and phenotypic profiles of B cells that encode for anti-HIV bNAbs and their precursors/intermediates. I will use longitudinal clinical samples from well characterized HIV-infected individuals who have broadly neutralizing sera. I have already isolated a bNAb from this cohort by FACS-sorting of epitope specific memory B cells and cloning the immunoglobulin genes. I am currently isolating bNAbs from the other individuals. This will create a platform for subsequent characterization of the B cells that encode for the bNAbs. I will then characterize the phenotypic and transcriptional profiles of epitope specific memory B cells that encode for the bNAbs lineages using paired flow cytometry, cloning and single cell RNA-seq. This will reveal the profiles that, if induced with appropriate adjuvants, could promote elicitation of protective anti-HIV bNAbs after vaccination.
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| 23/06/2020 |
£257,984 |
UNIVERSITY OF OXFORD |
Rickettsia typhi is an obligate intracellular Gram-negative bacterium causing murine typhus. The disease is globally distributed but neglected. It is an important cause of acute febrile illness in Laos. Although murine typhus is treatable, a clinical trial by Newton P et al. (2019) suggested that azithromycin is inferior to doxycycline. However conventional antibiotic susceptibility testing was not performed to corroborate this finding since no methods exist. Therefore, there is a need to develop a highly sensitive qPCR method comparable with the gold standard method of the plaque assay to assess antimicrobial susceptibility of R. typhi isolates as well as investigation of the genetics and/or metabolism of this bacteria, and to correlate the findings with clinical response to treatment. To estimate the rickettsia clearance, we will characterise the R. typhi DNA load using qPCR in patients from a pilot study of murine typhus patients receiving doxycycline or azithromycin. Moreover, optimised conditions for R. typhi growth including nutrient requirement for development of a host cell-free culture medium using R. montana as a model to simplify antibiotic susceptibility testing of this bacteria will be investigated. The proposed work will improve our understanding of appropriate murine typhus treatment in Laos.
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| 23/06/2020 |
£292,294 |
COLLEGE OF MEDICINE, UNIVERSITY OF IBADAN |
Depression is a common and disabling condition among the rapidly growing population of older people in low- and middle-income countries (LMICs). The burden is particularly high among older Nigerians. Yet, there is a large unmet need for treatment, possibly in part because available care is inaccessible and not age-appropriate for the older person. In line with global priorities, as envisioned in the Sustainable Development Goals to leave no one behind in the provision of quality health care, there is a pressing need for an integrated model of community-based mental health care that encompasses health, social, and informal care for older people in LMICs. Building on prior considerable work by our group to scale-up mental health care with the aid of the W.H.O Mental Health Gap Action Programme Intervention Guide, we now wish to leverage on the e-version of the tool, by 1) adapting it for the care of older persons with late-life depression through a user driven iterative loop process in which contextual, socio-cultural and health factors in the lived experience of late-life depression are incorporated; and 2) testing, in a pilot hybrid (effectiveness-implementation) design, effectiveness, cost-effectiveness, and factors that may affect the delivery of the intervention in routine care.
|
| 22/06/2020 |
£17,900,000 |
UNIVERSITY OF OXFORD |
The Wellcome Thailand AAP has conducted high quality impactful research for 40 years on infectious diseases of major public health concern, leading to the widespread adoption of new approaches and treatments for many of them including malaria, melioidosis, and rickettsial infections. In our fifth decade we will focus on ensuring sustainable impact and influence on policymakers by strengthening our research network and developing the capabilities of our partner institutions. Our vision is to:
1. Through research continue to address public health problems with regional and global relevance, using cutting edge approaches to seek affordable and deployable solutions to disease prevention, diagnosis and patient management.
2. Maximise our public health research’s uptake and impact, incorporating health economics analysis and goal-driven engagement with policymakers, national academic institutions, hospitals, industry partners, communities and the general public.
3. Work with our local host institutions to increase their national and global impact by integrating activities including training programmes, joint research projects, and supporting partner-led programmes to translate research into policy and practice.
Our goal is to improve life quality and expectancy by reducing the adverse impact of infectious diseases, which account for much of the disparity in health metrics between low and high income countries.
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| 22/06/2020 |
£24,589,618 |
UNIVERSITY OF OXFORD |
The Wellcome Thailand AAP has conducted high quality impactful research for 40 years on infectious diseases of major public health concern, leading to the widespread adoption of new approaches and treatments for many of them including malaria, melioidosis, and rickettsial infections. In our fifth decade we will focus on ensuring sustainable impact and influence on policymakers by strengthening our research network and developing the capabilities of our partner institutions. Our vision is to:
1. Through research continue to address public health problems with regional and global relevance, using cutting edge approaches to seek affordable and deployable solutions to disease prevention, diagnosis and patient management.
2. Maximise our public health research’s uptake and impact, incorporating health economics analysis and goal-driven engagement with policymakers, national academic institutions, hospitals, industry partners, communities and the general public.
3. Work with our local host institutions to increase their national and global impact by integrating activities including training programmes, joint research projects, and supporting partner-led programmes to translate research into policy and practice.
Our goal is to improve life quality and expectancy by reducing the adverse impact of infectious diseases, which account for much of the disparity in health metrics between low and high income countries.
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| 22/06/2020 |
£1,052,228 |
UNIVERSITY OF OXFORD |
The Wellcome Thailand AAP has conducted high quality impactful research for 40 years on infectious diseases of major public health concern, leading to the widespread adoption of new approaches and treatments for many of them including malaria, melioidosis, and rickettsial infections. In our fifth decade we will focus on ensuring sustainable impact and influence on policymakers by strengthening our research network and developing the capabilities of our partner institutions. Our vision is to:
1. Through research continue to address public health problems with regional and global relevance, using cutting edge approaches to seek affordable and deployable solutions to disease prevention, diagnosis and patient management.
2. Maximise our public health research’s uptake and impact, incorporating health economics analysis and goal-driven engagement with policymakers, national academic institutions, hospitals, industry partners, communities and the general public.
3. Work with our local host institutions to increase their national and global impact by integrating activities including training programmes, joint research projects, and supporting partner-led programmes to translate research into policy and practice.
Our goal is to improve life quality and expectancy by reducing the adverse impact of infectious diseases, which account for much of the disparity in health metrics between low and high income countries.
|
| 18/06/2020 |
£39,193 |
KING'S COLLEGE LONDON |
This research project will develop a framework for systematically incorporating ethical values into WHO Evidence Informed Policy Network (EVIPNet) Europe policy dialogues. Although ethical values are central to the appraisal of evidence and deliberation that is involved in policy dialogues, there is currently no explicit guidance for facilitators or participants on how to identity, define, interpret and evaluate key ethical values, nor how to recognise and work towards resolving tensions between different values. Explicit consideration of ethical values in this context is essential to the accountability and legitimacy of policy dialogues in the health policy decision-making process. Without it, discussions and decisions risk being shaped by unacknowledged and potentially unfounded assumptions, and risk recommending policy solutions which do not adequately take into account their moral and social costs and benefits. My project will aim to identify and evaluate the major existing accounts of moral reasoning for complex, real world deliberative contexts, and to develop and defend a model which is appropriate for policy dialogues. Policy dialogues are highly pragmatic tools which do not seek to pre-determine the values, knowledge and reasoning that participants bring to the table, and an ethical framework for this context must be similarly inclusive and pragmatic.
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| 18/06/2020 |
£23,143 |
UNIVERSITY OF EXETER |
There is a growing recognition within public and third sector organisations that outcomes-based commissioning and management ignores the complexity (at an individual, organisational and systems level) in which services operate. Some in the sector are experimenting with more developmental, collaborative, place-based approaches. However strategic development has recently been disrupted by Covid-19, which has forced services to change overnight whilst increasing support needs within communities.
This project will analyse the ways in which community organisations have evolved during the crisis, and identify implications for future practice, not only in terms of service delivery models but also change processes and evaluation methods.
CoLab is a cross-sector ‘wellbeing hub’ hosting 30 organisations from community, social enterprise and public sectors supporting people with complex needs (e.g. homelessness, mental ill-health). As an embedded researcher I will work with staff and users as co-researchers, drawing on research tools from different methodological approaches (e.g. participatory action research, ethnography, developmental evaluation) to explore their experiences of using, delivering and adapting services in a rapidly changing context.
Key goals include producing recommendations for service development, identifying appropriate research methods to sustain an ‘action research’ culture moving forward, and sharing learning more widely within the sector and related academic fields.
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| 18/06/2020 |
£6,181 |
UNIVERSITY OF GLASGOW |
Initiatives such as ‘The NHS at 70’ show strong public interest in the histories of public health in the UK. Such discussions have particular resonances in Scotland with the country’s reputation for poor public health and devolved responsibilities for healthcare. During my secondment, I will research the representation of hospitals, institutions of care and healthcare professions in Scotland, as found in the National Library of Scotland’s Moving Image Archive. The collections include documentaries, promotional and public information films, amateur works and newsreels, from the 1890s to the present day. My project will involve researching, contextualising and connecting key recordings to create appropriate narratives about public health in Scotland. I will research the histories and legacies of key Scottish institutions represented in the archive (such as East Fortune Sanatorium for tuberculosis patients, the innovative ‘therapy communities’ at Dingleton Hospital and ‘modern’ institutions such as Glasgow’s Stobie Hospital), situating this within a larger context of changing attitudes and policy about health and healthcare professions. I will create a curated interactive package, including clips and additional written information, for display at the Kelvin Hall premises.
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| 18/06/2020 |
£35,349 |
UNIVERSITY OF BRISTOL |
The overarching aim of this project is to provide theoretical and measurement expertise in the economics of health and wellbeing into the work of a UK-based charity, Centre for Thriving Places, and specifically, their Thriving Places Index (TPI). More specifically, this project will be developing a better understanding of the key indicators that influence the wellbeing of individuals at different stages of the life course. Currently the TPI is summarised at the local authority level in England and Wales and is arranged into three headline elements: Local Conditions for wellbeing, Equality and Sustainability. This project will seek to inform how reflective TPI is of different population groups wellbeing at different stages of the life course, looking at wellbeing in younger and older population groups in particular. Specifically, this research project will focus of wellbeing at different stages of the lifecourse based on the indicators that feed into the TPI. The Centre for Thriving Places would use the work from this secondment to better inform local authority decision-making targeted as specific populations in their community. For instance, different public health policy responses may be required depending on the age profile of diverse local authority populations.
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| 18/06/2020 |
£14,673 |
UNIVERSITY OF YORK |
Alternative indices of poverty may classify different individuals as being ‘poor’; these mismatches are problematic for charities and policy makers who aim to identify and reduce poverty. I will compare mismatches in poverty indices by considering distributional changes over time amongst different groups in the population. The analysis follows from Meyer and Sullivan (2008), who identify changes over time in consumption and income poverty in the USA. I will extend their analysis to the development context; using the Uganda National Panel Survey dataset (n≈3,000) multiple poverty measures will be constructed at the household-level, across the period 2009-2016. By focusing on distributional changes over time, mismatches between these measures can be identified, providing insights for policy makers trying to identify poverty trends. By disaggregating these measures a more in-depth analysis on the attributes of well-being, rather than aggregate summary statistics, will be conducted. Utilising a panel structure to follow individual households over time will allow for insights into potential causes of declines in well-being and the consequences of volatility. The paper will provide a methodological contribution to poverty analysis in the developing world, and offer policy relevant analysis of poverty in Uganda.
Keywords: Poverty Mismatches, Development Economics, Distributional Effects
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| 18/06/2020 |
£17,912 |
UNIVERSITY OF OXFORD |
Fast Track Cities (FTC) is a multi-partner initiative aimed at addressing the challenge that cities bear a large share of the global HIV burden. London signed up to FTC in 2018 with the aim of eliminating HIV from the capital by 2030. The Healthy London Partnership (HLP) is the delivering organisation for London, bringing together representatives from Public Health England, NHS England, the Mayor of London and the London Councils. The aim of this fellowship is to work closely with HLP and support translation of the global goals of the FTC programme into the local context of London-specific initiatives, which include: funding and facilitating a quality improvement collaborative to increase HIV testing, access to HIV care and support for people living with HIV; and developing strategies to end HIV-related stigma. This project builds on my HIV social science research and on the extensive work on complexity in healthcare by our Oxford team, including current Medical Research Council and Wellcome Trust funded projects on context and complexity in health interventions. I plan to increase synergy between methodological research (Oxford) and gain experience of the translation of city-wide HIV policies and interventions through to implementation activities (HLP), with benefits to both partners.
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| 18/06/2020 |
£16,413 |
UNIVERSITY OF OXFORD |
To control the spread of the 2019 coronavirus disease (COVID-19) outbreak governments around the world have introduced public health measures including social distancing, isolation, and quarantine. This has created conflicts between competing ethical values, particularly protecting the publics’ health and safety v. respecting individuals’ liberty and preferences.
Concerns have been raised about the impact of currently-implemented measures on people’s mental health. Children and young people may be affected in unique ways, due to their younger age and specific role in society. Yet, their mental health needs may be easily overlooked when professional care is devoted to those who are in most immediate need, i.e. the immunocompromised and the elderly.
The aim of this project is to conduct a systematic review of the evidence on the impact of social distancing, isolation, and quarantine on young people’s mental health and wellbeing, and to interpret it in light of the ethics literature on public health emergencies. This work will be used to develop a UNICEF working paper focused on ethically-robust policy recommendations, so that public health measures that will be implemented in future infectious disease outbreaks are mindful of children’s mental health needs.
Children, young people, COVID-19, mental health, ethics, UNICEF, systematic review
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| 18/06/2020 |
£15,224 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
There is evidence that the global value of health co-benefits that result from climate action, are greater than the financial costs of mitigation measures around climate change. However, policy decisions at national and sub-national levels seldom reflect a connection with these global assessments. The World Health Organisation (WHO) has recognised this as an area of priority, and over the course of 2020-21 are committed to work with Health Economists to provide economic evidence that can be integrated into national level considerations, and specific policy measures for climate change.
As a Health Economist, I will work with the Department of Environment, Climate Change and Health at WHO headquarters, to support the generation of reliable country-level estimates of potential health gains and savings from national climate mitigation commitments of member countries. I will use mixed methods in my research, including cost-benefit analysis for feasible interventions and policy analysis to appreciate successful policies in neighbouring countries. The outputs of my work, which will highlight the health implications of climate change for policy-makers within and outside the health sector, will include a policy report highlighting country level health benefits due to reduced emissions, as well as a paper for submission to an academic journal.
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| 18/06/2020 |
£13,629 |
GOLDSMITHS, UNIVERSITY OF LONDON |
The proposed project will support the Science Museum with idea development for a future exhibition on health activism through research in three interrelated areas. Firstly, knowledge will be built around the recently acquired quilt block #3 of the Dutch AIDS Quilt by gathering information about the NAMES Project Netherlands Foundation (donor of the quilt) and the 8 individuals commemorated in quilt block #3. Suitable parties will also be identified for interviews regarding the history of the quilt. The relationship between Amsterdam and London with regards to health activism and quilting will also be investigated. Secondly, by exploring the symbolism and materials used in the quilt block, the project seeks to understand the myriad of different purposes the quilt serves. Given that the quilt and its functions are tied up with an array of different emotions, the project also aims to study how quilt, affect and health activism are entangled. Relatedly, if the planned exhibition is conceived also as a form of activism, what role then might emotions play in the organisation of the exhibition? Lastly, the project will also examine contemporary forms of health activism so as to identify potential artefacts for collection and display by the museum.
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| 18/06/2020 |
£15,521 |
UNIVERSITY OF CAMBRIDGE |
This project investigates the function and value of material culture associated with contemporary women’s experiences of health, such as menstruation, fertility and contraception. Drawing on recent work in LGBTQ+ and health activism, I will systematically research related objects in the Science Museum’s collection, share my findings through the museum’s online public engagement networks, identify further areas for collecting, and create a collecting proposal for consumer products designed to control, restore or facilitate bodily functions. This project asks four questions: What is the material culture of contemporary women’s experiences with health, and how does it fit into museum collections? What types of objects should be collected to represent the contemporary material culture of this theme? How can these objects be used in public engagement work in the present and the future? How can they be used to support ongoing efforts to break cultural taboos about women’s health and bodies in the context of museums? An analysis of these objects and their collection will shed light on their historical significance and reveal new ways that they might be used to highlight experiences of women’s health and medicine in the past, present and future.
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| 18/06/2020 |
£7,625 |
UNIVERSITY OF WARWICK |
In 2019, the NHS Long Term Plan and GP Contract committed doctors to making online their default patient access point by 2023. The widely used NHS app and web-based appointment and repeat prescription systems will be updated to facilitate, e.g. video consultation and remote monitoring. England's provider, NHS Digital, claims these changes will increase capacity and cut costs by reducing physical attendance. Many consumer champions and academic experts have questioned the lack of independent evaluations of the technology, and stress the likelihood that privileging digital access will exacerbate existing healthcare inequalities. The expedited roll-out of these technologies required by the current COVID-19 crisis may heighten such concerns by evidencing a 'digital divide'.
A rapid review will bring together current research from academia, the public sector, industry, and third sector. This will demonstrate the current state of digitisation and each group's specific concerns and interests in implementation. Interviews will then concentrate on areas of consensus surrounding best practice, establishing several case studies of leadership.
For policymakers, it will set out possible solutions for avoiding the exclusion of patients from specific age, income, or ethnic backgrounds; and draw attention to the possibilities for partnership by highlighting shared interests across stakeholding groups.
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| 17/06/2020 |
£1,016,701 |
UNIVERSITY OF EDINBURGH |
Stroke patients are increasingly surviving long-term after the primary neurological insult. Post-stroke complications have thus rapidly become an area of unmet clinical need. Infection is a common and dangerous complication of stroke associated with increased death and disability. Stroke-induced immune suppression is associated with infection susceptibility, but the majority of studies have focused on short-term (hours to days) changes to immune function. My recent data show early reduced numbers of lymphocytes and dendritic cells in experimental and clinical settings. It is unknown whether this impacts adaptive immune function and immunological memory. Using experimental animal models and parallel analysis of population health data sets, key goals of this proposal are:
1. To understand the extent and persistence of changes to adaptive immune cells after stroke and how this relates to infection susceptibility.
2. To determine if previously generated adaptive immunological memory is lost after stroke.
3. To determine if generation of new adaptive immunological memory is impaired after stroke.
This will generate understanding of the extent of adaptive immune memory deficits after stroke and the window of susceptibility in which stroke patients are vulnerable to infection and could result in new therapeutic approaches to reduce infection and improve long-term patient outcome.
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| 17/06/2020 |
£916,159 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
Almost half of the 435,000 malaria deaths each year occur in countries of the Sahel region of Africa, and the majority of these deaths occur during the three-four month rainy season. Monthly seasonal malaria chemoprevention (SMC) is highly effective in these areas, reducing malaria cases by 75-80% in trials, and malaria-specific mortality by 40-50% under programmatic conditions. However, malaria remains a leading cause of disease and death in several countries deploying SMC.
The key goals are therefore to understand how to 1) maximise the impact of SMC as currently designed (e.g. by timing it more accurately in different areas), 2) modify the SMC strategy to make it more effective (e.g. by identifying the causes of severe malaria in the context of SMC), 3) use other control tools, including seasonally-targeted vaccination, alongside SMC and 4) understand how improving malaria prevention in childhood would affect naturally-acquired immunity.
Analysis of data from a comprehensive evaluation of SMC in 7 countries, an SMC trial in 20,000 children, and the first-ever trial of seasonally-targeted vaccination alongside SMC provides a unique opportunity to answer these questions. Mathematical models incorporating these results will enable malaria prevention packages to be optimised according to the local epidemiology.
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| 17/06/2020 |
£1,163,672 |
UNIVERSITY OF EDINBURGH |
Macrophages are essential mediators of tissue repair but we lack fundamental knowledge about how they are regulated in the endometrium. Androgens regulate macrophage function in other tissue repair contexts but their role in endometrial repair has not been defined. This project will determine how macrophages are regulated in endometrial repair by assessing their turnover and phenotype and how this is affected by androgens by using a highly reproducible mouse model of endometrial repair that we have developed.
The key goals of this project are;
to determine whether monocytes contribute to the endometrial macrophage function in repair,
to define how androgens mediate intrinsic and extrinsic effects on endometrial macrophage function and
to investigate how androgen excess alter macrophage function in aberrant repair.
This will be achieved by using fate-mapping techniques, transcriptomics analysis, multiparameter flow cytometry and immunohistochemistry combined with pharmacological and genetic approaches to modulate androgen action.
These studies will establish that macrophages are critical mediators of endometrial repair and modulation of their phenotype by androgens determines the balance between healthy and disordered tissue repair. These important insights will provide a platform for assessing macrophage AR as a potential therapeutic target in reproductive health.
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| 17/06/2020 |
£413,761 |
UNIVERSITY COLLEGE CORK |
The recently discovered crAssphages are the most abundant group of viruses in the human body, reaching up to 20% of gut microbial DNA. They infect bacteria of the order Bacteroidales and demonstrate incredibly stable, sometimes years-long colonisation of the human gut. Our preliminary results, based on the first isolation of a crAss-like phage in culture, indicate that they use an unusual mechanism of infection that allows them to continuously co-exist with the bacterial host population at high levels. I hypothesize that bacterial interactions with their phage ‘partners’ is an essential aspect of microbiome functionality. The long term persistence of crAssphages in the human gut microbiome is an epitome of such phage-host interaction. My key research question is to provide a mechanistic and structural explanation of this interaction and gain insights into its significance for host physiology and overall microbiome structure. My research program consists of three specific aims: 1) developing methods for genetic manipulation with crAss-like phages; 2) using structural biology to get insights into mechanisms of phage-host interaction; 3) investigate persistence mechanism and its effect on community structure. Taken together these efforts should significantly advance our understanding of this new and elusive group of viruses in the human microbiome.
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| 17/06/2020 |
£1,196,484 |
UNIVERSITY OF LEEDS |
Membrane-less organelles (MLOs) are multicomponent structures that form by liquid-liquid phase separation (LLPS) of proteins/RNA. They play key roles in organising cells, signalling, stress and viral factory formation, whilst aberrant LLPS is associated with several neurodegenerative diseases (e.g. MND). MLOs are heterogeneous and dynamic, making it challenging to elucidate their composition, structure and biogenesis. New tools are urgently needed to study LLPS in vitro and in vivo to address fundamental questions of the molecular mechanism of LLPS, and to unravel how it contributes to homeostasis and disease. Here, I will develop a toolkit of MS-based methods to study LLPS, focussing on two systems: TDP-43, implicated in MND, and NSP2/NSP5, involved in Rotavirus viral factory formation. This will reveal new insights into the structure/dynamics of these proteins (which promote/suppress LLPS) and the protein-protein/RNA interactions which nucleate LLPS. I will study LLPS in vivo using, and developing, structural MS methods to reveal the proteins recruited into MLOs and the interactions mediating recruitment. This toolkit of MS methods, reinforced with biochemical/cellular/functional assays, will afford new mechanistic insights into two important systems, uncover new targets to combat neurodegeneration and viral infection, and open the door to revealing how LLPS controls many other cellular processes.
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| 17/06/2020 |
£1,547,266 |
UNIVERSITY COLLEGE LONDON |
In humans, as with all mammals,, the loss of auditory sensory hair cells (HCs) is irreversible. However, different degrees of HC regeneration occur in vestibular sensory epithelia, at early developmental stages, or in non-mammalian species. HC regeneration results from division and/or trans-differentiation of neighbouring supporting cells (SCs). It is generally accepted that poor/absent HC regeneration relates to the differentiation state reached by SCs and HCs, but the mechanisms behind this are unknown.
What dictates HC regeneration potential? Taking on a multi-layered approach, combining single-cell multi-omics, in-situ sequencing and transcriptional manipulations, I will study the vestibular utricle to evaluate the connection between maturation and HC regeneration potential. First, I will identify the cell/tissue level factors that interact during maturation to distinguish the mouse (marginally-regenerating) and chick (fully-regenerating) utricle. Second, I will study the regeneration trajectories of postnatal and adult mouse utricle to zoom-in on the factors driving the age-related decrease in regeneration potential. Finally, I will perform simultaneous transcriptional manipulation of identified targets aiming to overturn the poor HC regeneration of the adult mammalian utricle.
My research will generate unprecedented cell/tissue-level insight on the maturation and regeneration of sensory epithelia, identifying potential novel therapeutic avenues for recovery from pathological HC loss.
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| 17/06/2020 |
£1,065,085 |
UNIVERSITY OF CAMBRIDGE |
Enteric viruses are a major cause of mortality and morbidity in the young, the elderly, and the immunocompromised. Even after decades of research, it is still poorly understood why these viruses replicate particularly in the gastrointestinal tract and what triggers virus dissemination beyond the gut. Despite their worldwide prevalence, and recently emerged neuropathogenic strains, astroviruses represent one of the least studied groups of human RNA viruses, mainly due to difficulties with culturing and molecular manipulations.
My research will focus on understanding the molecular determinants of astrovirus infection – starting with basic replication mechanisms and moving towards physiologically relevant translational outputs. Key goals include:
Characterisation of the viral RNA structure and replication strategy to understand their role during virus infection.
Functional dissection of the astrovirus polyprotein processing strategy and its role in virus infection.
Identification and assessing the importance of gut-specific determinants in virus infection.
Identification of the molecular mechanisms responsible for neurovirulence.
Elucidation of the fundamental molecular biology of astroviruses underpins an understanding of their pathogenesis, both in the gut and in the central nervous system. It will also facilitate the development of vaccines and antiviral therapies, addressing an unmet need for young children in developing countries.
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| 17/06/2020 |
£1,178,961 |
UNIVERSITY OF CAMBRIDGE |
Endocytosis is a highly dynamic process that determines the composition of the plasma membrane (PM). The dysfunction of endocytic pathways is a causal factor behind a number of human genetic diseases, and its dys-regulation can contribute to neurodegeneration.
Despite the critical role that endocytosis plays in health and disease, surprisingly little is known about how it is regulated. A major potential regulation point is the dynamic phosphorylation of endocytic components by kinases. However, it is poorly understood which kinases (and phosphatases) control endocytosis and the PM proteome, even though they represent potential targets for disease-modifying therapies.
My long-term vision is to understand the integration of protein kinases within membrane-trafficking machinery. My starting focus is on the Numb-associated kinase family (NAK). NAKs were identified as a susceptibility factor in Parkinson’s disease and neuropathic pain but the molecular mechanisms behind this are not clear.
I will elucidate the key cellular functions of NAKs: (1) which cellular processes and substrates are associated with NAKs (2) the consequences of their activity for cellular physiology and (3) the regulatory processes and interaction partners which govern NAK activity states.
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| 17/06/2020 |
£1,113,271 |
UNIVERSITY COLLEGE LONDON |
Tuberculosis is the leading cause of death from infectious diseases and requires a long treatment. Various initiatives aim to develop shorter and more effective treatment. However, this is complicated by the (1) absence of a biomarker that can predict treatment response during early phases of treatment and; (2) interactions between drugs when given together which makes dose selection/optimisation difficult.
My aim is to address these shortcomings by, for the first time, studying relationships between pharmacology, microbiology and immunology markers, using data from patients with drug sensitive and multidrug resistant tuberculosis and statistical modelling. This will help developing a test that predicts cure during the first 2 months of treatment which can contribute to improved efficiency of clinical trials evaluating tuberculosis treatment. Secondly, I aim to characterise overall antimicrobial activity and emergence of persistence and resistance, whilst accounting for drug-drug interactions using an innovative combination of in-vitro kill-curve and hollow-fibre experiments, in-vivo pharmacokinetic data and statistical modelling. This will inform optimisation of tuberculosis treatment.
I will undertake this work at University College London in collaboration with the University of Cape Town, South Africa, giving me access to a large and diverse tuberculosis patient population and state of the art laboratory facilities.
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| 17/06/2020 |
£1,551,810 |
CARDIFF UNIVERSITY |
Aerobic glycolysis (AG) plays a vital role in brain disease, development, and ageing. Elevated AG has been linked to axonal elongation and synaptogenesis in childhood, synaptic plasticity in adulthood, and is a hallmark of cancer. There is also evidence of a significant reduction in AG in older age and in neurodegeneration. The development of a non-invasive method for imaging AG has the potential for significant impact in basic neuroscience and clinical practice. For example, in cancer therapy, post-treatment mapping of AG is anticipated to be a sensitive measure for assessing recurrence and for the planning of salvage therapy.
I propose to develop ultra-high field (7T) MRI methods to safely and non-invasively map aerobic glycolysis and tissue oxygen availability in the human brain, providing a new window into brain metabolism and metabolic dysfunction. The methods development involves two main paths. 1) Glucose labeled deuterium imaging to directly map cerebral AG. 2) Development of vascular imaging methods, including deuterium perfusion and blood volume imaging. The combination of these two methods will enable calculation of cerebral glucose metabolism, oxygen metabolism, and tissue oxygen availability. These methods will be validated experimentally using a controlled pharmacological modulation of aerobic glycolysis with sub-anaesthetic ketamine administration.
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| 17/06/2020 |
£789,591 |
UNIVERSITY OF CAMBRIDGE |
Blood formation ultimately relies on the function of rare haematopoietic stem cells, canonically defined as multipotent and serially transplantable (c-HSCs). Mounting evidence, primarily from mouse models, indicates that these cells are activated in situations of extreme stress (e.g. transplantation). Day-to-day haematopoiesis and responses to less severe stresses are postulated to be instead driven predominantly by cell types that do not fulfil the canonical definition of HSCs, herein termed non-canonical (nc-) HSCs. nc-HSC generation, regulation and functional relevance remain unclear because reliable models to study them are lacking, especially in human.
During my current fellowship, using state-of-the-art single cell approaches, I identified and provided purification strategies for two types of human nc-HSCs. During the extension, I will i) investigate how nc-HSC are generated from c-HSCs, characterising a newly-derived model of human nc-HSC formation at the cellular, transcriptional, proteomic and epigenetic level. Focusing on erythroid differentiation, I will then ii) validate novel molecular mechanisms that drive lineage commitment of nc-HSCs; iii) define to what extent nc-HSC contribute to responses to stress.
These experiments will 1) provide proof-of-principle of the functional relevance of nc-HSCs to human haematopoiesis; 2) establish a much-needed tractable experimental framework to further study their role in ageing and disease.
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| 16/06/2020 |
£60,000 |
INTERNATIONAL LIVESTOCK RESEARCH INSTITUTE, KENYA |
Antimicrobial resistance (AMR) is a global health threat, associated with increased morbidity, mortality, and financial costs. Identifying the potential reservoirs of antibiotic resistance and resistance mechanisms is an important task to tackle AMR. Klebsiella pneumoniae and Escherichia coli which can cause severe and often fatal infections such as septicemia and pneumonia are among the identified priority antimicrobial-resistant pathogens by the World Health Organization in 2017. Cephalosporins and Carbapenems are considered critically important antibiotics in the treatment of Gram-negative infections however their resistance has been reported in clinical settings.
The contribution of livestock as potential reservoirs and source of resistance genes to humans, which can be acquired by direct contact or through the environment and food-chain in Kenya is not known.
This study will investigate antibiotic usage, knowledge and practices amongst farmers and levels of AMR in different cattle dairy production systems to give an insight to Antimicrobial Usage and AMR, in particular focusing on the carriage of Cephalosporins and Carbapenem-resistant Enterobacteriaceae (E. coli and K. pneumoniae). Moreover, we will investigate the genetic determinants conferring resistance and mobile genetic elements harboring resistant genes. Additional information on AMR would aid further research focused on combating AMR in developing countries.
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| 16/06/2020 |
£60,000 |
LIVERPOOL SCHOOL OF TROPICAL MEDICINE |
Malawi suffers a substantial burden of chronic respiratory diseases (CRDs) which causes significant morbidity and loss of economic productivity, and affects patients, families and health systems alike. CRDs are a major risk factor for Coronavirus Disease 2019 (COVID-19). Pharmacotherapy for CRDs is of limited benefit and costly. Its rational use could be complemented by non-pharmacologic treatments. For chronic obstructive pulmonary disease, pulmonary rehabilitation (PR) is well established as highly effective intervention which improves symptoms, quality of life and survival. PR is comprehensive package of interventions including exercise training. PR is now sufficiently understood to obviate further randomized trials in High Income Countries (HICs). However, given the design and delivery of programmes should be adapted to patient groups and context, high-quality data are needed outside HICs. My pilot study will determine feasibility and acceptability of PR in Malawi. Specifically, I will: (1) co-design, with service users and stakeholders, a locally appropriate PR program for patients with functionally limiting CRDs in Malawi, (2) examine lung function, exercise capacity and health status of participants before and after their participation in a PR program, and (3) examine participants’ levels of attendance, participation and adherence to the programme.
Keywords: chronic respiratory diseases, pulmonary rehabilitation, Malawi
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| 16/06/2020 |
£120,000 |
UNIVERSITY OF OXFORD |
Burkholderia pseudomallei (Bp) is a Gram-negative environmental bacterial pathogen. It causes melioidosis, a deadly infectious disease endemic in tropical and subtropical countries. Despite an increase in prevention efforts, the mortality rate of human melioidosis is still high. Bp is intrinsically resistant to several classes of antibiotics, which limits treatment options. The bacterium also synthesises antibiotics primarily to compete against other organisms in its soil habitats. I am testing the hypothesis that antibiotic resistance in Bp is either evolved as a self-protection mechanism against the antibiotics produced by itself, or interspecific competition or both. Using a dataset of 2,500 whole-genome sequences of Bp, I propose to mine the genes involved in the antibiotic synthesis, antibiotic resistance and their associated mobile genetic elements, thereby creating the first comprehensive antibiotic resistance and synthesis database for Bp. Long read sequencing will be employed to aid further identification of mobile genetic elements which will help determine the route of acquisition of these genes. I will use several bioinformatics methods to test the co-inherited patterns of antibiotic synthesis and resistance genes, their evolutionary stability and their mobility. Together, this will provide new ecological insights into antibiotic synthesis and resistance mechanisms in Bp and other bacteria.
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| 11/06/2020 |
£100,000 |
UNIVERSITY COLLEGE LONDON |
In low-resource settings, the locus of care for women during childbirth, and for sick and/or vulnerable newborns, has shifted dramatically from community-based contexts to formal facility-based settings. Furthermore, low-cost digital quality improvement solutions such as the NeoTree, are increasingly part of the healthcare landscape.
How mothers, caregivers, families and communities experience and perceive an increasingly biomedical, institutional model of newborn care, is not well understood. During our field visits to Zimbabwe and Malawi in developing the project, and in 2019 on commencement of the grant, our partners expressed concern that some mothers/caregivers fear the use of digital technologies, and formal health providers may lack sensitivity to patients’ social and cultural beliefs surrounding childbirth and the newborn. Furthermore, the benefits of digital health innovations, including electronic data capture, are not widely distributed within communities.
Our vision is to strengthen the partnerships between patients, families, communities and facility-based health professionals to ensure that quality improvements achieved by the NeoTree under our main award are sustainable and equitable. By the end of this enrichment activity, we will have achieved the following:
Empowered parent/caregivers to articulate and represent their experiences of using facility-based health care via participatory art methodologies;
Created opportunities for parents/caregivers and families to disseminate these experiences and spark critical reflection and dialogue with researchers, health professionals and policy makers;
Established and strengthened links between communities including participatory women’s groups and the NeoTree team/system.
Built public engagement capacity and disseminated lessons learned among our partners and research communities in our partner countries.
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| 11/06/2020 |
£78,960 |
UNIVERSITY OF LINCOLN |
Converging environmental, health, welfare and political agendas make the future of food and farming one of today’s most contested issues. Media representations are often unhelpfully polarised. Criticisms rest frequently on simplistic understandings coloured by false memories of an earlier ‘golden age’, while defensive farmers can struggle to articulate the challenges they face. In creating opportunities for more inclusive, reflective, non-judgemental exchanges, our enrichment work - based around creative practices that engage with livestock health and farmer/livestock relationships - will encourage farmers and diverse consumers to work through their differences, and develop mutual respect, empathy and understanding. Achievement of these objectives will be assessed through formative and summative evaluation.
Three creative professionals - an artist (of any media), photographer and filmmaker, who are experienced with socially engaged art practices - will reside with the project's researchers and the farming communities they are studying. Their outputs will be taken back to these communities, and to various consumers, in conjunction with other engagement activities that are built around project research and its historical resources. Participants will be invited to respond, reflect, remember, converse, comment and learn about each other's perspectives on livestock health, welfare and production, and to engage with farmer/livestock relations in the past, present and anticipated future. To promote interactions between farming and non-farming audiences, the filmmaker will capture early participants’ reactions before adding their documentary to the exhibition. Researchers, farmers and practitioners will reflect on, and share their experiences of working together. Afterwards, the MERL will accession creative outputs.
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| 11/06/2020 |
£94,290 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
COVID-19 has helped to illuminate the fundamental importance of young people and scientists effectively communicating the urgency of infectious disease. This project will develop the ways in which our science explains and communicates discoveries to a wider audience, using story and narrative devices familiarly used in animation and graphic novels as gateways to complex ideas. The body of work created will be a snapshot of where Mostowy lab research is in 2020, and a tool to develop the way in which the lab communicates its research.
The project will be made with members of the Mostowy lab, with input from students and young people in London and Manchester, collaboratively producing an animated film examining central research concerns of the Mostowy lab including; Shigella, superbugs, antimicrobial resistance in a post-antibiotic environment, and the global health challenge these present.
Inclusive sharing events will bring together the professional film we make with the creative work made by young people, giving an opportunity for us to discuss and appraise the learning from each experience. The work will be shared, at different stages of its development, at public events in London and Manchester, online, and at festivals internationally.
Developing from the award-winning Wellcome Trust funded animation Loop (2016), this new project will be a legacy tool to explain the lab’s most recent discoveries to a non-scientific audience, as well as to any researcher, healthcare professional or stakeholder. It will include ideas from young people as well as researchers, creating engaging visuals about compelling material.
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| 11/06/2020 |
£245,213 |
BIRKBECK UNIVERSITY OF LONDON |
Shameless! is a bold and exciting cross-arts festival intersecting academic research, activism and art in confronting sexual violence. A three year project with each edition of the festival hosted in the UK and Brazil; London 2021, Rio de Janeiro 2022, and sharing learning across the UK in 2023. Shameless! brings together diverse communities of survivors and the expertise of researchers, medical, psychiatric and legal professionals, artists and activists in a transformative programme of talks, performances, workshops, ‘how to’ clinics, wellness spaces, and a schools’ programme.
A wide range of partners will be engaged in varying capacities. Our principal partner, The WOW Foundation (WOW), will co-produce the two festival editions in London and Rio de Janeiro. Given WOW’s robust experience and network, including in Brazil, Shameless! will implement WOW’s methodology in producing both festivals. Shameless! will also work with national, international and grassroots organisations and charities, and commission local artists and wellness practitioners to facilitate safe spaces for dialogue and healing. Offering a unique environment for children, families, young people, women, gender- and trans-diverse people, the festival will provide safeguarding measures to protect members from vulnerable and marginalised communities (race, class, abilities, sexualities and genders).
In 2023 Shameless! will share our public engagement and festival programmes with UK universities through a series of workshops, conferences and publishing reflective articles.
Shameless! aims to revolutionise conversations around sexual violence between survivors and professionals; burst open the constructed and inherited ideas of shame; and create an emboldening attitudinal shift from stigma to agency.
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| 11/06/2020 |
£56,388 |
UNIVERSITY COLLEGE LONDON |
What the activity will look like:
We will bring together health-interested publics and population-health decision-makers for a series of workshops engaging with key aspects of the AI System and co-producing a toolkit of resources to facilitate appropriate trust in AI systems applied to population health.
What we will have achieved
1: Co-produced toolkit of resources
Exact nature of the resources will depend on outcomes of the workshops. We envisage resources that explain and prompt questioning about key features of the AI System and promote consideration of personal values/preferences regarding those aspects to decide upon trust in the System. The toolkit will also be applicable to discussions of trust in other AI systems applied to population health.
2: Multi-media documentation of discussions in workshops
Developed in partnership with participants
Made publicly available online
Documenting issues raised and providing case studies of public engagement
3: Interactive public talk on facilitating appropriate trust in AI in population health decision-making
With live web video link and video-recording
Opportunities for Q & A’s during and after
4: Additions to the HBCP AI System user interface
Toolkit resources will be linked to the System’s online interface and their use promoted to people querying the AI System.
Overarching these achievements will be efforts to achieve long-lasting and widespread reach
The dissemination and engagement strategy will be both broad and targeted, maximising exposure to and engagement with the outputs, including a social media campaign. Long-term availability of the outputs will be ensured through hosting them on the HBCP website.
|
| 04/06/2020 |
£89,973 |
EUROPEAN MOLECULAR BIOLOGY ORGANIZATION |
A scaleable, interoperable mechanism to establish transparent peer review in scientific journals and preprints as a standard optimized for the browsing, interpretation and assessment of research papers and preprints. The proposed tools and standards will allow inclusion of peer review formally in research assessment by funders and research institutions.
|
| 04/06/2020 |
£62,082 |
MICROBIOLOGY SOCIETY |
This project aims to convert one of our journals, Access Microbiology, into an Open Research Platform (ORP), offering greater peer review transparency and fast-tracking the communication of valuable research, maximising potential for impact and influence.
At submission, articles will be made available on microbiologyresearch.org with a DOI, with clear links to open data, methods, and code, and accompanied by the reports from the machine learning review tools (e.g. Statcheck). Peer review will be transparent, and a version history maintained from preprint to Version of Record.
Many societies are seeking new ways to serve their communities but are reluctant to adopt the pre-existing F1000 ORP software. This may be because they wish to maintain a single portal for access to all the work they publish; they are reluctant to enter into a publishing agreement with a commercial player; or they are concerned that the concept may not be embraced by their communities. Through this project, we hope to prove that an ORP can be provided using software in common use by publishers of all types, and that self-publishing societies can set up such a platform independently. We also hope to provide a financial model that proves ORPs can be financially self-sustaining.
|
| 04/06/2020 |
£82,906 |
AMERICAN SOCIETY FOR CELL BIOLOGY |
The proliferation of scholarly content and implementation of transparent peer review are creating challenges for readers and evaluators to assess research significance and review outcomes, and for journals to curate field-specific content. We propose controlled experiments in which we test the utility of badges and impact statements to signal the significance of articles published by the American Society for Cell Biology (ASCB) in its research journal, Molecular Biology of the Cell (MBoC). We will devise badges that alert readers to article attributes such as new concept, broadly relevant, technical advance, teaching resource, etc. We will also experiment with new peer review processes, including a streamlined process designed to concisely identify points of significance and key issues, and one in which authors, reviewers, and editors work together to craft concise impact statements for display on articles. The effects of these innovations will be assessed relative to traditional practices by comparing article-level metrics including article views, downloads, and Altmetrics attention scores and by surveys. We will then use these innovations and the expertise of ASCB members, including early career scientists, to curate preprints and articles in other venues with the goal of providing standard, portable tools for use by other publishers.
|
| 03/06/2020 |
£20,000 |
MANCHESTER METROPOLITAN UNIVERSITY |
Reimagining:
On completing the activities, I will have collaboratively re-imagined rhythms, pace, practices, planning and policies of an inclusive, interdisciplinary research cycle and research culture
I will have forged trusting, authentic, sustainable connections with staff, students and research partners, that values difference in generating and making knowledge culturally relevant, usable and accessible.
I will have developed a collaborative inquiry to inform equitable and inclusive research bids
Make valued, recognised contribution to improving D & I
Researchers are energised and motivated to submit bids that research partners feel improve working conditions for diverse researchers and lives of communities and make research culture inclusive
My university, communities, networks are proud of contributions, perceive research as a valuable and researchers as authentic leaders shaping the future of inclusive research internally, in wider academic networks and society.
My university will have a sense of the barriers that prevent inclusive research, an action plan/tools to work with in order to remove barriers, an example of a research cluster that has proved it possible and a culturally relevant race equality chartermark action plan
Potential PhD students, researchers and future partners will recognise our efforts and want to learn from our research cluster. We will have tools, practices and approaches to onboard them to our inclusive ways of working.
Sharing and extending our influence
Researchers, partners, senior leaders will identify, invest further (time/money) and be positioned to plan, share and embed with peers, centres and networks the ethical principles, road map and practice map through which success was achieved.
|
| 03/06/2020 |
£3,995 |
STREETINVEST |
The 30 street-connected children trained as researchers represent a diverse range of gender identities, ethnicity, religions and castes, however staff report that one major barrier to inclusion remains: literacy. During the process of recruitment, several children volunteered, but were unable to engage with the project materials and tasks required, including the development and delivery of surveys and documentation of responses.
This activity will in the first instance address this barrier for the remainder of the project by ensuring that children with low or no literary participate equally in the interpretation and dissemination of findings, including formulating messages and demands for health responses. Secondly, it will ensure that materials are accessible to all, regardless of literacy, so that research respondents can understand the findings. Thirdly, this activity will strengthen the research toolkit and training manuals by specifically addressing the issue of literacy.
This will ensure all children regardless of their literacy level, who have responded to the 500 surveys completed to date, are included in the sharing of research findings and 30 with low or no literacy play a central role in developing demands and messages for health service providers, so that all children have the opportunity to inform responses to their health needs. In the future, teams will be equipped with the methodology, tools and and training to make it possible for children of all literacy levels to participate as Street Champions.
|
| 28/05/2020 |
£50,000 |
UNIVERSITY COLLEGE LONDON |
The underlying software code for the NeoTree is open source and the NeoTree system provides an exemplar vehicle with which to facilitate and accelerate the sharing and re-use of nationwide newborn care data. Our proposed goals of this proposal are to maximise the efficient and meaningful sharing and re-use of data collected via the NeoTree, and the re-use of the NeoTree source code. This moves beyond the delivery of an open research database and is transformative in its approach to substantially enhance the impact of the overall project to improve newborn care in resource-poor settings. This work will showcase the potential impact and pathways of conducting open research in newborn care, maximise impact of the NeoTree platform for use in other disease and patient groups and enhance capacity for international partners to re-use the NeoTree data and thus improve population health and health systems delivery. We will deliver the following:
A guide for downloading and adapting the NeoTree code (to be hosted alongside the source code in GitHub under the MIT license);
A guide for implementing the NeoTree in a new setting, including downloading and setting up the open source code, configuring the technology to match the local healthcare setting and extending and adapting the code;
Data pipeline and guide for deployment;
Metadata for the full NeoTree data;
Training manuals for interrogation of NeoTree open data.
|
| 28/05/2020 |
£49,929 |
UNIVERSITY OF OXFORD |
The main aim of this proposal is to enable wider access to analysis tools that we are developing within our collaborative award, with particular emphasis on usability for non-technical, time-poor researchers and clinicians. This will primarily be achieved by focusing on the development of open, interactive visualisation tools that allow users to have an easier and more intuitive interaction with a wider set of our imaging and non-imaging outputs. Such interactive tools will lead to greater uptake of our analysis methods and a greater understanding and application of the research outcomes.
The secondary aim, supporting the primary aim, is to increase engagement and provide greater leadership to the open science neuroimaging community. This will be provided by going beyond the adoption of current methods of data structuring (BIDS) and containerisation of code (BIDS apps), by integrating them into the core level of the interactive visualisation tool. This tool will create simple, interactive ways of calculating and applying normative biomarkers, without requiring users to spend substantial amounts of time in training and installation of our current software tools. To do this we need to refine and extend the current neuroimaging open science data structures (BIDS), especially for atlases, spatial transformations and population-level measurements. Increasing the usability and access will encourage a wider variety of users and associated datasets, leading to greater feedback about our research tools and outcomes, which will form a crucial feedback loop and be a prime factor in measuring and improving the reproducibility of all of our research.
|
| 14/05/2020 |
£63,753 |
BLACK CULTURAL ARCHIVES |
The project has three central activities.
One: Access. Cataloguing the papers of Melba Wilson OBE (fl. 1965-2010). Wilson’s career included leading national and regional mental health programmes, policy units and services, specifically with a focus on minority ethnicity people.
Two: New descriptive practice. The cataloguing of Wilson’s papers will be used as a springboard into new approaches around cataloguing and dissemination of archival sources.
Three: Collections development. Scoping hidden histories of activism in the intersection of race and mental health, including the histories/ archives of organisations such as Ipamo (1995-1998) a Lambeth based Black mental health initiative, and the Afiya Trust (founded 1997) a national charity that works to reduce inequalities in health and social care provision.
Supporting these three strands is our collaborative studentship with the University of Roehampton, and a programme of public engagement to disseminate the outputs of the project and to ensure a wider impact of the project outcomes.
The key outcomes of the project are:
Enhancing the resources available in this field of research.
Creating new opportunities for discursive research.
Making a lasting change to the availability and range of minority mental health archive collections.
Innovating in the field of archival practice.
|
| 14/05/2020 |
£326,594 |
UNIVERSITY OF WARWICK |
This is a project to conserve, catalogue and exploit the archives of the National Union of Mineworkers (NUM). It presents the opportunity to develop a nationally significant archive for occupational and industrial health at the MRC and a Midlands network for coal related archive collections. The NUM records are currently held in poor conditions at the union’s headquarters in Barnsley. The project involves the removal of the archives to professional conservation facilities for drying and cleaning prior to storage at the MRC. It includes the sorting and cataloguing of the collection for research use as well as a public engagement programme. The project will:
Remove the collection to Harwells for conservation treatment
Re-box, sort and summarise the collection for immediate access and use in promotional activities
File/item list the collection for full online catalogue access
Select and digitise items for research, teaching and exhibitions.
Develop a project website
Co-host seminars with the Centre for the History of Medicine (Warwick) on coal, industry and health
Develop a Midlands network of coal related archive collections for future collaboration, education and outreach activities
Use the NUM archive as a focus for the development of a national industrial health and welfare archive
|
| 14/05/2020 |
£52,532 |
THE MULBERRY BUSH ORGANISATION |
Since 1989 the Planned Environment Therapy Archives have been unique in their remit to capture and preserve the records of therapeutic communities and care.
In 2002 the Archives acquired the papers of the psychoanalyst Harold Bridger. The collection spans the whole of Bridger’s career, from his pioneering work as the Commanding Officer at the Second Northfield Experiment, through his role as a founding member of the Tavistock Institute of Human Relations, and on to his groundbreaking work concerning team dynamics in the workplace.
Bridger’s papers have enormous research potential in the fields of psychiatry, psychology and sociology as well as the history of medicine, economics and social reform.
The project will look to address the under-use of Bridger’s Archive by cataloguing the collection to international standards, identifying and carrying out preservation work, and promoting the collection.
To achieve this, a Project Archivist will be appointed to appraise, arrange and describe the materials. During the project, the post holder will carry out basic preservation to support long term use of the collection, and will oversee the digitisation of obsolete media. The Project Archivist will promote the collection by creating a network of stakeholders and attending relevant conferences and events.
|
| 14/05/2020 |
£209,931 |
UNIVERSITY OF LEEDS |
Women’s Aid Federation England (WAFE) is the national coordinating body for all local and domestic violence services, including refuges in England. It provides information, training and resources to these services as well as to other agencies. It monitors the experiences of and the provision for women and children suffering abuse. It lobbies, advocates and campaigns throughout England.
The archive encapsulates the broad spectrum of its work. Growing out of the Women’s Liberation Movement in 1974 the organisation moved in twenty years from being one which met with aggression from the police to one which was highly regarded for its knowledge and research. The organisation marks its 50th year in 2024. WAFE is working in collaboration with the University of Leeds Special Collections and the Feminist Archive North (FAN) to safeguard the historical record and make it accessible for research. Collection, appraisal, documentation and preservation will ensure the collection is publicly available before this milestone year. New research collaborations will become active, learning resources will be created, and knowledge of WAFE's activity and significance will be shared and exchanged. The collection has interdisciplinary research significance and is a major resource for WAFEs own understanding of its contribution to health and society.
|
| 14/05/2020 |
£154,842 |
LONDON METROPOLITAN ARCHIVES |
The aim of this project is to make accessible for research three recently acquired archive collections held by London Metropolitan Archives which together illuminate two important threads of the AIDS crisis of the 1980s and its aftermath: pioneering medical treatment, care and support; and lived experience of not only those diagnosed with HIV/AIDS, but their carers, partners, relatives and friends. They comprise: Mildmay Hospital archive including 4000 patient case files; 103 interviews of people with AIDS, their families, partners and carers, filmed by the AIDS Since the 80s project; and the archive of peer-led support charity Positively UK (formerly Positively Women). The key outcomes will be: freely available online catalogues to item level of all three archives; a research database of key information extracted from the Mildmay Hospital case files, and full digital access to the 150 hours of filmed interviews supported by time-coded summaries, transcriptions and captioning. The archives, and the areas they inform such as the history of sexuality, science and medicine, as well as social and cultural change, and the methodologies used to make them discoverable, will be promoted through a conference, two professional skill-sharing events and two film-screenings, building on existing demonstrable interest in these archives.
|
| 14/05/2020 |
£236,339 |
UNIVERSITY OF BIRMINGHAM |
This 24-month project focuses on cataloguing and preserving the archives of two influential youth movements:
The Young Men’s Christian Association (YMCA)
The Youth Hostels Association (YHA)
Both archives are held at the Cadbury Research Library, University of Birmingham.
Health and welfare of young people are guiding principles of these charities. Since their creation, both organisations have focused their activities on improving the mental and physical health of young people, with emphasis on working with those from disadvantaged backgrounds.
The YMCA archive comprises 978 boxes and the YHA archive comprises 405 boxes; all of which require detailed cataloguing in order to realise their full research potential. Both collections include minutes, reports, publications, photographs and ephemera. Material documents the work of both charities in improving young people’s physical health, mental wellbeing, and general fitness.
The outcome of this project will be two fully searchable electronic catalogues which will enable access and reveal the full research potential of these internationally significant collections.
Engagement activities with academics, researchers, students and members of the public will ensure that the collections are visible across a broad range of audiences.
|
| 06/05/2020 |
£84,054 |
UNIVERSITY OF CAPE TOWN |
The research questions are - How has indigenous medicine responded to the substance abuse crisis in SA? What might future interventions look like?
An auto-ethnographic reflection on addiction and recovery, that seeks to deepen local understandings and narratives to include notions of historical trauma, dispossession and ‘insecure attachment’ to ancestors, nature and land.
Working with indigenous health practitioners (IHPs), the research will explore indigenous medicine’s response to the high levels of substance abuse in South Africa. Drawing inspiration from indigenous-led treatment programmes in Canada, Peru and the United States, that fuse indigenous and biomedical approaches, future interventions will be explored with indigenous and allopathic health practitioners, researchers and people in recovery as co-researchers.
The project will experiment with various research methods; introducing the notion of dreaming as a research method; story-telling; and indabas. We aim to collectively envision interventions that integrate ancient indigenous methods, biomedical/psychological approaches and technological tools. The research will be based in Cape Town but will include participants from all over South Africa.
Public engagement methods will be decided collectively during indabas to tailor the dissemination of findings to the various communities needs, this could be through podcasts/community radio, web-based audio-visual material, community indabas, ceremonies and performances.
|
| 06/05/2020 |
£85,336 |
UNIVERSITY OF EDINBURGH |
This research examines the relationship between the biotechnology industry and consumers, to determine what effect(s) this relationship may have on the outcome of clinical trials. Despite regularly being referred to as the ‘new genetics’, there has been little substantive change over the past two decades in the ways we have studied social aspects of genetic testing. Studies are largely embedded in the dichotomy of ‘consumption’/‘production’, treating 'patients'/'industry' as discrete categories in an unchangeable hierarchy. However, medical biotechnologies do not exist in a theoretical vacuum: they are continuously evolving products of social, political and economic endeavours, which have social, political and economic consequences. This research will follow the Phase 3 Study of RG6042 (previously IONIS-HTTRx), the first drug specifically targeting the mechanism responsible for HD, and a Phase 1 trial of a novel gene therapy. Methodology includes interviews, group interviews, and participant observation to determine how information moves and mutates, and how this effects medico-social pathways. Drawing on concepts of translational science, this research will examine how/when/why and to what effect 'scientific' knowledge is communicated among and between actors, and what effect this may have on the outcome of the trial for both participants and industry.
|
| 06/05/2020 |
£114,971 |
UNIVERSITY COLLEGE LONDON |
This proposal is for a year-long ethnography of an internet addiction rehabilitation centre in rural Washington State. It will develop an anthropological understanding of internet addiction, the study of which has so far been limited to neuroscience, psychology, and psychiatry. This will allow the cultural, social, and systemic background to the condition to be revealed.
The ethnography will be phenomenological, exploring the changes in the experience of space and time that rapid withdrawal from the digital causes – putting the living body at the centre of study. I will do this with the aim of establishing how use of the digital changes the experience of everyday life, explaining internet addiction through these changes. I will also ask whether the experience of extreme cases is shared by ordinary users.
I will investigate whether the condition can be used to denaturalise the broader category of addiction, unpacking and challenging suppositions established in the study of addiction and mental health.
As well as generating new knowledge and raising awareness, I will assist in the formation of patient groups, as well as supporting charities and healthcare facilities dealing with the condition. I will also aim to persuade healthcare services to fully recognise the condition.
|
| 06/05/2020 |
£98,900 |
UNIVERSITY COLLEGE LONDON |
My research focuses on XIII-XV Old Norse medical treaties featuring classics and continental models, to assess the extent to which Mediterranean medical practices were assimilated and re-elabotared within the Old Norse framework to understand the cultural dialogue between medieval Scandinavia and the continent. I will provide annotated translation of remedies, herbaria and antidotes contained in manuscripts preserved in Copenhagen and Reykjavík, comparing them with their continental counterparts at the British Library, Cambridge and Oxford. Consequently, the nature and the usage of these texts as sources of healing will be problematised and I will challenge the obsolete term "pseudoscientific" used in scholarship to refer to medieval medical practices and elaborate a new interpretive frame of understanding. I will demonstrate that Old Norse participated to the cultural syncretism in the Middle Ages by assimilating the occurrence of Classics and continental medical knowledge in manuscript context. This will lead to study a materiality of practices which allowed for a physical impact on the body. My research will address the cultural biases that have greatly affected certain topics within Old Norse scholarship which have not been considered in a comparative perspective and have led to the study of Old Norse culture in isolation.
|
| 06/05/2020 |
£108,868 |
UNIVERSITY OF OXFORD |
This mixed-methods project will treat Greater Manchester’s integrated budget in 2016 and the delayed roll-out of Integrated Care Systems across the country as a quasi-natural experiment.
I will use a nested-analysis method with qualitative research and three ‘diverse' cases studies will be chosen non-randomly to understand how each Local Care Organisation are specifying their policy delivery according to different population needs.
The hypotheses from the small-n analysis will then be tested by further large-n analyses. My research will use advanced methods in order to isolate causal effects of the intervention of integrated care in Greater Manchester. I will use synthetic control methods to create a synthetic counterfactual trend of Greater Manchester if it had much less developed health and social care integration. My synthetic control will be developed from weighted trends from other city-region combined authorities in England. This method is an alternative to traditional methods such as difference-in-differences.
This research is interested in the consequences of integrating healthcare at a city-region geography on population health outcomes, this project hopes to understand whether this policy trend is likely to induce new inequalities into the health system, tackle those already in place, or both.
|
| 06/05/2020 |
£72,174 |
UNIVERSITY OF OXFORD |
I am invested in researching the history of the female body in British colonial Punjab from 1885 - 1947, as it lived and experienced British colonial medicine. I want to study the character of the relationship between British colonial medicine and the princely states of Punjab, and between biomedicine and religious nationalism, and the impact of these relationships on women’s bodies, and their motility, mobility, and embodied subjectivity. I have located hitherto unutilised primary sources – women’s magazines, journals, and quasi-medical magazines run by women written in Punjabi, and medical and administrative records of local women’s hospitals in the six princely states of Punjab – in order to investigate the lives of Punjabi women who experienced the biomedical regime through practicing medicine or becoming patients.
Through the position and practices of women under investigation, I wish to question the conceptualisation of ‘medicalisation’ that has often been applied to understand the impact of biomedicine on societies such as India. I wish to understand women’s decisions and choices during this period not only as representative of the medical-religious dichotomy or alliance, but also as representative of the impact biomedicine had on their experiences of their own bodies.
|
| 06/05/2020 |
£97,554 |
UNIVERSITY COLLEGE LONDON |
The 1960s and 1970s marked a decisive change in the history of psychiatry critique, when in the UK, in Germany, and the US therapeutic communities and patients’ collectives formed outside of psychiatric institutions. Some of them were guided by psychiatry reformists, for instance R. D. Laing, others were self-managed by psychiatric patients as a counter-reaction to existing psychiatric institutions.
My research pursues two main goals: first, to offer an understanding of critical psychiatry as an international counter-cultural network which circulated knowledge and subversive practices across national borders; second, to analyse how psychiatry critique became a powerful tool for patients to confront social marginalisation, lack of rights and isolation.
Based on original oral history, archival sources, and literary sources, I will map out a transnational historiography of critical psychiatry that revises existing narratives within the limits of national borders. My project constitutes the first attempt to examine in depth the Philadelphia Association, the governing body of various housing projects for psychiatric patients in London, as well as it does justice to the under-researched critical psychiatry scenes in Germany and the US.
In sum, I will produce new perspectives on key historical developments that have lead up to critical psychiatry’s contemporary significance.
|
| 06/05/2020 |
£106,077 |
UNIVERSITY OF OXFORD |
Psilocybin-assisted psychotherapy is likely to become a licensed treatment in the US within two years. However, clinically-relevant doses have a number of surprising ‘side-effects’: they can cause long-term changes to political values and personality, increase prosociality and aesthetic appreciation, and induce mystical experiences of long-lasting spiritual significance connected to changes in religious belief. These changes remain under-researched but challenge several ethical concepts, including authenticity and autonomy, beneficence, and informed consent. The project will begin by systematically reviewing the non-clinical changes reported in the empirical literature to develop a conceptual analysis of these changes within a medical ethics framework. In addition, the perspectives of patients and practitioners of psilocybin-assisted psychotherapy concerning these changes remain unknown, and they are not addressed either in the informed consent process or in therapist training manuals. As such, the project’s second stage will use qualitative empirical methods to provide an account of their experiences and understanding of these changes. Together, the two elements of the project will demonstrate how psilocybin-assisted psychotherapy challenges orthodox conceptualisations of psychiatry, which marginalise spirituality and experiences of awe, as well as requiring policymakers such as NICE and their National Collaborating Centres to revise their approach to foreseen-but-unintended consequences of treatment.
|
| 06/05/2020 |
£93,106 |
UNIVERSITY OF WEST LONDON |
Particular reproductive technologies can make visible elements of the process of biological procreation, but this is not a neutral process. How these technologies see, and are themselves seen, influences the way reproduction itself is understood. Even within current feminist theorising, there is insufficient research into the role of visual cultures of reproductive technologies in the construction of cultural imaginaries surrounding biological reproduction.
Using social reproduction theory as a framework, this PhD will explore the gender politics of the visual representation of historical and emerging reproductive technologies, and investigate the cultural impact of this representation. It will use archival research (extending to advertising, product design, media coverage, and activist ephemera) to explore three case studies: 1. Conception – egg-freezing and IVF; 2. Gestation in process – from ultrasound to the artificial womb; 3. Political contexts – alternative feminist reproductive technologies.
The thesis will explore the gender (and racialised) politics of how historical and emerging reproductive technologies represent gestation, and how they themselves are visually represented. It will analyse the effect of this representation of reproductive technologies on the cultural imaginary, particularly in terms of its role in facilitating or prohibiting social recognition of gestation as a form of reproductive labour.
|
| 06/05/2020 |
£173,371 |
UNIVERSITY OF BRISTOL |
Existing research and training in palliative care ethics appear not to focus on, or be tailored to, practice in China. This research aims to fill these gaps by: first, identifying and exploring the ethical challenges Chinese healthcare professionals have confronted during their provision of palliative care; second, identifying the ethical training they have received and the extent to which they feel prepared to address relevant challenges; and, third, proposing changes, for example, to existing training in order to better equip these professionals. The significance of this research includes offering up-to-date knowledge of palliative care provision and relevant ethical training in China, assessing the utility of these training schemes and eventually making insightful suggestions.
This is an empirical bioethics project, which has three phases (mapping-framing-shaping). The mapping phase involves literature reviews. The framing phase involves qualitative research. The researcher plans to retrieve and thematically analyse empirical data via one-to-one semi-structured interviews. Considering the unique cultural and social background, the data collection will be undertaken in Mandarin in selected hospitals in China. The shaping phase then combines the previous theoretical and empirical findings, using an empirical bioethics methodology - reflexive balancing - with a view to making recommendations for future practice.
|
| 06/05/2020 |
£96,988 |
UNIVERSITY OF DURHAM |
A growing body of psychological research has identified a population of individuals who hear voices outside of the context of pathology. These "non-clinical" voice-hearers have been the subject of a variety of studies aimed at understanding their relationship with clinical voice-hearers. This research, which often relies on standardized psychological measures, fails to explore the broader context in which these experiences occur. Non-clinical participants are often recruited from spiritual communities who accept anomalous experiences and offer meaningful frameworks in which to understand them. The proposed research will address this gap in the literature. Drawing on theory and methodology from anthropology, psychology, and philosophy this research will explore the ways in which the voice-hearing experiences of these individuals are shaped by the larger contexts of their lives. In particular it will seek to understand the ways in which community attitudes towards anomalous experience such as voice-hearing may impact appraisals of these experiences.
|
| 06/05/2020 |
£174,156 |
UNIVERSITY OF CAMBRIDGE |
Early modern Paracelsian physicians, natural historians, chemists and lay practitioners were united in their belief that a plant’s morphological resemblance to a human body part indicated its curative effect. My doctoral research will result in the first monograph to examine how the doctrine of signatures was applied, developed and transformed through medicinal and chymical practice in Germany and England. Through the exploration of personal archives, prescriptions and recipes, I will trace the formation and transmission of this doctrine among chymical physicians, apothecaries and domestic practitioners. I hope to connect histories of mystical philosophy and intellectual developments with recent works on the practices of healing and knowledge transmission. I hold that the doctrine of signatures was not a unified mystical theory once proposed and discredited by "modern science", as argued by philosophers and historians since Michel Foucault, William Ashworth, James Bono or Peter Harrison. Instead, it was a fluid, malleable set of ideas developing in conversation with humanistic learning, experiential knowledge and everyday practice, which survived well into the late seventeenth century. In this way, I hope to challenge the still-dominating narrative on the rise of modernity and scientific revolution.
|
| 06/05/2020 |
£111,099 |
UNIVERSITY COLLEGE LONDON |
This interdisciplinary PhD explores how different stakeholders involved in water delivery affect access to water in the Makoko settlement in Lagos, and which implications this holds for socio-spatial health inequalities. In Lagos, vested interests behind public health agendas manifest through urban water insecurity while informal water networks emerged as a counter-narrative to public service absenteeism partly rooted in a colonial urban planning legacy. The main hypothesis is that the reproduction of power relations along socio-spatial gradients is facilitated by reinforced idioms of informality, aiming to justify the lack of water infrastructure and underservicing of specific low-income groups and thereby intrinsically re-producing the very informal networks that disrupt municipal water services and leading to a widening of the urban health gap. Methodologically, I will intersect statistical and geographical data with cognitive mapping, semi-narrative qualitative interviews and dwellers’ self-report on health conditions. Further linking historical explanations for the water crisis to empirical data, my research strives to challenge orthodox development and planning discourses based on notions of an "African exceptionalism" vis-à-vis the "European master narrative" while contributing to the theoretical and empirical development of the "right to health" as a prerequisite for the "right to the city" and the universal human rights.
|
| 06/05/2020 |
£84,857 |
UNIVERSITY OF GLASGOW |
This thesis will consider experimental form in female-authored representations of mental illness in British and American writing, 1965-present. The narrative and formal experimentation of modern women’s literature challenges both literary conventions and the valorisation of testimonial mimetic narratives about mental illness within the Medical Humanities. Previous study on the topic of women and madness focuses on the content of women’s writing about mental illness more than their formal strategies, thus assessing their writing for its testimonial value rather than its literary sophistication. This thesis will locate illness, not as a metaphor or a device, but as an embodied state, which produces rich aesthetic possibilities and textual forms. It will investigate the opportunities that intermediality - images and non-standard typography - offers for challenging narrative homogeneity and how women writers have critiqued the narrative expectation of empathy in the context of mental health. Considering women’s experimental literature as a genre, I will look at prose fiction, graphic novels, and zines. By comparing the relationships between activism and art, personal experience and experimental fiction, image and text in women's writing, this thesis will offer a fresh framework for approaching the representational politics of mental health across disciplines and within mental healthcare provision.
|
| 06/05/2020 |
£147,166 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
Vaccine policy agendas, decision making process and influences to the decisions highly vary across countries. In recent years, mandatory vaccination policies have been introduced globally, to enforce specific vaccinations on target populations in a country. The policies pose various ethical and legal dilemmas that have been highly debated by academics, policy makers, and country citizens. Some studies have evaluated the policy impact on vaccine coverage and discussed ethics and perspectives of stakeholders. However, research has been geographically biased to Europe and United States; though the policies have been adopted globally, including among the member states of the Association of Southeast Asian Nations. Given the disparities in results and controversy of the policy, the policy decision-making on mandatory vaccinations have not been well understood. To fill this gap in research, this qualitative study will select two countries in ASEAN as cases, and apply policy theories to data collected through literature reviews and key-informant interviews. The study aims to understand the emergence of mandatory vaccinations in policy makers agenda and the actors involved, context of policy adoption and the process and influences of the policy decision. This study aims to develop a vaccine policy decision framework to guide future vaccine policies.
|
| 06/05/2020 |
£102,177 |
UNIVERSITY OF OXFORD |
The NHS is currently facing a ‘perfect storm’ of challenges: increasing demand, a rise in chronic disease, and increasing resource constraints. It is increasingly argued that the 'solution' to these challenges lies in making the NHS more informationally mature, able to capitalise on the opportunities presented by digital, data and – especially - artificial intelligence. Developing this strategic intent is, however, only one half of the ‘solution.’ The other half is provided by the operational implementation of new technologies which is a far more complex and under-researched problem.
The objective of this proposed research is, therefore, to contribute to current work addressing: (a) the slow adoption and spread of technology throughout the NHS; and (b) the development of governance frameworks for emerging technologies, by researching and developing a conceptual framework that can identify the process for the safe, effective and ethical implementation of AI into the NHS. As such, it will aim to answer:
How do social, structural and contextual factors influence the willingness and readiness of different levels of the NHS to adopt Artificially Intelligent technologies? And to what extent does variation in these factors influence the ‘success’ of implementation from the perspective of safety, efficacy and ethics?
|
| 22/04/2020 |
£300,000 |
THE FRANCIS CRICK INSTITUTE |
Groups of cells called 'organizers' release signals to induce cell fates during development. Remarkably, organizers can undergo ‘self-organization’ in 3D organoids. Understanding this phenomenon has profound implications for engineering and regenerating patterned tissues with bonafide cell-type complexity and 3D-architecture.
Mouse pluripotent stem cells (PSCs) can form neural-tube (NT) organoids. Timely retanoic acid (RA) addition induces scattered precursors that self-organize into a floorplate organizer, which drives ventral-dorsal patterning. I will create cognate human (h)NT organoids from single naïve hPSCs. Exploiting advanced bioengineering technologies, I will isolate organoids from confounding inter-organoid communication and promote robust self-organisation. This interdisciplinary approach will enable me to probe previously inaccessible questions regarding complex mechanisms.
Using this system, I will study how cellular competence to express morphogens is subject to strict temporal regulation. Why is there a restricted window-of-competence for RA response, and how does this trigger self-organization? I will molecularly profile the transient competent state, functionally define the gene-regulatory basis for competence restriction, and investigate how molecular changes at this time serve as the basis for long-range self-organizing behaviour.
This will provide a 3D model for critical stages of human nervous system formation, and reveal how self-organization processes are adapted for human-specific developmental size and timing.
|
| 22/04/2020 |
£300,000 |
THE FRANCIS CRICK INSTITUTE |
The aryl hydrocarbon receptor (AHR) has essential functions in the intestine, protecting mice from infection and cancer. However, the underlying mechanisms are still unclear as research has been hindered by the complex regulation and multiple feedback loops governing mammalian AHR. I will therefore use a simpler model system. Spineless, the homolog of AHR in Drosophila, binds the same DNA motif as AHR, but is regulated only on the gene expression level. My preliminary data suggest that Spineless may have similar functions to AHR, influencing epithelial regeneration and survival during infection. I will take advantage of this simpler pathway and the genetic tools and ease of manipulation in the fly in order to rapidly dissect how AHR/Spineless expression is regulated and to systematically analyse its target genes. I will first generate the necessary tools and then answer three main questions: what are the target genes of Spineless, how is Spineless gene expression regulated, and how does Spineless function in the context of intestinal infection. Results obtained from these experiments will be compared with existing data from the Stockinger group on AHR in mice to advance our understanding of intestinal physiology and the critical functions of AHR/Spineless that are conserved across species.
|
| 22/04/2020 |
£300,000 |
CARDIFF UNIVERSITY |
Emerging evidence suggests that sleep traits could be useful indicators of risk, relapse and potential treatment targets for mood disorders. However, the longitudinal and genetic relationships between sleep and mood disorders are complex and remain poorly understood. In this fellowship, I will address these gaps and build on my previous work by using cutting edge methods in genetic epidemiology, sleep neurophysiology and longitudinal data analysis.
Key goals:
(1) Determine the neurophysiological correlates of genetic liability to sleep traits and mood disorders using polysomnography – the gold-standard objective measure of sleep. Examining this in healthy populations will circumvent medication effects and bidirectionality, major confounds in existing polysomnography research.
(2) Examine genetic and longitudinal relationships between adolescent sleep and depression to determine whether genetic variants for sleep traits in adult populations also influence sleep in younger populations, and delineate prospective associations between sleep and depression onset.
(3) Investigate whether sleep disturbances can be used as an indicator of liability to relapse in bipolar disorder. Using in-depth longitudinal data from digital technologies will elucidate the role of sleep in predicting mood episodes in bipolar disorder.
This work will inform sleep interventions and further knowledge on the role of sleep in mood disorders.
|
| 22/04/2020 |
£300,000 |
UKRI-MRC |
The process of endosomal sorting, where internalised transmembrane proteins (cargoes) are sorted for lysosomal degradation or recycled back to the cell surface, maintains and regulates the cell surface proteome. Thus, endosomal sorting regulates numerous cellular processes including cell signalling.
A fine-tuned amount of endosomal branched actin is required for recycling of cargoes from endosomes to the cell surface. Yet the mechanistic roles of endosomal actin in this process are not understood. Moreover, cargo such as the beta-2 adrenergic receptor (beta2-AR), signal in actin-decorated endosomal recycling domains, suggesting that endosomal actin plays a role in both endosomal recycling and signalling. My project aims to determine the mechanistic and physiological roles of endosomal actin.
I will focus on the major endosomal actin polymerisation machinery – the Arp2/3 activating Wiskott–Aldrich syndrome protein and SCAR homolog (WASH) complex. I will investigate the intrinsic regulation of the WASH complex and how external factors it recruits, cumulatively regulate polymerisation of endosomal actin. Furthermore, I will develop new tools including blocking nanobodies and in vitro reconstitution. In combination, these multi-disciplinary approaches will establish a mechanistic and quantitative model of the role of endosomal actin in sorting and signalling. This will further our mechanistic understanding of endosomal recycling.
|
| 22/04/2020 |
£300,000 |
IMPERIAL COLLEGE LONDON |
Parkinson’s disease (PD) is diagnosed by a clinical examination which typically comes 20 years after the initial symptoms. By this time approximately 70% of vulnerable dopaminergic neurons in the substantia nigra (SN) have already been lost. The nigrosomes (small clusters of dopaminergic cells in the SN) have differential histopathological features which make them ideal targets for detecting and monitoring PD.
MRI is highly sensitive to the pathological iron accumulation in the nigrosomes, which is a hallmark of the earliest stages of PD, but quantitative imaging on this sub-millimetre scale is beyond the limits of traditional techniques. I have developed a non-traditional approach to MRI, based on super-resolution approaches from optical microscopy, which can surpass these limitations and rapidly generate quantitative images of the nigrosomes in vivo. I will develop this as an accurate measure of iron accumulation in PD.
The aims of this fellowship are:
Producing accurate microstructural maps at sub-millimetre resolution
Modelling and correcting for subject motion
Testing the hypothesis that microstructural MRI measures in the nigrosomes distinguish PD subjects from healthy controls
If successful, this would enable PD diagnosis in its earliest stages, and maximise the likelihood of finding an effective therapy.
|
| 22/04/2020 |
£300,000 |
UNIVERSITY OF CAMBRIDGE |
Professional phagocytes engulf bacteria inside phagosomes that mediate cargo degradation via lysosome fusion. Some intracellular pathogens evade this fate by disrupting the phagosomal membrane, which triggers antibacterial autophagy. While autophagy may eliminate bacteria for host defence, more recent studies have demonstrated that autophagy can also promote intracellular bacterial survival or be irrelevant for bacterial restriction. Recently, Endosomal Sorting Complex Required for Transport (ESCRT) proteins have been shown to repair small membrane disruptions, potentially providing an alternative pathway for bacterial restriction. The interplay between autophagy and ESCRT machinery during phagosomal damage, the factors triggering each pathway and their contribution to intracellular bacterial killing are poorly understood.
Using the important human pathogen Staphylococcus aureus, I will:
(1) investigate the interplay between autophagy and ESCRT machinery;
(2) identify novel bacterial components that modulate autophagy and ESCRT recruitment; and
(3) uncover unknown host regulators of autophagy, ESCRT and cell-autonomous immunity.
To complete these objectives, I will use high-resolution microscopy to follow bacteria recruiting autophagy and / or ESCRT machinery at the single bacterial cell level. Additionally, I will use high-content genetic screens to discover novel bacterial (using transposon libraries) and host factors (using CRISPR/Cas9) shaping host-pathogen interactions.
|
| 22/04/2020 |
£300,000 |
UNIVERSITY COLLEGE LONDON |
Cancer stemness is linked to therapy resistance and metastasis. Emerging evidence suggests that PIK3CA-H1047R, a hotspot mutation in breast cancer and the PIK3CA-related overgrowth spectrum (PROS), elicits a stemness phenotype characterised by dedifferentiation and cell plasticity. Nevertheless, PIK3CA-H1047R does not cause malignancy in PROS, perhaps reflecting molecular differences between mammary (cancer) and endothelial (PROS) cell lineages.
By learning and applying novel systems biology tools, I aim to address the mechanism(s) behind PIK3CA-H1047R-driven stemness in a quantitative manner, taking into account cell type, genetic mosaicism and the strength of genetic PI3K pathway activation. I will generate mosaic cell models with doxycycline-inducible PIK3CA-H1047R expression, focussing on human breast epithelial cells and human endothelial cells due to their relevance for breast cancer and PROS, respectively. The cells will be exposed to short- and long-term PIK3CA-H1047R expression, followed by temporal assessment of: 1.Cell-state-transitions by single-cell RNA sequencing; 2.PI3K signalling dynamics by candidate-based quantitative single-cell imaging. Next, I will use data integration and mathematical modelling to infer the underlying regulatory principles. My ultimate goal is the identification of PIK3CA-mutant- and cell type-specific pharmacological therapies for reversal of aberrant stemness regulation, followed by validation in physiologically-relevant 3D models based on the established mosaic cell systems.
|
| 22/04/2020 |
£300,000 |
UNIVERSITY OF CAMBRIDGE |
The aim of this fellowship is to accelerate detection of and response to infectious disease outbreaks, particularly where surveillance, diagnosis, and control are under-resourced.
My first goal is to develop and validate machine learning methods to rapidly infer outbreak properties. I have demonstrated proof-of-concept for this approach, and I expect to be able to train machine learning models on synthetic outbreak data to infer outbreak properties almost instantaneously from data. By building on this approach, understanding its validity and weaknesses from application to historical data, and creating a database of simulations and trained models, I hope to allow outbreak data to be interpreted more quickly and simply than currently possible.
My second goal is to complete and test—first against historical data and then prospectively—algorithms for aetiological identification of outbreaks. These algorithms have the potential to allow outbreaks to be detected and controlled faster, as well as to improve guidelines for syndromic surveillance.
Finally, I plan to integrate these analytics for outbreak identification and analysis into lightweight software tools. After testing them in collaboration with field epidemiologists, I hope to enable public health officials to take advantage of epidemiological insights with minimal training, supporting capacity of public health systems.
|
| 22/04/2020 |
£300,000 |
UNIVERSITY COLLEGE LONDON |
I will develop powerful statistical methods that leverage estimated genealogies to reveal the key processes driving human genetic diversity and how these have evolved over time. Genealogies have the potential to transform how we analyze genomes, by providing a single framework for addressing a broad range of population and statistical genetics questions, and by substantially increasing power compared to conventional approaches.
I have four key research aims that will impact distinct areas. Firstly, I will develop a novel method for uncovering how genetic structure changes through time and along the genome. This method can uncover unknown ancestral groups; for example, I will characterize previously-reported deeply diverged ancestry of unknown origin in the genomes of modern Africans. Secondly, I will develop a framework for incorporating ancient genomes of diverse ages and data quality into genealogies of modern individuals, enabling the direct study of how ancient and modern genomes interrelate. Thirdly, I will study the evolution of complex human traits through time under various modes of selection, to explain genetic architectures observed in genome-wide association studies. Fourthly, I will investigate the evolution of the molecular mechanisms of recombination, a key driver of human genetic diversity and hybrid incompatibility.
|
| 22/04/2020 |
£300,000 |
UNIVERSITY OF CAMBRIDGE |
Gestational diabetes mellitus (GDM) is a serious and common pregnancy complication that can evolve in type-2 diabetes (T2DM) years after delivery. Placental hormones have wide-ranging effects on maternal physiology, including the regulation of glucose metabolism. However, we lack information on whether placental hormones could drive changes in maternal metabolism that leads to GDM and the subsequent progression to T2DM. This fellowship aims assess this by using a newly-developed genetic mouse model of placental endocrine malfunction. This is achieved by selectively disrupting the expression of the imprinted Igf2-H19 locus in the placental endocrine cells. Using this approach, I obtained data showing that mice with placental endocrine malfunction have metabolic disturbances, including high blood glucose concentrations during pregnancy. Also, these females show changes in their metabolism in the months after delivery. This project will further these findings in the model by using state-of-the-art in vivo metabolic tests and use transcriptomics, proteomics and methylome analyses to identify how placental hormones induce changes in maternal tissues that cause metabolic problems during and after pregnancy. My long-term aim is to identify biomarkers that could be explored as diagnostic tools or therapeutic targets to prevent the development of GDM and T2DM.
|
| 22/04/2020 |
£300,000 |
UNIVERSITY OF OXFORD |
Efficient T cell responses rely on heterogeneity, characterized by the rise of effector and memory cells. Autophagy, responsible for homeostatic degradation and recycling of cell cargo, is crucial for T cell differentiation. Upon ageing, autophagy is impaired, which is detrimental for the generation of memory cells retaining stemness. Interestingly, I have observed that naïve CD8+ T cells from aged mice are unable to undergo asymmetric cell division (ACD) (unpublished). ACD is a conserved mechanism to generate diversity, by endowing daughter cells with different fate determinants. As both autophagy and ACD are involved in T cell differentiation and impaired upon ageing, unravelling how they synergistically influence T cell stemness is at the centre of this project. We propose to use state-of-the-art imaging, proteomics, and metabolomics to investigate whether autophagy impacts cell asymmetries upon T cell mitosis. Functional validation will be addressed by using the novel combination of autophagy-deficient and organelle-tagged cells (SnapTag mice), which will enable us to evaluate whether asymmetry inheritance of cell cargoes leads to asymmetric fates in vivo. We anticipate that this research will be relevant to better understand how stemness is coordinated, and potentially lead to the development of therapeutic strategies in the context of regenerative medicine.
|
| 22/04/2020 |
£300,000 |
UNIVERSITY OF CAMBRIDGE |
Unconventional myosins of class I can directly associate with membranes, thereby providing a dynamic link between the actin cytoskeleton and the plasma membrane or intracellular organelles. Immune cell-specific myosin 1F and myosin 1G (MYO1F and MYO1G respectively) have roles in immune cell migration and regulation of membrane tension. Studies show both motors are upregulated in microglia during neuroinflammation. To uncover the temporal regulation of these motors, a number of biophysical assays will be employed, such as in vitro motility assays, optical trap experiments and stopped-flow spectroscopy. The molecular interactions of MYO1G that determine cellular function will be explored using a combination of proteomics and cell biological assays to identify the motors’ interacting partners and elucidate its spatial regulation in vivo. The effects of two distinct phosphorylation sites on motor domain activity of MYO1G will be explored with mutations to mimic the non- and phosphorylated states. Protein crystallography studies of MYO1F and MYO1G will enable the design of small molecule inhibitors using structure-based in silico screening, with the ultimate goal to treat neuroinflammation in humans. Taken together these approaches will elucidate the cellular and physiological role of these motors and uncover the potential use of MYO1F and MYO1G as therapeutic agents.
|
| 22/04/2020 |
£300,000 |
QUEEN MARY UNIVERSITY OF LONDON |
When hearing voices, we can perceive a wealth of information about the speakers, such as their identity, regional background, and age. This project will investigate how listeners achieve this, thus probing fundamental mechanisms of person perception from voices. To achieve this, I will take a broad perspective to integrate the usually distinct fields of identity perception and the perception of other speaker characteristics.
Through a programme of behavioural research using acoustic signal processing and methods from the statistical or distributional learning literature, I will first explore how listeners form representations of voice identities through a programme of training studies: What is the acoustic content of mental representations of voices? What kind of information is encoded in such representations?
I will then extend these findings from voice identity perception to the perception of other speaker characteristics: Are such population-level representations formed based on similar mechanisms to identity representations or are there differences?
Finally, I will conduct a magnetoencephalography (MEG) study to describe the timecourse of person perception from voices: Which speaker characteristics are decoded by listeners at which point during perception? Does familiarity with a person change the processing of that voice? Can the low-level acoustic properties (partially) explain the timecourse?
|
| 22/04/2020 |
£300,000 |
EUROPEAN BIOINFORMATICS INSTITUTE |
Understanding how cell fate decisions are regulated is a key question in molecular biology. Building on the CRISPR revolution, exciting technologies (e.g., CROP-seq or direct capture Perturb-seq) induce a genetic perturbation that is characterised, alongside the transcriptome of the cell, by single-cell RNA-sequencing. This enables a range of experimental designs that can, in principle, shed light on the transcriptional response to gene perturbations, its pathogenic and non-pathogenic variation, and the role of gene regulation during differentiation.
However, current computational methods do not exploit this potential: in particular, the ability to accurately measure the effect of a given perturbation is lacking, and the potential to efficiently explore the space of all possible perturbations and conditions remain untapped.
To address this, I will develop a comprehensive suite of computational tools (i) to infer transcriptomic effects of gene knockouts unconfounded by perturbation efficacy, (ii) for optimal experimental setup to increase insights gained from experiments and improve their scalability, (iii) to identify differences in gene regulation across individuals, and (iv) for the study of knockout effects during differentiation. This will lead to an improved understanding of gene regulation, its variation across individuals, and to improved differentiation protocols, with important consequences for cell therapy.
|
| 22/04/2020 |
£300,000 |
UNIVERSITY COLLEGE LONDON |
Motivation: Interventions mobilising communities in collective action for their own health are some of the most effective known global health interventions. However, they do not always succeed and we cannot presently predict or explain why this happens.
Aim: Taking as an example a community mobilisation programme to prevent violence against women in urban slums in Mumbai, India, I will test theory concerning the drivers of collective action from behavioural economics and social psychology.
Method: (1) To unpack how a community mobilisation programme may stimulate collective action in urban India, I will collect and analyse qualitative interview, media and observational data.
(2) To uncover the determinants of participation in collective action, I will conduct cross-sectional and difference-in-differences analysis of secondary data from a randomised controlled trial of the same community mobilisation programme.
(3) To produce causal evidence for the drivers of collective action, I will conduct a behavioural experiment to test the behavioural effects of changing key messages on programme participants. I will use the answers to (1) and (2) to guide message design.
Impact: The study results will be able to guide policy-makers and practitioners on when, how and why complex participatory interventions work to promote health and gender equality.
|
| 22/04/2020 |
£300,000 |
UNIVERSITY OF OXFORD |
I will explore how structural variation can be used to understand the evolution of antimicrobial resistance (AMR) on mobile genetic elements (MGEs).
Most previous research is biased towards nucleotide-level variations in the core genome (high-effect SNPs). Now, the availability of complete genomes means that resolving the larger structural variation of MGEs is both possible and increasingly relevant for the spread of AMR. I will develop a framework to model the non-mutational processes which generate this variation, then apply this to the linked evolution of MGEs and their ‘host’ genomes.
During this fellowship, I will sequentially:
Aim 1. Develop a tool to quantify structural variation and resolve common blocks around the flanking region of AMR genes, which I have previously shown can be used for phylogenetic reconstruction.
Aim 2. Apply this to longitudinal datasets and obtain rate estimates for non-mutational processes.
Aim 3. Investigate the compensatory evolution of MGEs as they move between genomic backgrounds.
Two major applications will be:
Application 1. Small transposons, leading on from my pioneering work on the mcr-1 transposon.
Application 2. Clinical class 1 integrons, which carry multiple AMR genes.
This proposal tackles questions of fundamental importance for the evolution of flexible genomes.
|
| 22/04/2020 |
£300,000 |
ROYAL VETERINARY COLLEGE |
Yellow fever virus (YFV) outbreaks are escalating worldwide despite the existence of a vaccine. Global travel raises the chance that YFV will become established in Asia, where populations are not vaccinated and an outbreak would be catastrophic. Our ability to predict and control YFV outbreaks is reduced by our lack of knowledge about (i) transmission of YFV in its sylvatic reservoir (non-human primates) and (ii) how YFV escapes from this reservoir to spread amongst people in urban areas. Severe under-reporting in both humans and non-human primates hampers our ability to directly study YFV transmission behaviour. Recent advances in portable genome sequencing and virus genomic epidemiology (including phylodynamics) offer new opportunities to use virus genomic data to reconstruct unobserved outbreak dynamics, even when sampling is sparse. I will combine these techniques to improve our understanding of YFV epidemiology, by: (i) integrating viral genomic data into newly-refined YFV mathematical models for improved outbreak prediction; (ii) implementing phylodynamic approaches to identify drivers of sylvatic transmission, and; (iii) exploiting new strategies to generate virus sequences from traditionally neglected times and locations. My Fellowship research findings will improve YFV outbreak prediction and contribute to the development of refined vaccination strategies.
|
| 31/03/2020 |
£1,391,495 |
UNIVERSITY OF EXETER |
More than 1 in 5 UK pregnant women are clinically obese, a condition associated with heterogeneous health outcomes for mother and baby. Only limited understanding of the associations (e.g. gestational diabetes and high birth weight, hypertension and preterm birth/low birth weight) has been possible in traditional observational studies due to complex interrelated exposures and outcomes. My research will use human genetics to dissect causal pathways and understand how a higher maternal BMI can lead to such diverse outcomes. I hypothesise that maternal effects on fetal growth and gestational duration are moderated by fetal genetics. My first aim is to understand how a fetus regulates its own growth and gestational duration in different maternal environments. We will apply results of new genome-wide association studies of placental weight and umbilical cord insulin to give mechanistic insights. My second aim is to understand how raised maternal BMI impacts gestational duration and growth, and my third aim is to examine whether fetal genetics can influence the maternal environment. By identifying causal mechanisms, this fellowship will be an advance towards better targeting of antenatal healthcare and advice to pregnant women, according to their level of risk to reduce the incidence of adverse pregnancy outcomes.
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| 31/03/2020 |
£1,639,257 |
UNIVERSITY OF WARWICK |
Kinesin-microtubule systems transport intracellular cargo in eukaryotes and are essential for life. Recently, we discovered that dynamic microtubules can respond to kinesin by changing their conformation, lattice spacing, curvature and stability, and conversely that kinesin stepping can sense and respond to conformational shifts in the microtubule lattice. These insights fundamentally redraw our picture of the function of kinesin-microtubule transport systems. I now propose to dissect the mechanical mechanisms by which kinesins and microtubules instruct one another, using protein engineering combined with single molecule optical trapping at unprecedented resolution. Working with both wild-type and mutant kinesins and tubulins, principally from S. pombe, we will determine the structural requirements for different microtubule lattices to control kinesin substeps, backsteps and bidirectionality; and the converse requirements for kinesins to manipulate the conformation and fate of microtubules. Our experiments will reveal how tubulins communicate mechanically with one another and with kinesins. Illuminating the molecular mechanisms of active mechanical feedback in kinesin-microtubule systems will transform understanding of the transport machinery and open the way to improved chemical biological manipulation of its in vivo function.
|
| 31/03/2020 |
£2,035,881 |
KING'S COLLEGE LONDON |
I propose to use my SRF to investigate the intergenerational transmission of mental health problems. Previously, in my Sir Henry Dale Fellowship, I have developed statistical models for use with genetically informative intergenerational data (composed of many extended families) for use in distinguishing genetic transmission from the potential causal effects of parent on child. In my SRF I will build on this work:
1. I will establish to what extent the treatment of mental health problems in parents reduces the transmission of problems to children (and vice versa).
2. Combine pedigree-based approaches with genomic data to draw on the strengths of each. This will enable the identification of the direction and magnitude of intergenerational causal effects, and identify polygenic scores involverd in gene-environment interplay relevant to the intergenerational transmission of mental health problems.
3. Explore the biases inherent in our use of volunteer based cohorts to understand mental health aetiology.
4. Extend my own children-of-twins study, funded as part of my SHDF, CoTEDS (the Children-of-TEDS). CoTEDS is the second generation of an ongoing twin study, and the first twin study in the world to include information on parents and children from birth.
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| 31/03/2020 |
£4,119,965 |
UNIVERSITY OF CAMBRIDGE |
Building on advances during our successful connectomics collaboration (2016-20), we now propose a very ambitious new goal: a complete, high-quality connectome for the male Drosophila central nervous system (CNS). With Wellcome support and leveraging Janelia’s unique electron microscopy imaging capability, we could turn image data into a fully analysed connectome. This would be the first CNS connectome of an animal with complex motor and cognitive behaviours. In contrast to existing fly datasets, it will be bilaterally complete, include brain and nerve cord and have intact sensory-motor connectivity.
This connectome should have an enormous impact on the understanding of CNS-spanning circuitry underlying complex behaviour. We will publicly release initial draft and high-quality versions as soon as they are complete. We will immediately use it to study multisensory integration, memory recall, decision making, modification of brain states, the flexible organisation of motor behaviour, and sexually dimorphic circuits. It will provide a critical resource for > 200 labs worldwide studying Drosophila neurobiology (with impacts on developmental biology and molecular cell atlases) and provide new opportunities for theoretical neuroscientists to study complete, biologically-defined neural networks in a richly investigated organism. We expect general principles, applicable to all nervous systems, including those of humans, to emerge.
|
| 31/03/2020 |
£1,909,584 |
UNIVERSITY OF DUNDEE |
The Type VI secretion system (T6SS) is used by many Gram-negative bacteria to deliver toxic ‘effector’ proteins into rival bacterial cells as a means of inter-bacterial competition. The T6SS likely plays a central role in shaping many polymicrobial communities, but important aspects of effector delivery and action in target cells, and the ‘real-life’ relevance of T6SSs in a clinical context remain elusive. We will investigate the journey of individual and co-operating groups of effectors, from their recruitment by the T6SS to their fate and action in targeted cells, and dissect the mechanism of individual anti-bacterial effectors. We will also consider the global availability and mobility of anti-bacterial effectors and how the T6SS and its effectors can influence bacterial success in a clinical context. Using multidisciplinary approaches, we aim to:
Determine the mechanism of toxicity of novel anti-bacterial effectors
Elucidate the fate of effectors inside target cells
Define mechanisms of versatile effector recruitment and delivery in attacker cells
Use genomics to reveal the diversity, evolution and real-life relevance of T6SS effectors
Our findings, combining mechanistic detail with insight into biological relevance, will provide fundamental advances in our understanding of T6SS-mediated anti-bacterial activity and may inform future strategies to counter bacterial pathogens.
|
| 31/03/2020 |
£689,181 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
Our research programme will deliver mechanistic understanding of how cyclic nucleotide signalling controls the development of two key phases of the malaria parasite lifecycle: the asexual blood stage that causes pathology, and gametogenesis that is required for transmission to the mosquito vector. We have previously shown that there is a temporal switch from cyclic GMP (cGMP) signalling to cAMP signalling as the asexual parasite progresses from egress (escape from its host erythrocyte) to invasion. Cyclic GMP signalling also controls egress of sexual stage parasites to enable fertilisation in the mosquito. In both lifecycle phases, egress requires cGMP-dependent calcium flux. We have recently identified a unique, essential membrane-bound binding partner of the cGMP-dependent protein kinase (PKG). We have also identified a set of high confidence targets of cAMP signalling required for invasion and subsequent parasite development, and have obtained exciting new insights into how cGMP production is governed. We now want to: (1) determine the mechanisms underlying the interrelationship between cGMP and calcium signalling; (2) dissect the role of cAMP-dependent phosphorylation in erythrocyte invasion; and (3) identify the parasite proteins that interact with cyclase and phosphodiesterase enzymes (which balance cellular levels of cyclic nucleotide) to understand how the pathways are regulated.
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| 31/03/2020 |
£669,703 |
THE FRANCIS CRICK INSTITUTE |
Our research programme will deliver mechanistic understanding of how cyclic nucleotide signalling controls the development of two key phases of the malaria parasite lifecycle: the asexual blood stage that causes pathology, and gametogenesis that is required for transmission to the mosquito vector. We have previously shown that there is a temporal switch from cyclic GMP (cGMP) signalling to cAMP signalling as the asexual parasite progresses from egress (escape from its host erythrocyte) to invasion. Cyclic GMP signalling also controls egress of sexual stage parasites to enable fertilisation in the mosquito. In both lifecycle phases, egress requires cGMP-dependent calcium flux. We have recently identified a unique, essential membrane-bound binding partner of the cGMP-dependent protein kinase (PKG). We have also identified a set of high confidence targets of cAMP signalling required for invasion and subsequent parasite development, and have obtained exciting new insights into how cGMP production is governed. We now want to: (1) determine the mechanisms underlying the interrelationship between cGMP and calcium signalling; (2) dissect the role of cAMP-dependent phosphorylation in erythrocyte invasion; and (3) identify the parasite proteins that interact with cyclase and phosphodiesterase enzymes (which balance cellular levels of cyclic nucleotide) to understand how the pathways are regulated.
|
| 31/03/2020 |
£2,141,982 |
INSTITUTE OF CANCER RESEARCH |
Splicing and polyadenylation are two essential steps of gene expression that account, to a great extent, for the complexity of eukaryotes. The two processes are catalysed by the spliceosome and the polyadenylation apparatus – two macromolecular machines of megadalton-size which contain more than 70 and 20 proteins, respectively.
The two machines associate physically to form composite assemblies, where cross-talk events support emerging layers of regulation of splicing and polyadenylation. These assemblies are primarily unexplored from a mechanistic perspective, due to their excessive size, complexity and dynamics.
By employing state of the art technologies and our long-standing expertise in the structural biology of splicing, the time is now ripe for a thoroughgoing investigation of these assemblies. Thus, we aim to stall and isolate composite assemblies relevant for: (i) the coupling between splicing and polyadenylation, (ii) the definition of exons during constitutive and alternative splicing and (iii) protection of genes from premature polyadenylation. Afterwards, we will characterise their 3D structures and functions by electron cryo-microscopy and complementary biochemical methods. The proposed research is expected to be eye-opening and bring a substantive contribution to our understanding of how fundamental processes of gene expression integrate mechanistically.
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| 31/03/2020 |
£2,049,477 |
UNIVERSITY OF EDINBURGH |
As cells build the body, they use information from localised secreted signals to guide differentiation and morphogenesis. It is often assumed there is unidirectional flow of information from these biochemical signals to the resulting morphological changes, but this 'linear' model cannot explain how development is orchestrated with such remarkable reproducibility.
We have found that changes in epithelial structure provide a previously underappreciated source of information that feeds back into differentiation decisions by modulating biochemical signalling. Using mouse gastrulation as a paradigm we have identified candidate molecular mechanisms that mediate this feedback: 1) A cadherin-mediated community effect that dampens anti-neural signals to synchronise neural differentiation 2) a cell-clustering process that amplifies juxtacrine pro-mesoderm signalling to coordinate differentiation across collectives of cells.
We propose that these two interlinked mechanisms coordinate distinct sources of information across different time scales. We will test this in vitro and in vivo using a unique toolkit based on molecular and biophysical manipulation of epithelial structure, mosaic analysis, and custom-developed quantitative image analysis software.
Generalisable principles emerging from this work will help resolve the currently unpredictable relationship between signalling-input and differentiation-output to give us better control over in-vitro differentiation, organoid formation, tissue repair, and tumorogenesis.
|
| 31/03/2020 |
£2,580,251 |
UNIVERSITY COLLEGE LONDON |
This proposal examines the neural mechanisms supporting decision-making and prospective planning. We will examine how prefrontal cortex (PFC), hippocampus, and entorhinal cortex (EC) interact to support these processes. We will examine how non-human primates (NHPs) make choices in large decision spaces, particularly when novel choice-values have to be inferred ‘online’. We will test different models of value-coding, particularly whether PFC uses a ‘place-like’ and ‘grid-like’ code to construct cognitive maps of values spaces. We will examine how NHPs make ‘online’ choices when sequentially navigating between stimuli/states as rewards move or paths blocked. We will test whether ‘replay’ provides a neural mechanism supporting model-based planning. We will use Transcranial Ultrasound Stimulation to selectively disrupt regions of PFC/hippocampus/EC to examine its effect on neural selectivity and behaviour. These tasks are high-dimensional, yet amenable to mathematical description, and will be combined with high-density recordings to map these computations. Exp.3 will integrate our home-cage training system with wireless data-logging to record neural data continuously, across tasks and sleep, to examine how neural signatures change across days with learning, and acquisition of ‘learning set’. This provides the technology to continuously map the NHP brain during performance of diverse and naturalistic tasks, radically transforming primate neuroscience.
|
| 31/03/2020 |
£1,580,335 |
UNIVERSITY COLLEGE LONDON |
Many severely and profoundly deaf children struggle to learn to read because written text is a visual representation of spoken language, to which they have limited access. I have shown that speechreading (lipreading) relates to deaf children’s reading development. Fully understanding the mechanisms underlying the speechreading-reading relationship is fundamental to harnessing speechreading as a tool to improve deaf children’s reading. My goal is to investigate this mechanism in 1) a longitudinal study, to determine the relationships between speechreading, phonological skills, language skills and reading over time and 2) in neuroimaging studies with deaf children and adults to investigate neural representations of visual speech and written text and the relationships between them.
All deaf participants involved in the studies above will use speechreading. A subset will also have learned British Sign Language from an early age. Good quality early sign language exposure is beneficial to reading development in profoundly deaf children. However, the mechanism underlying this relationship is unclear. I will employ parallel methods to those used in the speechreading studies to examine 1) the longitudinal relationships between sign language, fingerspelling and reading and 2) the neural representation of these visual language inputs in deaf children and adults.
|
| 31/03/2020 |
£2,236,593 |
UNIVERSITY OF SUSSEX |
Retinal ganglion cells (RGCs) are the vertebrate eye’s only projection neurons to the brain. Through RGCs, species transmit ~50 visuo-ecologically relevant image features in parallel. However, what these features are, and how their information is used by central circuits to inform visual decisions remains unclear in any species. A key difficulty has been to link the activity of RGCs in the in vivo eye with behaviour. To address this major knowledge gap, I will capitalise on the visual system of the larval zebrafish where the activity of RGCs in the eye and their presynaptic terminals in the brain can be non-invasively monitored and manipulated in the live animal. I will ask:
What information does the fish’s eye send to the fish’s brain?
Does the brain "tune" its own input from the eye?
How does the brain use information from RGCs to guide behaviour?
Taking reference of our and others’ data on RGC processing from mice and primates, we ultimately aim to arrive at a more general theory of how an eye can communicate with its brain, that encompasses coding strategies employed by diverse species with distinct visual abilities and requirements.
Key-words: Vision, projection neuron, zebrafish, 2-photon imaging
|
| 31/03/2020 |
£2,078,748 |
UNIVERSITY COLLEGE LONDON |
Animals accomplish goal-directed behaviours by performing sequences of motor actions. A central goal of neuroscience is to understand how neural circuits regulate behaviour in accordance with external events and internal drives and precisely choreograph diverse actions for a successful outcome. To meet this challenge, I will exploit the unique accessibility of the larval zebrafish and focus on a conserved behaviour – hunting – in which a sequence of discrete, specialised actions mediates pursuit and capture of prey. I will use a powerful experimental strategy that combines cellular-resolution calcium imaging, behavioural analyses, optogenetic circuit manipulations, neuroanatomical tracing and computational modelling to discover how brain-wide circuits operate at the cellular level to flexibly control the expression and coordination of behaviour. This paradigm will enable me to discover (1) how sensory and internal state information are integrated to control the sensorimotor decision to hunt, (2) how specific hunting actions are generated and (3) how command signals operate alongside dynamic sensory inputs to assemble a goal-directed sequential behaviour. Overall, the project will produce a mechanistic, cellular-resolution circuit model that explains how the brain controls and patterns multi-component behaviour. I expect this will reveal fundamental principles about the operational logic of the nervous system.
|
| 31/03/2020 |
£2,381,203 |
UNIVERSITY OF CAMBRIDGE |
This project aims to identify new strategies to target the gut for the treatment of type 2 diabetes and obesity. Intestinal hormones regulate intestinal nutrient absorption, insulin secretion and appetite, and therapeutics based on the gut peptide GLP-1 are widely used for type 2 diabetes and obesity. Bariatric surgery causes weight loss and resolves diabetes at least in part via gut endocrine changes.
This project will characterise human enteroendocrine cells using intestinal organoid cultures, building on our previous work using transgenic mouse models. To identify cells of interest, organoids will be engineered by CRISPR/Cas9 to express fluorescent sensors driven by hormonal promoters, allowing cellular analysis by transcriptomics, electrophysiology and real-time fluorescence imaging of e.g. Ca2+ and cAMP. We will characterize nutrient sensing pathways and identify receptors and signaling pathways potentially modifiable therapeutically. Using mouse and human tissues, we will identify circuitry involved in bidirectional cross-talk between gut endocrine cells and enteric/autonomic nerves.
Building on our new methods to analyse peptides and the low molecular weight proteome by mass-spectrometry, we will investigate how plasma peptides respond to nutrient ingestion in health and metabolic diseases including diabetes, obesity, lipodystrophy and anorexia nervosa, and following bariatric surgery or dietary calorie restriction in obesity.
|
| 31/03/2020 |
£2,214,779 |
UNIVERSITY OF CAMBRIDGE |
Plasmodium falciparum parasites still cause nearly half a million deaths each year. The repeated emergence of antimalarial drug resistance and the lack of a highly effective vaccine mean that there is an urgent need to identify new intervention targets. Erythrocyte invasion is an excellent target as it is essential for both parasite survival and for malaria pathology. Invasion involves multiple parasite ligands, but little is known about their function at the cellular level and even less about how they fit into the broader network of invasion proteins. This proposal will revolutionise our understanding of the function of two families of P. falciparum invasion ligands, the EBLs and the RHs, that are together responsible for the key decision point in the invasion process. The key goals are to:
Systematically dissect functional equivalence between EBLs and RHs
Establish the roles that EBLs and RHs play in discriminating between erythrocyte variants within and between humans
Use innovative combinatorial approaches to move from a gene to a network understanding of EBL and RH function.
The proposal will provide a step change for the field, both biologically and technically, and will identify new candidates for testing in a rationally designed, multi-component invasion-blocking vaccine.
|
| 31/03/2020 |
£1,914,685 |
UNIVERSITY OF BRISTOL |
An intracellular nexus for regulating the membrane trafficking of many of the 5,000+ integral proteins encoded by the human genome is the endosomal network. Composed of vesicular and tubular early and late endosomes, the network’s principal role is to sort integral proteins (termed ‘cargoes’) arriving from the cell surface and the biosynthetic pathway between two fates: either sorting to the lysosome for degradation, or retrieval from this fate for export to the cell surface, the biosynthetic pathway or other specialised organelles. Whilst the molecular details of degradative cargo sorting have been well documented, those events that conduct cargo retrieval and export remain poorly understood. Our research has sought to fill this fundamental void in metazoan cell biology.
A master conductor of endosomal retrieval and export is the retromer pathway - in human cells this orchestrates the sorting of > 900 cargoes. Establishing how this pathway functions is central to understanding the evolution, organisation and activity of endosomal sorting. With Wellcome support we will address two integrated questions:
The fundamental question of how the retromer pathway is organised and integrated with other pathways to orchestrate global endosomal cargo sorting.
How understanding of retromer pathway function may provide vital insight into neurodegenerative diseases.
|
| 31/03/2020 |
£2,025,694 |
UNIVERSITY OF CAMBRIDGE |
To treat and prevent dementia in patients, it is essential to understand how microscopic changes in the human brain cause complex cognitive and behavioural disorders. My program addresses this critical gap in translational research, to facilitate clinical application of basic science discoveries. I have three goals, set in the context of frontotemproal dementia and progressive supranuclear palsy.
First, I will develop quantitative biophysical models of human brain function that capture key cellular and pharmacological pathologies in vivo, with regional, laminar and synaptic specificity. These models of degenerating neuronal circuits are informed by individual measures of synaptic density (PET imaging with a SV2a ligand), GABA and glutamate (ultrahigh-field MR spectroscopy). They are optimised in vivo by inversion to magnetoencephalography, and tested post-mortem against neuropathology. This synergy of multi-modal imaging, together with Bayesian model comparison of Dynamic Casual Models, means one can drill down to the best mechanistic model of the human cognitive disorder.
Second, I will show how harmful effects of dementia like apathy can be explained in terms of changes in synaptic density and loss of precision in hierarchical brain networks.
Third, I will I demonstrate the readiness of my approach for experimental medicine, through longitudinal designs and pharmacological interventions.
|
| 31/03/2020 |
£875,659 |
UNIVERSITY OF CAMBRIDGE |
The molecular mechanisms by which mitochondrial reactive species, metabolites and redox signals contribute to physiology and pathology are unclear. This is in large part because these processes are difficult to assess and modulate in vivo. Our goals are to establish general chemical biology approaches to determine the mechanisms of mitochondrial physiology and dysfunction in vivo and from this develop new therapeutic strategies. The aims are based on the success of our previous Joint Investigator Award, but the specific chemical biology approaches to be used, the insights to be attained and the models have been refined and developed, based on our work over the past four years. These goals will be achieved by addressing three research challenges in cells and in vivo:
A: Can we determine how mitochondria operate during normal physiology, and are disrupted during pathology, by targeting probes to measure reactive species and alterations to signaling pathways?
B: Can targeting bioactive molecules to mitochondria prevent pathological disruption of mitochondrial function and generate potential therapies?
C: Can the above methods to monitor and modulate mitochondrial function be assessed in animal models of human diseases and thus drive the development of rational, translatable therapies?
|
| 31/03/2020 |
£803,027 |
UNIVERSITY OF GLASGOW |
The molecular mechanisms by which mitochondrial reactive species, metabolites and redox signals contribute to physiology and pathology are unclear. This is in large part because these processes are difficult to assess and modulate in vivo. Our goals are to establish general chemical biology approaches to determine the mechanisms of mitochondrial physiology and dysfunction in vivo and from this develop new therapeutic strategies. The aims are based on the success of our previous Joint Investigator Award, but the specific chemical biology approaches to be used, the insights to be attained and the models have been refined and developed, based on our work over the past four years. These goals will be achieved by addressing three research challenges in cells and in vivo:
A: Can we determine how mitochondria operate during normal physiology, and are disrupted during pathology, by targeting probes to measure reactive species and alterations to signaling pathways?
B: Can targeting bioactive molecules to mitochondria prevent pathological disruption of mitochondrial function and generate potential therapies?
C: Can the above methods to monitor and modulate mitochondrial function be assessed in animal models of human diseases and thus drive the development of rational, translatable therapies?
|
| 31/03/2020 |
£2,654,295 |
IMPERIAL COLLEGE LONDON |
This application will test the hypothesis that pulmonary immune homeostasis is maintained by a network of tissue resident cells that continually monitor environmental change. Disruption of local neuro-immune-stromal interactions either by genetic or environmental factors, alters the threshold for immune responses to usually innocuous particles such as dust, pollen or dander leading to chronic airway inflammation and tissue remodelling. I will ascertain the cellular and molecular composition of the airway wall parenchyma in children and adults with severe asthma and use machine learning tools and mouse models to determine the impact on lung function. Viral infection and pollution are common triggers for asthma severity, and I will establish how the immune/stromal niche communicates with the external environment to react to these inhaled stimuli, focussing on interaction with neuronal systems. I will examine how these interactions differ in severe asthma and contribute to the ensuing inflammation, remodelling and lung dysfunction. I will investigate the cellular interactions between fibroblasts, extracellular matrix and type 2 immune cells that facilitate repair versus remodelling during severe asthma. Ultimately this programme will reveal insight into mechanisms underlying tissue remodelling versus repair during severe asthma.
|
| 31/03/2020 |
£1,639,854 |
UNIVERSITY OF GLASGOW |
Proteins entering the secretory pathway at the endoplasmic reticulum (ER) undergo a vast array of post-translational modifications some of which are essential for correct folding, assembly and secretion. Failure to fulfil these functions results in several diseases due to the lack of secretion of proteins such as insulin and antibodies, or due to cell death triggered by an unfolded protein stress response. The ER provides a unique environment for protein modifications such as disulfide formation and glycosylation. To ensure efficient protein folding and secretion the cell maintains the environment within the ER that ensures these processes occur efficiently and reacts to situations of cell stress. This proposal builds on exciting new observations from my group to dissect molecular mechanisms involved in secretory protein biogenesis. Our particular focus will be on how the cell maintains ER redox balance, how the repertoire of ER folding factors orchestrate correct protein folding and N-linked glycosylation and how the UPR sensor ATF6 is activated following proteotoxic stress. Our aims will be achieved using a combination of innovative new technological approaches and previously established robust assays to follow protein folding and assembly in both reconstituted and cellular systems.
|
| 31/03/2020 |
£2,088,673 |
THE FRANCIS CRICK INSTITUTE |
Cohesion between sister chromatids, mediated by the chromosomal cohesin complex, is a prerequisite for faithful chromosome segregation during cell division. The ring-shaped cohesin complex is a multisubunit ATPase that topologically loads onto DNA in the G1 phase of the cell cycle. The first part of the proposal will elucidate the molecular mechanism of cohesin function. We will employ and develop biophysical, structural and DNA-protein crosslink mass spectrometry tools to map the trajectory by which DNA enters the cohesin ring, fuelled by ATP-dependent conformational changes. The second part of the proposal examines the establishment of sister chromatid cohesion during S phase. We will investigate how, as the replication fork moves along DNA, cohesin transitions from containing one DNA to embracing two newly replicated DNAs. This includes the functional characterisation of replisome components with roles in sister chromatid cohesion, known as ‘cohesion establishment factors’. Furthermore, we will take advantage of recent success with the biochemical reconstitution of complete DNA replication and work towards recapitulating sister chromatid cohesion establishment in vitro. This will open unique experimental opportunities to understand the process. Together, this programme will provide insight into the molecular mechanism of how cohesin safeguards faithful chromosome segregation.
|
| 31/03/2020 |
£1,756,223 |
UNIVERSITY OF MANCHESTER |
The evolution of antibiotic resistance is a threat to modern medicine. Patients with chronic bacterial infections are at particular risk from antibiotic resistant genotypes, which typically arise from within the infection. However, a lack of controlled studies means that we don't understand how antibiotic resistance evolves within the human host environment, and why the emergence of resistance varies among patients.
We identify randomised clinical trials (RCTs) of new antibiotic treatments as a powerful way to study resistance evolution in action during a controlled, replicated natural experiment. We will exploit a unique opportunity to perform an evolutionary analysis of two parallel Phase-III RCTs for inhaled ciprofloxacin treatment of chronic lung infections caused by Pseudomonas aeruginosa, which is a WHO Priority-1 pathogen in critical need of improved antibiotic therapies. Ciprofloxacin resistance emerged in ~40% of the treated patient infections but this patient-to-patient variation is unexplained.
We aim to explain why resistance evolved in some patients but not in others. To do this, we will (1) discover the evolutionary mechanisms of resistance emergence in patient infections, (2) identify the bacterial and host properties that drove resistance evolution, and then (3) test how well biomarkers of these drivers predict resistance emergence in other patients.
|
| 31/03/2020 |
£2,280,346 |
KING'S COLLEGE LONDON |
Undernutrition during the early years of life has a harmful and irreversible impact on child growth and cognitive development. Many of the interventions tested to improve outcomes across infancy have had disappointing or inconsistent impact, a common feature being the absence of any attempts to provide nutritional supplements to infants during the first six months. With increasing evidence of micronutrient deficiencies in this age group, alongside strong evidence that growth and developmental deficits begin before six months, a renewed focus on the micronutrient status of infants is required.
Here I propose a randomised efficacy trial of micronutrient supplementation to mothers (during pregnancy or pregnancy and lactation) and infants (birth to six months) in rural Gambia, where rates of micronutrient deficiencies are high. 600 pregnant women (
This novel research will identify the most efficacious way of improving micronutrient status in infancy, and assess impact on infant developmental outcomes, providing an evidence base for future effectiveness trials and policy recommendations.
|
| 31/03/2020 |
£2,464,967 |
MRC LABORATORY OF MOLECULAR BIOLOGY |
The co-ordinated development and differentiation of lymphocytes is critical to producing the bespoke immune responses required to combat specific pathogens, but also to maintaining tissue homeostasis and repair. However, dysregulated immune reactions underlie undesirable chronic inflammation and autoimmunity. Our discovery of type-2 innate lymphoid cells (ILC2) and the description of other ILC subsets has highlighted additional, previously unappreciated, complexity in the processes of lymphocyte specialisation. Our challenge is to unravel the microenvironmental cues, critical cell-surface receptors, and key transcription factor interactions that lead to lymphocyte specification, tissue-specific roles and cellular interactions. We will employ a unique repertoire of lymphocyte transcription factor reporter "polychromILC" mice in combination with CRISPR-mediated screens to identify new regulators of lymphocyte development, differentiation and function. To facilitate the investigation of these new pathways in specific lymphocyte subsets in vivo we will produce a new generation of mouse strains designed to limit off-target events by employing multiple positive and negative determinants, comparable to Boolean operators (AND, OR, NOT or AND NOT). Finally, using a combination of genetic screens and in toto adaptive light-sheet microscopy we aim to define molecules and cells that delineate the migration and development of ILC in the context of the stromal environment.
|
| 31/03/2020 |
£2,407,240 |
KING'S COLLEGE LONDON |
The majority of lung cancer deaths result from ineffective treatment of late-stage disease. Currently, there is no satisfactory way to identify patients that will not respond to standard-of-care treatments. Positron emission tomography (PET) imaging offers a potential solution to this clinical problem through the non-invasive assessment of molecular processes that underpin therapy-resistance. The identification of cancer patients that are refractory to treatment will allow the selection of second-line therapies that have the potential to improve patient response and survival.
For this SRF, I will develop novel PET radiotracers to predict therapy resistance in mouse models of non-small cell lung cancer. These radiotracers will non-invasively image the aberrant activity of key antioxidant pathways that are causal to therapy resistance. Specifically, I will use structure-activity relationships and in vivo imaging to design highly-specific radiotracers for the cancer stem cell marker, aldehyde dehydrogenase 1A1; nuclear factor erythroid 2-related factor 2, the master regulator of the antioxidant response; and de novo glutathione synthesis. Our library of redox radiotracers will subsequently be used to detect drug resistance in syngeneic, isogenic and patient-derived models of lung cancer. Finally, I will use the radiotracers developed in this programme to assess response to immunotherapy in drug-resistant lung cancer.
|
| 31/03/2020 |
£1,734,742 |
UNIVERSITY COLLEGE LONDON |
During development the embryo needs to generate functional organs composed of many different cell types, often originated in different embryonic location. Thus, it is clear that cell differentiation and migration need to be tightly coordinated, although they are often studied as independent processes. Here I will test the hypothesis that cell migration and differentiations are coordinated by tissue mechanics in vivo. Specifically, I will challenge the current view that cell migration is the result of differentiation, by testing instead whether the reverse occurs, i.e. migration controls differentiation. I will use neural crest cell, a multipotent embryonic cell population in which cell differentiation is always linked to cell migration.
One of the problems to study biomechanics in vivo is the limited number of tools to measure and modify mechanical properties in vivo. Here I will develop new tools to analyse and change tissue stiffness in vivo. We will analyse how these mechanical changes influence cell migration and differentiation, and we will identify the molecular response elicited in the neural crest cells. We expect that this multidisciplinary project will provide answers to a central yet unresolved question in developmental biology: how cell fate and migration are integrated during embryo development.
|
| 31/03/2020 |
£532,692 |
BABRAHAM INSTITUTE |
The cell fate decisions that accompany exit from pluripotency and entry into gastrulation and early organogenesis establish the vertebrate body plan. Recent advances in single-cell multiomics have allowed transcriptomes and epigenomes to be mapped at single cell resolution during mouse embryogenesis. These studies suggest that cell fate decisions can be made autonomously, where cell fate derives from an intrinsic regulatory programme, or signalling-based, in which fate is determined by the reception of local extrinsic cues. The potency of precursors is progressively restricted as fate is allocated, but separate developmental routes can lead to convergent cell fates. To understand the fundamental principles of these cell fate determination processes, we will combine in vivo mechanistic studies and quantitative mechanistic modelling. We will integrate cell lineage relationships with spatial information and single cell multi-omics, using (epi)genome editing to perturb cell fate decisions in vivo. By comparing early organogenesis across the three germ layers, we will seek to understand the shared and unique features of the mechanisms that establish the underlying fate map.
|
| 31/03/2020 |
£338,511 |
MEMORIAL SLOAN KETTERING CANCER CENTER |
The cell fate decisions that accompany exit from pluripotency and entry into gastrulation and early organogenesis establish the vertebrate body plan. Recent advances in single-cell multiomics have allowed transcriptomes and epigenomes to be mapped at single cell resolution during mouse embryogenesis. These studies suggest that cell fate decisions can be made autonomously, where cell fate derives from an intrinsic regulatory programme, or signalling-based, in which fate is determined by the reception of local extrinsic cues. The potency of precursors is progressively restricted as fate is allocated, but separate developmental routes can lead to convergent cell fates. To understand the fundamental principles of these cell fate determination processes, we will combine in vivo mechanistic studies and quantitative mechanistic modelling. We will integrate cell lineage relationships with spatial information and single cell multi-omics, using (epi)genome editing to perturb cell fate decisions in vivo. By comparing early organogenesis across the three germ layers, we will seek to understand the shared and unique features of the mechanisms that establish the underlying fate map.
|
| 31/03/2020 |
£389,120 |
THE FRANCIS CRICK INSTITUTE |
The cell fate decisions that accompany exit from pluripotency and entry into gastrulation and early organogenesis establish the vertebrate body plan. Recent advances in single-cell multiomics have allowed transcriptomes and epigenomes to be mapped at single cell resolution during mouse embryogenesis. These studies suggest that cell fate decisions can be made autonomously, where cell fate derives from an intrinsic regulatory programme, or signalling-based, in which fate is determined by the reception of local extrinsic cues. The potency of precursors is progressively restricted as fate is allocated, but separate developmental routes can lead to convergent cell fates. To understand the fundamental principles of these cell fate determination processes, we will combine in vivo mechanistic studies and quantitative mechanistic modelling. We will integrate cell lineage relationships with spatial information and single cell multi-omics, using (epi)genome editing to perturb cell fate decisions in vivo. By comparing early organogenesis across the three germ layers, we will seek to understand the shared and unique features of the mechanisms that establish the underlying fate map.
|
| 31/03/2020 |
£507,346 |
UNIVERSITY OF OXFORD |
The cell fate decisions that accompany exit from pluripotency and entry into gastrulation and early organogenesis establish the vertebrate body plan. Recent advances in single-cell multiomics have allowed transcriptomes and epigenomes to be mapped at single cell resolution during mouse embryogenesis. These studies suggest that cell fate decisions can be made autonomously, where cell fate derives from an intrinsic regulatory programme, or signalling-based, in which fate is determined by the reception of local extrinsic cues. The potency of precursors is progressively restricted as fate is allocated, but separate developmental routes can lead to convergent cell fates. To understand the fundamental principles of these cell fate determination processes, we will combine in vivo mechanistic studies and quantitative mechanistic modelling. We will integrate cell lineage relationships with spatial information and single cell multi-omics, using (epi)genome editing to perturb cell fate decisions in vivo. By comparing early organogenesis across the three germ layers, we will seek to understand the shared and unique features of the mechanisms that establish the underlying fate map.
|
| 31/03/2020 |
£2,379,992 |
UNIVERSITY OF CAMBRIDGE |
The cell fate decisions that accompany exit from pluripotency and entry into gastrulation and early organogenesis establish the vertebrate body plan. Recent advances in single-cell multiomics have allowed transcriptomes and epigenomes to be mapped at single cell resolution during mouse embryogenesis. These studies suggest that cell fate decisions can be made autonomously, where cell fate derives from an intrinsic regulatory programme, or signalling-based, in which fate is determined by the reception of local extrinsic cues. The potency of precursors is progressively restricted as fate is allocated, but separate developmental routes can lead to convergent cell fates. To understand the fundamental principles of these cell fate determination processes, we will combine in vivo mechanistic studies and quantitative mechanistic modelling. We will integrate cell lineage relationships with spatial information and single cell multi-omics, using (epi)genome editing to perturb cell fate decisions in vivo. By comparing early organogenesis across the three germ layers, we will seek to understand the shared and unique features of the mechanisms that establish the underlying fate map.
|
| 31/03/2020 |
£3,181,816 |
UNIVERSITY OF OXFORD |
Having founded the new Centre for Prevention of Stroke and Dementia (CPSD) to allow junior/intermediate colleagues to develop their programmes, my own research will continue to focus on better phenotyping of TIA and stroke and of known risk factors in order to substantially improve the targeting of preventive treatments. My work involves four core themes:
Understanding the distinct temporal trends in incidence of different stroke subtypes to monitor the effectiveness of prevention and to develop new strategies;
Obtaining reliable data on prognosis of different TIA/stroke subtypes to better target preventive treatments;
Having proved the impact of better prediction and prevention of early recurrent stroke, I aim to substantially improve prevention of later recurrent stroke, focussing particularly on the utility of more detailed phenotyping (e.g. identification of occult atrial fibrillation, intracranial stenosis, and PFO, and remote monitoring of home-BP);
By more detailed assessment of BP I will inform the treatment of hypertension in primary prevention of stroke (by studying long-term pre-morbid BP) and in secondary prevention (home telemetric BP-monitoring);
Taken together the results of this work will impact on the treatment of almost all patients with TIA or stroke (2 million prevalent cases in the UK alone).
|
| 31/03/2020 |
£1,933,956 |
CARDIFF UNIVERSITY |
Adoptive transfer of patient T-cells expressing cancer-targeting chimeric antigen receptors (CARs) has achieved remarkable success with some soluble tumours. Unfortunately, CAR-T therapy cannot treat solid tumours. Contrastingly, tumour-infiltrating lymphocyte and checkpoint inhibitor therapies demonstrate that natural T-cells can eradicate end-stage solid cancers in some patients raising interest in engineering T-cells with T-cell receptors (TCRs) for "TCR-T" therapy. Conventional anticancer TCRs recognise endogenous proteinaceous antigens as short peptides presented by human leukocyte antigen class I (HLA-I) allowing killer T-cells to scan the internal proteome and eliminate cells bearing anomalies associated with cancerous transformation. Unfortunately, even the best conventional TCR approaches are only applicable in a minority of patients due to substantial variation in HLA across the population. The ultimate TCR-T therapy would bypass HLA-restriction to enable targeting of shared cancer antigens in all individuals. Our recent discoveries that some T-cells can recognise multiple types of cancer without the need for HLA could represent a major advance for immunotherapies. I want to understand the molecular mechanisms by which such ‘HLA-agnostic’ T-cells recognise cancer and utilise these remarkable cells to identify the cell surface changes that distinguish normal from cancerous cells. These potential cancer-biomarkers and cognate TCRs could underpin novel, broad-spectrum immunotherapies.
|
| 31/03/2020 |
£1,773,692 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
There is increasing concern about the long-term vascular health of the large and growing population of cancer survivors. I recently showed that survivors of most types of cancer have increased risks of one or more cardiovascular diseases, beyond those explained by shared risk factors such as smoking.
The key priorities now are to understand (i) the drivers of these increased risks, and thus how and when we can most effectively intervene; and (ii) whether broader vascular-related outcomes, in particular dementia and kidney disease, are also affected.
In this fellowship I will address these two priorities by conducting analyses underpinned by cutting-edge statistical and epidemiological methods, and capitalising on rich UK and international e-Health datasets, including game-changing new cancer treatment data.
I will investigate in detail the role of anti-cancer treatments (e.g. chemotherapies/radiotherapy) and changes in traditional vascular risk factors (e.g. blood pressure, BMI) in driving late cardiovascular risk. I will then investigate whether, and through what mechanisms, cancer history affects risk of vascular dementia, chronic kidney disease, and pre-clinical cognitive and renal outcomes (uniquely identifiable in the 500,000-strong UK Biobank cohort).
Throughout, this research will contribute actionable evidence informing clinical/public health policies to improve the long-term outlook of cancer survivors.
|
| 31/03/2020 |
£2,299,755 |
UNIVERSITY OF OXFORD |
Antibody affinity maturation occurs in germinal centers (GCs) through iterative rounds of somatic hypermutation (SHM) in dark zones (DZs) and selection in light zones (LZs). Current models state that, following SHM, DZ cells exit cell cycle and move to LZs to test their newly mutated B cell receptors by competing T cell help. High affinity B cells preferentially "win" in receiving help, and this causes them to undergo cyclic reentry (defined by S phase initiation and DZ re-entry). We recently demonstrated the possible existence of a second checkpoint, because BCR expression is required for LZ entry. We propose testing the nature of BCR-dependent signals required for this (e.g. cognate vs tonic signaling). Next, we will re-examine the fundamental principle that affinity enhancements are favored by LZ cells competing for cyclic re-entry promoting cues. In unpublished studies, we unexpectedly find that T cell help in not required for initiating cyclic re-entry. We will therefore test whether LZ cells compete for other non-T cell-derived cues, or whether instead cyclic re-entry is controlled independently of selection events. Finally, we will investigate whether GCs utilize innate cell types and signaling pathways for sensing the continued presence of foreign material and for determining GC longevity.
|
| 11/03/2020 |
£20,000 |
UNIVERSITY COLLEGE LONDON |
The Imbizo is a 3-week long summer school designed to connect young African computational neuroscientists with the international community. Computational Neuroscience (CN) is underdeveloped as a research field in Africa. The Imbizo is changing this, providing educational and career development opportunities in a place where they are very scarce. We are applying for continued funding to run the Imbizo for the years of 2021-2023, in Cape Town, South Africa.
The Imbizo brings together world leaders in CN and machine learning with approximately 18 African and 12 non-African students. Students come from diverse quantitative backgrounds including computer science, mathematics, physics and engineering. These disciplines are strong in several African countries. The intensive course comprises of lectures, tutorials, coding and brainstorming sessions. Extra-curricular team building and networking opportunities also take place. We organise workshops and surgeries on grantsmanship, manuscript writing, and CV clinics to prepare candidates for future job applications.
After 18 days of intense course work, we will have exposed some of Africa’s most talented analytic students to a new field and helped them build networks with experts. We will create opportunities for students from relatively disadvantaged institutions to move into CN and potentially grow collaborations and develop their skills and scientific ideas. Every year we see more students take up internships and graduate school positions that would have not been available to them without the Imbizo. This is a direct injection of diversity into the international CN community, and an investment in Africa’s CN future.
|
| 04/03/2020 |
£1,199,999 |
UNIVERSITY OF OXFORD |
The spliceosome produces mRNAs in two sequential transesterifications – branching and exon ligation. The post-branching C complex is remodeled by the ATPase Prp16 into the C* complex. Prp16 allows binding of the exon ligation factors Cactin and FAM32A, which stabilise docking of the 3’-splice site (3’SS) at the active site. While in yeast Prp18 is constitutively bound to C* spliceosomes, in humans Prp18 and other exon ligation factors of unknown function appear to engage the C* spliceosome in a transcript-specific manner. Here, I will reconstitute the C to C* transition in vitro in mammals and use biochemistry and cryo-electron microscopy to isolate and visualize novel intermediates and dissect the structural mechanisms by which Cactin, FAM32A, Prp18, and additional exon ligation factors cooperate to promote Prp16-mediated remodeling and to ensure correct 3’SS choice. In parallel, iCLIP studies will reveal where these exon ligation factors bind across all human pre-mRNAs and how RNA sequences around the splice sites determine the association of subsets of factors on specific pre-mRNAs. This work will elucidate how Prp16 drives remodeling of the human catalytic spliceosome and will investigate whether exon ligation factors regulate alternative splicing in a sequence-specific manner while proofreading 3'SS recognition during exon ligation.
|
| 04/03/2020 |
£1,017,466 |
UNIVERSITY OF OXFORD |
Blood flow is critical for maintaining the steady supply of oxygen and nutrients to the brain, and blood flow changes are present in a range of diseases including stroke and dementia. Conventional methods for in vivo blood flow mapping have limitations and often cannot be used for longitudinal monitoring or research.
In this proposal I aim to develop highly sensitive imaging methods for measuring brain blood flow based on a non-invasive magnetic resonance imaging technique, arterial spin labelling, applied at ultra-high field. The main goals of this research are:
To establish a robust platform for ultra-high field arterial spin labelling by developing novel approaches to overcome a range of technical challenges associated with this technique;
To develop advanced imaging approaches which allow richer cerebrovascular information to be obtained, including high resolution angiography and vessel-selective imaging;
To demonstrate the high sensitivity achievable with these novel methods by measuring changes in white matter perfusion in patients with vascular cognitive impairment, and probing the brain’s response to tonic pain at unprecedented spatial resolution.
These new methods will be actively shared with local, national and international collaborators, enabling previously unfeasible clinical and basic science research studies to be performed.
|
| 04/03/2020 |
£1,392,083 |
UNIVERSITY OF BRISTOL |
Many adult epithelial tissues lose cells from constant environmental stress. Thus, an epithelium’s ability to sense stress, defend itself and stimulate repair (e.g. by stem cells) is vital to prevent tissue dysfunction, degeneration, inflammation and cancer.
Despite its importance, this process is poorly understood. Using the adult Drosophila intestine and its unparalleled genetics, combined with proteomics, transcriptomics and fixed and live imaging, I will determine how stress signalling promotes epithelial resilience, maintenance and regeneration focussing on three main aims.
1) Reactive oxygen species (ROS) produced by damaged fly intestinal epithelial cells (IECs) promote intestinal stem cell (ISC)-mediated regeneration, partly via p38 signalling in IECs. I will determine how ROS promote intestinal regeneration by identifying ROS-controlled regulators of regeneration and determining molecular responses to ROS/stress signalling.
2) I have recently found that some stress pathways display rhythmic, circadian activation. I will investigate their role in intestinal maintenance.
3) I have shown that when new IEC production by ISCs is inhibited, IECs increase their lifespan to prolong epithelial maintenance. I will identify adaptive mechanisms that extend IEC lifespan when new cell production is blocked.
Understanding these processes could provide novel therapeutic strategies for tissue regeneration, inflammatory diseases, cancer and age-related pathologies.
|
| 04/03/2020 |
£1,241,815 |
BABRAHAM INSTITUTE |
In mature B-cells, the generation of antibodies of different isotypes relies on class switch recombination (CSR) mechanisms. Although crucial for adaptive immunity, CSR imposes challenges to genome integrity as it involves programmed induction of DNA double-strand breaks (DSBs) in rapidly proliferating B-cells. A key player in the cellular response to CSR DSBs is the protein kinase ataxia telangiectasia mutated (ATM). Evidence suggests RNA-dependent mechanisms control the DNA damage response by ATM, although there is very limited understanding of how these function in B-cells and which RNA-binding proteins (RBPs) are required for CSR. This proposal aims to define the critical roles of RNA helicases as integrators of ATM signals to control class switch recombination mechanisms in B-cells. I propose an integrative approach combining genomic and proteomic methodologies together with ex vivo B-cell differentiation systems and conditional gene-targeting in mice. I will determine RNA helicase-dependent mechanisms controlling the cell-cycle and CSR DSB-repair and investigate their roles in B-cell immune responses. This work will provide new insight into RNA helicase-mediated pathological mechanisms resulting in CSR deregulation and the development of immune disease or B-cell lymphomagenesis.
|
| 04/03/2020 |
£1,255,243 |
UNIVERSITY OF SHEFFIELD |
Neuronal axons can be a metre long and are maintained for a lifetime, making them acutely vulnerable to defects in microtubule mediated long distance transport. There are two broad categories of axonal transport in neurons, fast and slow. Slow axonal transport carries at least three times the material of fast transport, but ten to a hundred times more slowly. Protein moved by slow transport can be months old in the distal axon, and this process slows further with aging. Despite dysfunctional axonal transport being common in neurodegeneration, where aging is the major risk factor for disease, the mechanisms that regulate slow transport are very poorly characterised. Critically, whether transport time directly affects the accumulated damage and function of its protein cargo is unknown. The aim of this project is to understand how slow transport is regulated, whether transit time can influence the half-life and function of proteins, and further - whether it’s possible to reverse age-related decline in transport. To do this I will employ a multidisciplinary approach through the application of single-molecule light microscopy techniques. This project will define the relationship between the machinery of transport and the life cycle of axonal proteins.
|
| 04/03/2020 |
£1,131,741 |
UNIVERSITY OF SHEFFIELD |
Compromised wounds are increasingly prevalent, affecting quality of life for millions of sufferers and incurring a substantial burden on the NHS. I will define how macrophages control angiogenesis to drive wound healing and how this process breaks down to result in compromised wounds, particularly in the context of diabetes, using zebrafish and human co-culture models. Using RNAseq, I will profile zebrafish macrophages and endothelial cells in response to wounding, identifying the critical signals driving angiogenesis and how these fail in diabetic mutants. I will visually verify the roles of these key signalling genes by generating zebrafish transgenic reporters to live-image their wound response. In combination with novel CRISPR gene editing tools, I will establish specific manipulations to clinically relevant candidates, defining their functions and developing models of compromised wounds. The macrophage-HUVEC co-culture model will complement these zebrafish studies, corroborating the functions of macrophages from healthy versus diabetic patients. Expanding on this assay, I will use siRNA knock-down in monocyte-derived macrophages to dissect the role of clinically relevant candidates in perturbing macrophage control of angiogenesis. Together, these fish and human tissue culture models will provide a platform to identify novel therapeutics and propel the translation of these treatments towards the clinic.
|
| 04/03/2020 |
£1,057,974 |
UNIVERSITY OF GLASGOW |
The malaria parasite (Plasmodium falciparum) has a complex life cycle in which it must transit through multiple environments in a vertebrate host and mosquito vector. Transmission begins with ingestion of an infectious blood meal by one of 40 potential Anopheles mosquito species capable of transmitting the disease. This initiates the most extreme population bottleneck in the life cycle in which the parasite must rapidly undergo fertilisation, develop into an invasive form and transit through the midgut epithelium. The overarching goal of this proposal is to understand how this transmission through the mosquito vector drives selection on the parasite. I hypothesise that parasites have adapted to their local vector community composition, and this shapes their ability to infect sympatric and allopatric vector species. Using large-scale transmissibility assays and single-cell RNA-sequencing, I will identify genomic and transcriptomic vector-dependent signatures of transmission. I will then generate allelic-replacement parasites to unambiguously attribute phenotypic variation in species-specific transmission to specific loci in the parasite. Comprehensively understanding how vector communities shape parasite populations will guide future interventions and vector control programs by providing information that will allow for strategies to be locally tailored based on parasite genomic-surveillance and entomological surveys.
|
| 04/03/2020 |
£1,393,480 |
UNIVERSITY OF CAMBRIDGE |
Protein coding and non-coding RNA can spread between cells and tissues of an organism. RNA mobility between organisms has been documented within and among different kingdoms of life including fungi, plants and animals. However, the underlying mechanisms and roles of such transmissible RNA are poorly understood. Our recent studies demonstrated that honeybees share biologically active RNA among members of the hive through secretion and ingestion of worker and royal jellies. The jellies harbor naturally occurring exogenous (e.g. viral) and endogenous RNA. These findings suggest that RNA transfer plays a role in social immunity and signaling between honeybees. Therefore, the key goals of this proposal are: to establish a metabolic RNA labeling system in honeybees; and to apply this system to study natural RNA transfer-mediated antiviral immunity and impacts on the physiology of recipient bees. To achieve these goals, I will combine RNA biology techniques and imaging with high-throughput sequencing to establish a functional transmissible RNA pathway in honeybees. This project will provide knowledge and tools that will enable studying the biology of RNA flow in other organisms, including humans, in diverse biological aspects; hence, will ultimately contribute to the development of RNA-based applications to promote health and disease control.
|
| 04/03/2020 |
£1,153,494 |
UNIVERSITY OF OXFORD |
Host and pathogen genetic variations are major causes of clinical outcomes of infectious diseases. Traditionally, genetic studies of infectious diseases have sought to explain between-individual variation in disease by assessing genetic factors separately in humans or pathogens, under the assumption that these factors are independent. However, there is strong theoretical evidence that genetic interactions between host and viruses play a major role in viral disease aetiology. The major limiting factor to date has been the lack of cohorts with paired host-virus data. Recent technological developments and reductions in the cost of high-throughput viral sequencing from clinical samples have provided new opportunities to analyse host-virus genomic data generated from the same patients. In this project I propose to analyse paired host-virus genomic data from patient cohorts infected with HBV, HCV and HIV (clinically the most important chronic viruses worldwide) to answer the following questions:
1) What are the host genetic pressures driving virus evolution across different host populations and virus lineages?
2) What host and virus genetic interactions drive disease phenotypes?
3) What are the host genetic variants and pathways linked to disease phenotype across the three chronic viral infections of HBV, HCV and HIV?
|
| 04/03/2020 |
£1,256,713 |
UNIVERSITY OF SUSSEX |
The project aims to uncover why and how behavioural states like arousal affect neural processing in the early visual system by recording from the retina and superior colliculus in awake mice using techniques I have previously developed. Behavioural states affect task performance but their effect on early sensation is unclear; understanding their impact on early visual processing will reveal fundamental computational principles of adaptation.
Our objectives are:
determine the effects of behavioural states on different cell types in the early visual system by recording activity of retinal and collicular neurons classified by function, genetics and projection targets in awake mice.
determine the purpose of behavioural state modulation in terms of information processing in the early visual system by recording activity of retinal and collicular cell types in awake mice viewing visual stimuli that elicit nonlinear responses or are behaviourally relevant.
determine the mechanisms by which behavioural states influence early visual processing by measuring and manipulating the activity of neuromodulators, serotonin and noradrenaline, controlling behavioural states while recording from retinal and collicular neurons.
The results of this project impact on basic neurosciences and other fields including the development of artificial intelligent systems and the treatment and diagnosis of psychiatric disorders.
|
| 04/03/2020 |
£844,817 |
UNIVERSITY OF MANCHESTER |
How do vision and motor actions interact? A textbook will answer that vision guides movements but this view has been challenged over the last decade. The most striking realisation was the extent to which locomotion modulates neural activity in primary visual cortex, thalamus dLGN, superior colliculus and even the retina (collectively Early Visual System or EVS). Therefore movements can guide visual processing but the nature of this effect is unknown.
The most pressing question regards the specificity of these interactions. In EVS different visual features (size, luminance, colour, direction ...) are processed along parallel channels, at least 30 in the mouse retina. Since different motor actions (e.g. picking a fine thread, kicking a ball) require different visual features, I expect the interactions between vision and movements to be quite specific to the nature of the actions performed.
Due to technological limitations the only available data are obtained in head-fixed animals where only one type of action – locomotion – can be observed. To overcome these limitations I developed a system to quantify movements in unconstrained animals. I will use this system to understand how different movements affect distinct visual channels in EVS, modify the neural code(s) and ultimately influence behaviour.
|
| 04/03/2020 |
£828,055 |
UNIVERSITY OF OXFORD |
Rare diseases (prevalence 250 million people globally. Current approaches for identifying the genetic cause of a disease focus on regions of the genome that code directly for protein, finding a disease-causing variant in only ~50% of cases.
My aim is to identify novel genetic variants outside of these protein-coding regions that lead to disease, and the mechanisms through which they do so.
I will do this by applying computational and statistical methods to pioneering large-scale genomic datasets, totalling ~700,000 individuals.
My approach will focus on ‘near-coding’ regions, defined as those directly adjacent to protein-coding sequence that have important functions regulating protein expression. I will use complementary approaches that (a) look for near-coding variants in rare disease patients without a causative coding variant and (b) assess the strength of negative selection acting on categories of near-coding variants to predict which are deleterious and cause disease.
The findings from my work will be translated into clinical care to enable more patients to receive a valuable genetic diagnosis. In addition, increasing our understanding of the near-coding variant types that are deleterious will inform on genetic mechanisms underlying disease and suggest novel therapeutic strategies.
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| 04/03/2020 |
£617,868 |
UNIVERSITY OF SHEFFIELD |
TB is a global crisis and treatment requires lengthy regimens of failing antimicrobials to clear infection. I propose that strategies that target the host, alongside antibiotics, would be more efficacious and combat the increasing prevalence of bacterial resistance. I have shown that HIF (hypoxia inducible factor) manipulation can activate pro-inflammatory responses against mycobacterial infection, specifically via Hif-1alpha stabilisation and resulting neutrophil activation. In addition, I can now demonstrate that arginase, a transcriptional target of Hif-2alpha, acts as a negative neutrophil immunoregulator, that on removal can activate neutrophils via an alternative mechanism to control mycobacteria. These findings indicate that neutrophils can be differentially activated via HIF manipulation, and that their protective properties could be therapeutically tuned during disease to clear infection. Therefore, I propose to address the following aims:
Determine the proinflammatory properties of Hif-1alpha-activated neutrophils
Characterise Hif-2alpha/arginase immunoregulation and their control of neutrophil phenotypes
Develop therapies to fine-tune neutrophil behaviours in infection
This work will extend our understanding of therapeutic targeting of HIF as a host-derived therapeutic strategy against multi-drug resistant infections. This extension will allow expansion and implementation of exciting neutrophil zebrafish models and the first steps translating these findings to human systems.
|
| 04/03/2020 |
£679,929 |
ZOOLOGICAL SOCIETY OF LONDON |
We know little about how future climate change, habitat destruction, human population increases and greater globalisation processes will impact human zoonotic diseases. Here, I investigate the use of dynamic, seasonal host population models to better predict the impact of real-time environmental change on disease-carrying host species, within a general systems-dynamics, disease framework. Specifically, I will combine a mathematical compartmental disease model with a host population ecology model, within a spatial and temporal Bayesian framework. Using this approach, I will first model Lassa Fever using climate and land-use observations, collaborating with the Nigerian government. I will then augment my model to account for animal movement patterns and vector species abundances, to examine arboviral disease spread in North America. Then, I will integrate these threads into a general, dynamic modelling framework for zoonotic diseases, which will contain both the newly developed components and my previously developed model of human movement and behaviour. Working with the World Health Organisation, I will create short- and long-term disease forecasts for a set of high priority zoonoses. Once validated against human case data, these mechanistic models can be used to test interventions and create future disease management plans that are robust to upcoming global change.
|
| 02/03/2020 |
£4,707 |
THE AGA KHAN UNIVERSITY, PAKISTAN |
I conducted research for my Masters thesis to explore, identify and examine ethical guidelines available for genetic studies and to then analyse and describe the extent to which researchers in Pakistan, comply with existing ethical standards specified for genetic research. I report in my thesis that there are no guidelines for genetic research, gene therapy or gene editing in Pakistan. I also found some other patterns in the studies reviewed that I would like to present in the form of a publication in a peer reviewed journal as I feel they will provide a foundation of behavioural practises of researchers in Pakistan.
I would also like to use the findings as a starting point to develop and propose guidelines for researchers for genetic research, gene therapy and gene editing in Pakistan. I want to propose guidelines that can be incorporated effectively into practise for which I will need to identify effective training, implementation and monitoring of the guidelines.
Key goals:
1. Develop a better understanding of the ethical review process of international collaborations in the UK
2. Produce a draft of a paper for submission to a peer reviewed journal
3. Propose an outline of guidelines for researchers in Pakistan
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| 02/03/2020 |
£7,340 |
UNIVERSITY OF IBADAN |
The purpose of this proposal is to develop an African, Regional interdisciplinary forum on the ethics, governance, engagement and social acceptability of Genome Editing in Africa. In spite of the discussions on Genomics, most African countries are yet to adequately engage in the critical debate on the regulation and ethics of genome editing. It is pertinent to have collaborative partnerships to focus on prudent research-based advocacy, to ensure truly informed policy decision making on gene editing in Africa. The key goals of this proposal is to disseminate the key outcomes of the 2019 GFBR meeting on" Genome Editing for Human Benefit: Ethics, Engagement and Governance", and to develop a proposal to take the outcome of this meeting further so as to begin an African oriented discussion on genome editing from the perspective of Africans. There will also be a research paper to be published in a peer-reviewed journal. Also, the focus of this proposal is to have a two-day workshop in Nigeria with key stakeholders from Africa discussing the ethical, governance and engagement issues relevant to Africa in Genome Editing that arose from the Singapore meeting.The meeting will promote collaborations between African Countries on the best practices in Genome Editing
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| 02/03/2020 |
£7,459 |
NO ORGANISATION |
The novel biotechnology of the CRISPR-Cas9 method has certainly precipitated unprecedented interest as well as concern with regard to the scientific reality of human genome editing. This excitement and anxiety become even more acute in resource-limited settings where there is limited awareness and engagement between the experts in human genomics and gene editing and the public. Hence, there is an urgent need for effective public engagement. The purpose of my fellowship is to get vital mentorship in public engagement with human genome editing. My aim is to benchmark with best practice at NHGRI and work towards developing an appropriate African framework for public engagement with human genome editing. My visit will also be a unique opportunity for me to network and cultivate opportunities for north-south collaborative partnerships. Besides, the acquired knowledge and skills will greatly contribute towards Africa’s capacity-building. I plan to effectively disseminate my work, including at least one publication in a reputable peer-reviewed journal. Thus my trip is in line with GFBR’s goal of bringing together key stakeholders from developing and developed countries in addressing frontier bioethical concerns in research. It is also relevant to GFBR’s goals of capacity-building and of fostering effective collaborative partnerships.
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| 02/03/2020 |
£5,841 |
UNIVERSITY OF CAPE TOWN |
There is established bio-ethical literature related to genomic research and technology, with this literature increasingly also focussing on gene drive technologies. While such questions are important, these questions often do not critically engage with how gene drive technologies interact with social, political and economic spheres. Furthermore, there is very limited critical discussion about these technologies from scholars situated in the global South, where some first field trials are set take place.
During this fellowship, I will work on a journal article for publication critically interrogating the social, political and economic dimensions of gene drive technology. This paper will focus on questions such as, why are the first field trials of this controversial technologies organised in one of the poorest countries in the world, who actually benefits from such research, especially given the convergence of funding from Western governments, philanthropic funders, and the commercial agricultural sector, and what is the impact of these arrangements of local communities and governance structures where gene drive technologies have been proposed to be used. The publication will begin to articulate these kinds critical questions that must be engaged with, if we are to ensure gene drive technologies does not reproduce historic patterns of inequality.
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| 02/03/2020 |
£7,783 |
NO ORGANISATION |
The main intention of this fellowship is to document the distinct ethical issues related to the use of genome research in eradicating Malaria. This will then result in identifying an ethical acceptable framework for genome editing that necessitates the progress of scientific research. The following key goals are expected to be met in the 6 week period.
Review and document the National commission for science and technology NSCT regulations and guidelines in regards to genome editing.
Review the regulations, guidelines and policies used by ethics committees and regulators at McMaster and some sub-Saharan countries that incorporates genome editing for malaria eradication.
Establish and document evidence that aid advocacy to implicating policies that are favorable for researchers to conduct genome research and at the same time beneficial for human health IN Malawi
Recommend ethical acceptable approaches and frameworks that can address the ethical issues surrounding genome research
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| 02/03/2020 |
£7,790 |
NO ORGANISATION |
The project aims to develop a better understanding of the general public and various stakeholders views on human gene editing in Argentina. Focus group sessions will be conducted for an in-depth exploration and description of the general public, patients and members of REC attitudes and perceptions towards human gene editing.
Key goals are:
The findings of the project will contribute to strengthening the evidence on an unexplored topic in Latin America.
The results will also serve as a basis for future research in Argentina and other Latin American countries.
The information obtained will provide information to Ministry of Health policymakers for future policy.
An academic paper for publication in a peer-review journal will be produced.
Key actors in Latin American countries will be identified to facilitate the dissemination of the findings.
A human gene editing workshop with experts for research participants to disseminate the findings of the project and to promote dialogue among stakeholders will be conducted.
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| 02/03/2020 |
£5,429 |
NO ORGANISATION |
To organize two meetings for the general public to raise awareness about gene editing in Argentina so they can be enriched with reliable information. The idea is to repeat the event held in Buenos Aires in 2018 that I presented in the Forum in Singapore 2019, in two different cities in Argentina: Santa Fe and Entre Ríos, in order to reach more people about the importance of this technology. A registration form will be available for the general public to sign up for the meetings.
On the other hand, Ana Palmero will apply to another Meeting Fellowship to organize a workshop to ask patients of gene therapies, which in the future could require treatment with gene editing, their opinion about the technique. This way, she will gather data.
Even my project can be carried out independently, the idea is to work together to empower the workshop of Ana Palmero. The patients of the interest for the workshop will be invited to participate in the meetings in where they will receive information that will be able to use later in the workshop. An informed person, can elaborate better answers.
This way, two ministries of Argentina will work together: Science and Health
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| 02/03/2020 |
£7,469 |
UNIVERSITY OF BOTSWANA |
The continuous growth and recent technical advances that have improved the precision, cost and simplicity of new gene editing technologies such as Somatic and germline therapy have since given birth to new hope in the fight against the burden of disease such as HIV in developing countries (sources). Despite facing dis-proportionally higher prevalence HIV rates, communities in Botswana to our knowledge the technologies have not been tried hence Batswana remain understudied in gene editing research. Therefore, I am proposing a study to engage with local communities to educate them about gene-editing technology research and collect their perspectives on how their cultural values norms and beliefs can have positive or negative implications on their benefiting from this technology.
1. The overall goal of the project is to explore the perceptions of communities in Botswana regarding perceived and real social ethical issues (cultural values, norms and beliefs) surrounding gene-editing technologies regarding its use for health benefits?
2. The project also aims to empower communities with knowledge through education and engagement about gene-editing technology for better informed decisions in preparation for participation in gene-editing technologies as well as learning about its potential benefits, risks and use of genomics, gene-editing technologies.
|
| 28/01/2020 |
£629,208 |
UNIVERSITY OF BIRMINGHAM |
Whilst perceived as a centralised, statist service, the NHS allows scope for voluntary financial support of its institutions, and for private provision of services outside the NHS. This has taken several forms: teaching hospital endowments; pooled endowment funds for non-teaching hospitals; and voluntary fundraising for individual institutions. Voluntary sector provision of health care has also continued: several voluntary hospitals disclaimed by the state in 1948 continued in existence, and a number of NHS hospitals have transferred back into charitable ownership.
These contributions to a public health service are little-known and our research is concerned with the distinctive contribution they make and the challenges they pose for policy. We therefore chart the scale, distribution and growth of these initiatives, as well as the niches which they occupy. We analyse how policy has been framed with reference to them – in other words how the balance between voluntary initiative and central planning has evolved over time – and we explore their role in innovation in the delivery of health and care, and their importance in engaging the public in supporting their local services. Overall this research programme provides novel insights into the debatable borderlands between statutory and voluntary initiative.
|
| 28/01/2020 |
£259,753 |
UNIVERSITY OF EDINBURGH |
Whilst perceived as a centralised, statist service, the NHS allows scope for voluntary financial support of its institutions, and for private provision of services outside the NHS. This has taken several forms: teaching hospital endowments; pooled endowment funds for non-teaching hospitals; and voluntary fundraising for individual institutions. Voluntary sector provision of health care has also continued: several voluntary hospitals disclaimed by the state in 1948 continued in existence, and a number of NHS hospitals have transferred back into charitable ownership.
These contributions to a public health service are little-known and our research is concerned with the distinctive contribution they make and the challenges they pose for policy. We therefore chart the scale, distribution and growth of these initiatives, as well as the niches which they occupy. We analyse how policy has been framed with reference to them – in other words how the balance between voluntary initiative and central planning has evolved over time – and we explore their role in innovation in the delivery of health and care, and their importance in engaging the public in supporting their local services. Overall this research programme provides novel insights into the debatable borderlands between statutory and voluntary initiative.
|
| 28/01/2020 |
£244,631 |
UNIVERSITY OF STRATHCLYDE |
Whilst perceived as a centralised, statist service, the NHS allows scope for voluntary financial support of its institutions, and for private provision of services outside the NHS. This has taken several forms: teaching hospital endowments; pooled endowment funds for non-teaching hospitals; and voluntary fundraising for individual institutions. Voluntary sector provision of health care has also continued: several voluntary hospitals disclaimed by the state in 1948 continued in existence, and a number of NHS hospitals have transferred back into charitable ownership.
These contributions to a public health service are little-known and our research is concerned with the distinctive contribution they make and the challenges they pose for policy. We therefore chart the scale, distribution and growth of these initiatives, as well as the niches which they occupy. We analyse how policy has been framed with reference to them – in other words how the balance between voluntary initiative and central planning has evolved over time – and we explore their role in innovation in the delivery of health and care, and their importance in engaging the public in supporting their local services. Overall this research programme provides novel insights into the debatable borderlands between statutory and voluntary initiative.
|
| 28/01/2020 |
£281,133 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
Whilst perceived as a centralised, statist service, the NHS allows scope for voluntary financial support of its institutions, and for private provision of services outside the NHS. This has taken several forms: teaching hospital endowments; pooled endowment funds for non-teaching hospitals; and voluntary fundraising for individual institutions. Voluntary sector provision of health care has also continued: several voluntary hospitals disclaimed by the state in 1948 continued in existence, and a number of NHS hospitals have transferred back into charitable ownership.
These contributions to a public health service are little-known and our research is concerned with the distinctive contribution they make and the challenges they pose for policy. We therefore chart the scale, distribution and growth of these initiatives, as well as the niches which they occupy. We analyse how policy has been framed with reference to them – in other words how the balance between voluntary initiative and central planning has evolved over time – and we explore their role in innovation in the delivery of health and care, and their importance in engaging the public in supporting their local services. Overall this research programme provides novel insights into the debatable borderlands between statutory and voluntary initiative.
|
| 28/01/2020 |
£740,926 |
UNIVERSITY OF EXETER |
Humans have a deep-seared proclivity to feed animals, a behaviour implicated in the origins of animal domestication (the Commensal Pathway to domestication). While animal domestication is widely considered a phenomenon of the deep human past, our hypothesis is that the process is not only continuing but accelerating. Today, humans are feeding wildlife, pets and captive animals at unprecedented levels. This exceptional human intervention has ramifications for global health.
However, the situation is complex and beyond the comprehension of any single discipline. This is because while animal-feeding decisions are cultural, with deep histories that reflect political-economy, identities and attitudes to the natural world, their impacts are biological and evolutionary, affecting behavioural ecologies, biodiversity and well-being.
The interconnected nature of animal-feeding and how decisions can have catastrophic effects on the health of all concerned is exemplified by the BSE outbreak, which manifested across livestock, pets, zoo animals and humans alike.
This One Health project will use a transdisciplinary ‘engaged research’ methodology to explore the drivers and consequences of animal feeding in Britain (500BC to the present). Through the shared conceptual lens of commensalism we will examine how bird-feeding, cat-feeding and zoo-animal feeding are shaping our collective futures.
|
| 28/01/2020 |
£193,448 |
NATIONAL MUSEUMS SCOTLAND |
Humans have a deep-seared proclivity to feed animals, a behaviour implicated in the origins of animal domestication (the Commensal Pathway to domestication). While animal domestication is widely considered a phenomenon of the deep human past, our hypothesis is that the process is not only continuing but accelerating. Today, humans are feeding wildlife, pets and captive animals at unprecedented levels. This exceptional human intervention has ramifications for global health.
However, the situation is complex and beyond the comprehension of any single discipline. This is because while animal-feeding decisions are cultural, with deep histories that reflect political-economy, identities and attitudes to the natural world, their impacts are biological and evolutionary, affecting behavioural ecologies, biodiversity and well-being.
The interconnected nature of animal-feeding and how decisions can have catastrophic effects on the health of all concerned is exemplified by the BSE outbreak, which manifested across livestock, pets, zoo animals and humans alike.
This One Health project will use a transdisciplinary ‘engaged research’ methodology to explore the drivers and consequences of animal feeding in Britain (500BC to the present). Through the shared conceptual lens of commensalism we will examine how bird-feeding, cat-feeding and zoo-animal feeding are shaping our collective futures.
|
| 28/01/2020 |
£276,268 |
ROEHAMPTON UNIVERSITY |
Humans have a deep-seared proclivity to feed animals, a behaviour implicated in the origins of animal domestication (the Commensal Pathway to domestication). While animal domestication is widely considered a phenomenon of the deep human past, our hypothesis is that the process is not only continuing but accelerating. Today, humans are feeding wildlife, pets and captive animals at unprecedented levels. This exceptional human intervention has ramifications for global health.
However, the situation is complex and beyond the comprehension of any single discipline. This is because while animal-feeding decisions are cultural, with deep histories that reflect political-economy, identities and attitudes to the natural world, their impacts are biological and evolutionary, affecting behavioural ecologies, biodiversity and well-being.
The interconnected nature of animal-feeding and how decisions can have catastrophic effects on the health of all concerned is exemplified by the BSE outbreak, which manifested across livestock, pets, zoo animals and humans alike.
This One Health project will use a transdisciplinary ‘engaged research’ methodology to explore the drivers and consequences of animal feeding in Britain (500BC to the present). Through the shared conceptual lens of commensalism we will examine how bird-feeding, cat-feeding and zoo-animal feeding are shaping our collective futures.
|
| 28/01/2020 |
£309,806 |
UNIVERSITY OF READING |
Humans have a deep-seared proclivity to feed animals, a behaviour implicated in the origins of animal domestication (the Commensal Pathway to domestication). While animal domestication is widely considered a phenomenon of the deep human past, our hypothesis is that the process is not only continuing but accelerating. Today, humans are feeding wildlife, pets and captive animals at unprecedented levels. This exceptional human intervention has ramifications for global health.
However, the situation is complex and beyond the comprehension of any single discipline. This is because while animal-feeding decisions are cultural, with deep histories that reflect political-economy, identities and attitudes to the natural world, their impacts are biological and evolutionary, affecting behavioural ecologies, biodiversity and well-being.
The interconnected nature of animal-feeding and how decisions can have catastrophic effects on the health of all concerned is exemplified by the BSE outbreak, which manifested across livestock, pets, zoo animals and humans alike.
This One Health project will use a transdisciplinary ‘engaged research’ methodology to explore the drivers and consequences of animal feeding in Britain (500BC to the present). Through the shared conceptual lens of commensalism we will examine how bird-feeding, cat-feeding and zoo-animal feeding are shaping our collective futures.
|
| 28/01/2020 |
£932,125 |
UNIVERSITY OF BIRMINGHAM |
Background: This project will provide a comprehensive understanding of the processes by which schools and workplaces invest in mental health promotion. This is urgently needed, as these organisations, though not traditionally designed for this function, are increasingly seen as a key influence on individuals’ mental health across the life-course.
Goals: The project will: (i) Establish the diversity of attitudes to mental health promotion (MHP) in schools and workplaces; (ii) Develop a typology of resource use for MHP and way of tracking resource needs; (iii) Identify the way in which evidence is used and needed in schools and workplaces to support investment decisions; and (iv) Explain how investment and provision decisions relating to MHP in schools and workplaces are made in practice.
Methodologies: A diverse set of case study schools and workplaces will be recruited. Interviews and focus groups will be conducted with individuals with responsibilities for MHP investment (managerial staff, senior teachers, wellbeing specialists). Targeted techniques will used to study participants' attitudes, reactions to evidence, and investment decisions.
Outputs: The research programme will guide policy-makers and researchers as to how to inform, support, resource, incentivise and regulate mental health promotion in schools and workplaces.
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| 28/01/2020 |
£984,271 |
UNIVERSITY OF SHEFFIELD |
Orphan drugs are a class of medicines that treat rare diseases. Their development has been incentivised to address the needs of neglected patient groups. They are growing rapidly, highly profitable and stimulating new business models based on high cost products for niche markets. However, the very high price of some orphan drugs has led countries, including the UK, to refuse to pay for them. This has provoked growing political concern that patients are being denied access to life saving therapies. A major international debate on how to improve access is ongoing, raising important questions about the value of these medicines and the ethics of resource allocation. Patient organisations have responded by sponsoring more sustainable, lower cost orphan drug development. This project will look systemically at the coproduction of industrial and technological change, the politics and governance of orphan drugs, and new forms of collaborative knowledge production. It is innovative in developing a new concept, "orphanisation", to understand contemporary change in the biopharmaceutical sector. Specifically, it will ask to what extent is orphanisation occurring in the UK and USA, how is it being shaped by different technologies, institutions and actors, and what are the implications for industry, health policy and patients?
|
| 28/01/2020 |
£1,009,755 |
UNIVERSITY COLLEGE LONDON |
This four year project examines birth cohorts as sites of knowledge, practice and participation in the UK, Europe and Latin America. It aims to understand how they provide an infrastructure for and are a technology of biosocial science. It is the first study to take birth cohorts as an object of ethnographic inquiry in comparative national contexts.
In an era of post-genomics, studies that follow research participants over their lifetimes have become vital to understanding how material and social environments ‘get under the skin’ and are dynamically shaped across the lifecourse. This is increasingly described as ‘biosocial science’, reflecting the importance to this field of the interaction between social and biological factors. Whilst a notion of the biosocial is not new, singular nor uncontested it is now being re-shaped in global research terrains with longitudinal cohort studies as important tools and technologies.
By examining the ‘biosocial lives’ of birth cohorts in the global north and south, I will provide insight on the socio-cultural specificity of these developments. Comparison will inform theorisation of what the biosocial is, whilst an ethnographic perspective will facilitate methodological innovation in examining and intervening on birth cohort research and how biosocial science is coming into being.
|
| 28/01/2020 |
£305,001 |
UNIVERSITY OF CENTRAL LANCASHIRE |
Zines (self-published magazines, graphic memoirs and comics) are rich, yet currently untapped, sources of knowledge about mental distress and psychosocial disabilities - how they are lived with, challenged and understood. This research will identify, analyse and co-produce Madzines: self-published magazines, comics and graphic memoirs, created by people with lived experience, which communicate critical ideas about mental health. Specifically, this research will explore how zines, due to their unique format, craft contention about mental health knowledge and practice. It will investigate how zines:
Challenge prevailing psychological, psychiatric and medical understandings, diagnoses and treatments;
Articulate specific forms of contention about controversial and hidden diagnoses; pathologised identities and experiences;
Communicate new understandings of mental health diagnoses, identities and experiences;
Function as a unique form of psychiatric survivorship offering new repertories of contention for the psychiatric survivor movement;
Utilise diverse styles of contention such as humour, parody and subversion.
This investigation will define a new genre of Madzines and help transform the way zines are researched, understood and theorised. It will be used to explore how zines can contribute to formal and informal learning about mental health, challenge stigma and discrimination and inform policy and practice.
|
| 28/01/2020 |
£917,922 |
UNIVERSITY OF EDINBURGH |
Suicide Cultures: Reimagining Suicide Research (SC) will undertake a transformational, qualitative mixed-methods study of the social contexts and cultural meanings of suicide in diverse communities across Scotland. The project aims to shift understandings of what suicide research can be and do, contributing to innovation in how societies might best respond to suicide as a social and cultural phenomenon. SC consists of five inter-related workpackages. WP1: a qualitative sociological autopsy study of up to 390 cases of suicide across 3 areas of Scotland. Data will include formal reviews of suicide deaths (300), and interviews with family/friends bereaved by suicide (90 cases). WP2: qualitative, in-depth interviews with 60 people, recruited from the same 3 areas, who have self-harmed– those who may have died, but who did not. WP3: will explore understandings of suicide among different community groups, using collaborative arts-based methods. WP4: entails close, ethnographic study of up to 6 localities, identified iteratively during fieldwork, and studied in-depth to develop social and cultural explanations for particular features (e.g. clustering, demographic peculiarities) of suicide in particular places. WP5: an embedded PhD studentship will analyse how race/ethnicity shape understanding and meanings of suicides, ensuring this sorely neglected area is addressed.
|
| 28/01/2020 |
£816,955 |
UNIVERSITY OF MANCHESTER |
What does it mean to sleep well? This is not just a modern concern but something that has exercised individuals and communities throughout history. This project will be the first to address this question by assessing how people's efforts to sleep well c.1500-1750 were influenced by a distinctive set of environmental relations and linked 'environing practies' in which people engaged with their physical surroundings to optimise their sleep timings, bedding materials, and to prepare soporific tonics. A PI-led team will reconstruct the principal agents, materials, and 'environing' practices that were used to manage sleep in ecologically distinct parts of Britain, Ireland and England's emergent American colonies of Virginia and Newfoundland, alongside the bodies of medical, botanical, climatic and material knowledge associated with them. The research is important because it brings a fresh environmental history perspective to bear upon cross-disciplinary debates about the significance that physical environments play in shaping healthy and unhealthy sleep habits. It will also be the first to assess the immediate and longer-term impacts of early modern processes of environmental change in shaping people's sleep care practices, which will encourage a reassessment of the assumed primacy of 'watershed' moments such as industrialisation in shaping human sleep fortunes.
|
| 21/01/2020 |
£286,353 |
UNIVERSITY OF YORK |
Vets and doctors are both involved in managing death, but the changing ways in which the professions are involved in end of life care have not been studied together. Nor has there been systematic examination of how the two professions might learn together in this field. Using cutting-edge post-human theories and inter-species empirical and ethical approaches, this project will drive forward such research. First, it builds on the small but growing literature which shows how companion animals are increasingly conceptualized as family members and can provide metaphors and models by which to discuss the care of human family members. Second, it responds to observable changes in practice by which the the end-of-life treatment of humans and non-humans animals are becoming much less distinct, for example, through the emergence of animal hospices and increasing discussion of medically assisted dying.
The project examines how contemporary trends might contradict and complicate the legal and ethical basis of both overlapping and divergent clinical practices. At a time when approaches to end of life care are being redrawn, it will create opportunities for the veterinary and medical professions to learn together, through accessing shared ideals and valued differences within the negotiation of a ‘good death’.
|
| 21/01/2020 |
£201,207 |
UNIVERSITY OF MANCHESTER |
Digital sensing promises new solutions to animal healthcare in farming through real-time capture and analysis of animals’ physiological and behavioural data. Sensor technologies influence routines, devices and everyday strategies for animal disease and stress prevention adopted by farmers and veterinarians. This reorganisation of healthcare practices has implications for human-animal relations and animal health assessment, including the wellbeing of animals and their carers and the control of diseases that pose a risk to human health. This project sits at the intersection of medical humanities, animal studies and science and technology studies (STS) to be the first to offer an investigation of the relationship between digital sensing, knowledge production and social relations within animal healthcare practices in farming. Drawing on historical and ethnographic research of the case of cattle farming in the UK and France, the research contributes unique methodological and theoretical insights on sensing practices by asking: Why and how sensor technologies have become part of animal health and welfare management in cattle farming? How does digital sensing influence knowledge production and understandings of cattle health, illness, and wellbeing? And, how does digital sensing transform social relations, including human-animal relations, in the context of cattle healthcare in farming?
|
| 21/01/2020 |
£250,779 |
LIVERPOOL JOHN MOORES UNIVERSITY |
The phenomenon of human enhancement through drugs (HEDs) has sparked intense public debates and a growing body of interventions and research from the social and health sciences. Sociological and philosophical inquiries have explored the ethics of such drug use and how such practices shape identities and ideas of what it means to be human. As new substances, modes of use and attitudes are popularised amongst people of diverse backgrounds, new risks for physical, mental and social health and wellbeing are being identified and assessed. This research aims at investigating the emerging trend of microdosing psychedelics as a new facet of human enhancement through drugs. Attracting significant media and scientific attention in recent years, microdosing is the regular use of sub-perceptive threshold doses of substances such as LSD or magic mushrooms. Self-reported benefits include enhancements in cognitive performance, mood, creativity, physical energy and inter-personal relations, as well as decrease in depressive and anxious symptomatology. Employing a combination of qualitative methods, the research will investigate this fascinating phenomenon and situate it in the larger context of the current psychedelics renaissance that is marked by new scientific investigations, policy change, a use and advocacy movement, and commercial interests in these substances.
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| 21/01/2020 |
£189,726 |
NORTHUMBRIA UNIVERSITY |
Sleep is in crisis in the twenty-first-century Global North. People fail to sleep the eight hours recommended by the WHO and sleep disorders are on the rise. In the first study to investigate cultural engagements with this public health issue, I consider a wide range of twenty-first-century Anglophone writings: fiction, non-fiction (memoirs and self-help manuals), and digital culture (mHealth apps and sleep hygiene blogs).
This focus on cultural production serves to interrogate the crisis’s affective dimension. Informed by critical theory, my literary/cultural analyses explore the affects and concerns about contemporary life mobilised by the discourse of a sleep crisis and what these reveal about the relationship between individual health and neoliberal ideologies. My aim is to articulate a new theory of the affects (such as insomnia, exhaustion, burnout, and anxiety) flourishing under the neoliberal temporal regimes and forms of subjectivity that arguably underlie the sleep crisis.
The project proposes an innovative medical humanities intervention, since sleep has only recently become an object of inquiry for the humanities and an exclusive consideration of sleep in twenty-first-century writings is lacking. With its timely exploration of mental health issues rife under neoliberalism, my project will have impact on mental health practice and activism.
|
| 21/01/2020 |
£544,026 |
UNIVERSITY OF SHEFFIELD |
This research will provide essential new knowledge for the design of successful policies to improve the health of Europe’s Roma populations. Roma, the largest ethnic minority in Europe, have faced generations of structurally sanctioned racism. Their health is the worst of any group in the region. Despite increasing policy attention, Roma disadvantage is increasing. Before we can know what needs to change in order to improve the situation, we need to understand the nature of the ‘problem’. Understandings must reflect Roma knowledge in order to challenge their on-going oppression. This study will employ critical participatory methods to begin a dialogue with specific self-defined Roma populations in England and Hungary. Creative approaches will bring to life contextually-embedded subaltern perspectives on the ‘who’, ‘what’ and ‘how’ of ‘Roma health’. Post-structuralist interviewing techniques will encourage policy specialists to reflect on contingent nature of policy understandings and the work that is required to sustain dominant discourses. The research programme will culminate in series of innovative workshops, performances, exhibitions and presentations that bring together policy specialists and Roma to share alternative accounts of ‘Roma health’ so that currently privileged policy problematisations can be rethought.
|
| 21/01/2020 |
£353,392 |
UNIVERSITY OF EXETER |
This project tackles the question of how people in the Middle East have experienced ‘addiction’ and how governments and social agents have reacted to changing drug phenomena in states of disruption (war, revolution, human displacement).
It explores the consumption of mind-altering drugs in Iran and Lebanon, and their respective displaced communities (Afghans, Syrians), unearthing an alternative framing of pleasure/illness/care and ways of living ‘addiction’ that differ from the West-centric scripts on health/illness.
Focusing on the life trajectories of past and present drug consumers during and after dramatic political change, armed conflict and human displacement, it questions how states of disruption affect the lived experience of ‘addiction’, how people make use of mind-altering drugs in dealing with unsettling conditions, and how health institutions and social agents transform their public agenda because of them.
The project considers the case of drug consumers, ‘addiction’ scientists, and religious/spiritual healers. This leads to the reframing of the cultural, scientific and political environments that have made ‘addiction’ into a biomedical and ethical category in the contemporary Middle East. It adopts a transdisciplinary approach to ‘addiction’ using regional archives, bottom-up oral history, ethnographic immersion and visual data collection, engaging them in debates across history, politics and anthropology.
|
| 21/01/2020 |
£188,162 |
UNIVERSITY OF WARWICK |
In recent decades, the 'safety' of patients and staff has become a pressing concern in the British National Health Service (NHS). However, little is understood about how and why these ideas and practices evolved historically, and were spread throughout the NHS.
My project, Hazardous Hospitals, addresses this lacuna by exploring ideas and practices around 'safety' in NHS general hospitals from 1960-2012. It analyses the development, promotion and institutionalisation of 'safety cultures': ideas, values and behaviours around safety, as well as the systems and processes which support and sustain them. My outputs will be a major monograph exploring the history and meaning of 'safety' in the NHS, an article in History & Policy, as well as 2-3 journal articles exploring sub-topics, such as occupational health. I ask:
1. What defines the ‘safety culture’ of NHS hospitals? How can these ‘safety cultures’ vary?
2. How was safety in hospitals assessed, and in what ways did it come to the attention of NHS managers and policymakers after 1960?
3. How did NHS managers promote safety among their staff?
4. What role did groups such as patient organisations, safety campaigners and the press play in depicting, challenging and promoting reform of hospital ‘safety cultures’?
|
| 21/01/2020 |
£255,244 |
UNIVERSITY OF LEEDS |
People with a learning disability have low rates of participation in health research. The acceptability of health interventions and medication are rarely tested on them in population based studies. This project examines 2 time points at which their participation in health research is subject to under-researched interactions and interpretations. It scrutinizes the operation of ideas of capacity, consent and autonomy at those time points.
This study will use ethnographic and interview methods to examine the role of NHS research ethics committees in their discussions of studies, looking for the ways intellectual disability is conceptualised and how this influences research design and approval. It will utilize autoethnographic and interview methods to tease out how researchers negotiate the everyday ethics of implementing mental capacity guidance during research. Thirdly, it will work with people with a learning disability to gain their perspective on health research participation, consent and capacity.
This project will generate innovative empirical data, ambitious theoretical engagement with concepts of capacity, consent and autonomy. I will also create practical guidance for ethical review committees, researchers, people with learning disabilities and the general public to challenge the lack of diversity in research samples and the inequality in research participation.
|
| 21/01/2020 |
£193,757 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
This project explores how HIV-affected people built and maintained families in Edinburgh, influencing national and international policy and practice through daily acts of love, care, and activism between 1981-2016. Adopting the broad understanding of ‘family’ deployed by queer scholars, it scrutinises how HIV-affected families of choice, origin, and necessity worked with – and included – communities of friends, activists, and health and social care practitioners, to meet the emotional, educational, and medical needs of the HIV-affected. In doing so, the project will trouble and historicise the varied definitions of ‘love’, ‘care’, ‘activism’, and ‘family’ deployed by actors to interpret acts, objects, and spaces involved in building and maintaining HIV-affected families. The key aims are to uncover how HIV-affected families’ needs were defined and met; to what extent meanings of ‘family’ and ‘activism’ were changed by the necessities of HIV-related care work; and what influence, if any, the experiences of HIV-affected families had on conceptions of reproductive politics and childcare. The project draws new links between histories of family, reproduction, risk, pleasure, social care and activism, identifying new actors, networks, and objects, advancing voices which, while present in the archive, are muted in the current historiography.
|
| 21/01/2020 |
£274,182 |
UNIVERSITY OF GOTHENBURG |
Patient behaviour plays a key role in determining whether health systems are able to maintain and promote health. One area where it is crucial to study patient behaviour is maternal and neonatal health, particularly in low and middle-income countries (LMICs). Every day, over 800 women in LMICs die from preventable pregnancy and childbirth related complications. Key international policy goals, such as the third Sustainable Development Goal, reflect the view that patient behaviour – specifically related to care-seeking, facility delivery and use of antenatal care (ANC) services – is key for preventing maternal deaths. Understanding patients’ healthcare-seeking behaviour and addressing barriers to uptake, is therefore crucial for improving maternal and neonatal health in LMICs.
This fellowship will generate new evidence on the determinants of patients’ healthcare-seeking behaviour, and its effects on maternal and neonatal health and survival in Kenya. It has four objectives:
Analyse the link between trust in the health system and care-seeking behaviour
Explore the relationship between perceived quality of care and care-seeking behaviour
Determine the effect of care-seeking behaviour on health outcomes in Kenya, including heterogeneity based on the quality of care and socio-economic status
Disseminate findings to policymakers and researchers
|
| 21/01/2020 |
£231,000 |
UNIVERSITY OF SHEFFIELD |
What are the implications for health professionals and patients when cancer develops during pregnancy? To what extent might existing care practices become reconfigured within this context? This Fellowship will address these questions through novel research exploring a rare condition: Gestational Trophoblastic Disease (GTD). GTD only arises following conception, and can result in the development of (pre-)cancerous tissue in place of a viable foetus. Nevertheless, in many cases women experience symptoms of pregnancy and anticipations for future parenthood. GTD disrupts conceptual boundaries between cancer and pregnancy as corporeal phenomena, posing vital questions around the status of foetal and malignant entities, and definitions of pregnancy and loss.
An exploration of this unique condition through the lens of medical sociology will enrich social scientific explorations of foetal personhood and pregnant embodiment. Further, whilst cancer is often studied sociologically, this research will prompt dialogue around cancer and pregnancy. This clash of life potential with life-threatening illness provides unique opportunities to explore how experiences of anticipated parenthood, loss, and cancer ‘survivorship’ co-exist. Key goals will be the interrogation of societal definitions of pregnancy/cancer as reproduced and reimagined through the phenomenon of GTD, exploration of women’s experiences, and the generation of relevant insight for clinical practice.
|
| 05/12/2019 |
£1,268,713 |
UNIVERSITY OF CAMBRIDGE |
Mitochondria are cellular organelles primarily involved in energy production. They are considered to be key to the function of eukaryotic cells. Nevertheless, mitochondrial diseases often only present in adulthood with tissue-specific symptoms. This means that cells and tissues must have coping strategies which temporarily maintain normal function when confronted with mitochondrial dysfunction.
This proposal aims to test the hypothesis that cell-type composition and metabolic interactions between different cell types renders specific tissues more or less vulnerable to mitochondrial dysfunction.
The neural stem cell (NSC) niche in the developing Drosophila brain is a powerful in vivo model for the microenvironment of neurons and NSCs in our human brain. I plan to study the in vivo metabolic requirements of Drosophila NSCs (Aim 1), and the metabolic and transcriptional response of surrounding niche cells upon mitochondrial dysfunction (Aim 2). In the last part of my proposal, I will investigate how metabolic regulation of the nuclear genome provide both a nuclear sensing mechanism and a buffer to tissue-wide mitochondrial dysfunction (Aim 3).
Elucidating generic mechanisms of the tissue-wide response to mitochondrial dysfunction will lead to better insight into metabolic origins of neurodegenerative diseases and cancer and has the potential to uncover novel therapeutic approaches.
|
| 05/12/2019 |
£755,905 |
UNIVERSITY COLLEGE LONDON |
Seizures are a common manifestation of brain injury in newborn infants. Controversies still exist over whether seizures may themselves cause further damage to the developing brain, when to treat them, what drugs to use and how to improve detection. There is an urgent need for a better understanding of the pathophysiological changes to improve our management strategies.
My key goal is to assess the impact of seizures on the newborn brain. I propose to use a new optical platform (combined broadband near-infrared spectroscopy and diffusion correlation spectroscopy) for a comprehensive real-time assessment of cerebral metabolism (using oxCCO and CMRO2), haemodynamics (using CBF and CBV) and oxygenation (using TOI) together with video-electroencephalography(EEG) at the cot-side to investigate seizure-induced changes inside brain. I aim to deliver a translational and clinical strategy to investigate these changes in healthy brains of an animal model and in a cohort of babies in neonatal intensive care who developed seizures after brain injury. I will further investigate the impact of phenobarbitone on brain metabolism and haemodynamics. Short and long-term impacts will be assessed with neuroimaging and neurodevelopmental outcome data.
These findings will improve our understanding and will support an evidence-based approach for the management of neonatal seizures.
|
| 05/12/2019 |
£697,263 |
UNIVERSITY OF EDINBURGH |
My research aims to further define the pathological biochemistry of RPGR-mediated X-linked Retinitis Pigmentosa (RPGR/XLRP), an inherited retinal dystrophy that causes blindness and has no treatment. I hope better understanding of disease mechanism will help identify potential therapeutic options.
Photoreceptor outer segments have evolved from primary cilia to compartmentalise the visual pigment rhodopsin into an elaborate structure of folded membranes, known as discs, enabling normal vision. Failure of disc morphogenesis results in photoreceptor degeneration; the hallmark of Retinitis Pigmentosa (RP).
Recent work suggests that photoreceptor disc formation is an actin-mediated process, but the exact mechanism by which they form is unknown. RPGR mutations account for 20% of RP and my previous work suggests RPGR regulates actin turnover in the photoreceptor connecting cilium.
I hypothesise that RPGR acts as an assembly platform that recruits actin binding proteins to promote morphogenic membrane curvature at the distal connecting cilium, resulting in disc formation.
My work in this application will examine my hypothesis. I will use animal models of RPGR/XLRP and endogenously tagged proteins to determine the biochemcial processes that underpin the disease using a combination of molecular biology, novel interactomic experiments and super-resolution imaging.
|
| 05/12/2019 |
£999,519 |
UNIVERSITY OF EXETER |
We are now in the genomics era where clinical and pre-emptive genetic testing is common. This has raised new problems in monogenic disorders such as Maturity-Onset Diabetes of the Young (MODY), a rare genetic form of diabetes: 1) identification of wide variation in the clinical features of people with MODY mutations, including non-diabetic individuals. 2) identification of people who are ‘MODY-like’ (slim, young and not on insulin) but without a MODY mutation and therefore without a known cause for their diabetes.
During my fellowship, I will address these new problems using our unique cohort of MODY/MODY-like diabetes and clinical and genetic data on 500,000 people from UK Biobank. I hypothesise that polygenic risk of diabetes-related traits will explain variation in the MODY phenotype and characterise new subtype(s) of diabetes which presents as classic MODY, but is due to extreme polygenic risk of diabetes-related traits (polygenic-phenocopies).
The outcomes of this research will be to provide accurate prediction of which people with MODY mutations will get diabetes and when, and define and characterise a new type of diabetes. This work will have important implications for individuals with MODY, for the wider diabetes community and will provide framework for other genetic disorders.
|
| 05/12/2019 |
£1,393,685 |
IMPERIAL COLLEGE LONDON |
Regulation of gene expression by DNA methylation (5mC) in response to genetic and environmental risk factors is considered important to human obesity and type-2 diabetes (T2D) pathogenesis. Yet, difficulty finding causal 5mC changes in humans is limiting downstream clinical applications. I have discovered 5mC changes robustly associated with obesity and their predicted effector genes in human adipocytes. I have then refined these loci and genes using human genomics, cross-species transcriptomics and biological evidence to 3 top candidates for discovery of novel mechanisms of disease – the MEDAG, FGFRL1 and TXNRD1 loci.
I will use sophisticated gene targeting to investigate the causal effects of the MEDAG, FGFRL1 and TXNRD1 genes on obesity and T2D in a mouse model of human disease, and detailed phenotyping to examine the pathophysiological mechanisms. In parallel, I will use functional and experimental genomics to explore the regulatory significance of obesity-associated 5mC sites on MEDAG, FGFRL1 and TXNRD1 gene expression, and the underlying epigenetic mechanisms, in human adipocytes. These complementary lines of evidence will establish whether locus-specific 5mC variations and subsequent gene expression changes impact on human obesity phenotypes, and may define epigenomic and molecular targets for new obesity and T2D therapies.
|
| 05/12/2019 |
£1,198,669 |
INSTITUTE OF CANCER RESEARCH |
Prostate cancer (PC) is a leading cause of cancer-related death in men globally. Advanced PC responds to androgen receptor blockade but inevitably remains lethal. Novel therapeutic strategies are urgently required, incorporating disease molecular stratification.
I have acquired data demonstrating that a gene cassette on chromosome (ch) 1q, incorporating the anti-apoptotic gene MCL-1, is amplified in 16% of lethal PC. Furthermore, patient-derived tumour models with ch1q (MCL-1) amplification are resistant to established treatments but respond to MCL-1 inhibition. I hypothesize that, interrogation of MCL-1 biology will elucidate superior strategies to target MCL-1. Consistent with this, RNA splicing factor SF3B1 knockdown drives expression of its pro-apoptotic isoform MCL-1S, and deubiquitinating enzyme UCHL3 knockdown degrades MCL-1 protein, inhibiting PC growth. Furthermore, UCHL3 is deleted in 7-13% of lethal PC which may reduce MCL-1 expression and sensitise to BCL-XL/BCL-2 inhibition.
I will therefore: (1) evaluate the impact of ch1q (MCL-1) amplification on PC cellular processes and response to standard therapies; (2) develop novel strategies to target MCL-1 (and other BCL-2 family members) in PC; and (3) identify novel targets to deliver innovative therapeutic strategies for ch1q (MCL-1) amplified PC. I envision that this work will improve outcome from this commonest of male cancers.
|
| 03/12/2019 |
£706,995 |
UNIVERSITY COLLEGE DUBLIN |
The idea that the brain forms decisions by accumulating evidence up to a criterion or "bound" has been the major driver of decades of fruitful theoretical, behavioral, neuroscientific and clinical research into decision making. However, the most prominent competing model variants disagree on whether and how the extent of accumulation is limited through either of two means: 1) growing "urgency" to respond, which effects a collapsing decision bound, and/or 2) "leakage" of past evidence. These model variants are indistinguishable based on the quality of behavioural data fits for most tasks, yet can yield fundamentally discrepant interpretations of the same data. Our recent discovery that sensory evidence encoding, evidence accumulation and motor preparation can be simultaneously traced in neurophysiological recordings from the human brain has opened a new path to gaining definitive, convergent insights into the operation of these mechanisms in any task. Pioneering a unique approach which exploits these dynamic neural signatures to construct, constrain and validate multi-tiered decision models, we will establish when and why urgency and leakage are invoked and adapted across diverse decision scenarios encompassing expanded judgements, discrete discriminations and continuous monitoring. These fundamental insights will have wide-ranging impact on basic and clinical research into cognition.
|
| 03/12/2019 |
£2,167,448 |
NEWCASTLE UNIVERSITY |
Acquired somatic mutation continually modifies the genomes of multicellular organisms, inevitably causing human disease. The over-arching aim of this proposal, is to define how somatic mutation impacts upon macrophages, immune cells that are critical for defence, regulation, and repair. Macrophages were thought to arise through continual recruitment of monocytes, but recent data indicate that they originate and renew in diverse ways. The first aim is to use silent mutation to study the origin of human macrophages. This will discern the difference between microglia, thought to arise exclusively from a primitive origin, self-renewing macrophages derived from definitive haematopoiesis, and macrophages that require a continual input of monocytes. The second ai, will study macrophages in clonal haematopoiesis. Somatic mutation in the bone marrow has the potential to alter macrophage function and accelerate prevalent diseases such as atherosclerosis. The final aim is to explore somatic mutation in clonal macrophage populations as a novel aetiology of idiopathic inflammatory disorders IgG4-related disease, granulomatosis with polyangiitis and sarcoidosis. These are noted for their overlap with histiocytosis, the archetype of a new class of inflammatory myeloid neoplasm. Together these studies will define novel functions of macrophages in pathology that reflect their independence or connection with haematopoiesis.
|
| 03/12/2019 |
£2,249,535 |
UNIVERSITY COLLEGE LONDON |
The brain utilises cortical and subcortical pathways to transform sensory information into action, giving rise to learned and instinctive sensory-guided behaviours. How these pathways interact to generate flexible behaviour, allowing animals to react differently to the same environmental stimuli depending on circumstance, remains poorly understood. We propose that inhibitory circuits in the thalamus are essential for flexible control of sensory-guided actions. Our pilot data show that the ventral lateral geniculate nucleus (vLGN) - a prethalamic structure composed of different classes of inhibitory projection neurons - provides inhibitory control of an instinctive visually-evoked behaviour. We will identify the neural circuit mechanisms of this control and determine when it is engaged. Moreover, since the vLGN is extensively connected with visual circuits in the neocortex and the midbrain, we will test if and how this nucleus can coordinate these visual pathways to guide both instinctive and learned visually-guided behaviours. We will achieve these aims by combining genetic tools with calcium imaging, electrophysiological recordings, cell-type specific optogenetic manipulations and quantitative behaviour in animals performing visually-guided tasks. This work will generate detailed understanding of mechanisms by which the brain can orchestrate behavioural responses to environmental stimuli.
|
| 03/12/2019 |
£1,884,223 |
UNIVERSITY OF EDINBURGH |
Protein synthesis is essential for the strengthening and weakening of synaptic connections between neurons, and it is pathologically altered in multiple genetic models of Autism Spectrum Disorders and Intellectual Disability (ASD/ID). The identities of the mRNAs translated to sustain changes in synaptic strength are not known, nor is the mechanism linking aberrant translation to functional changes in ASD/ID.
This proposal will address two key questions: (1) How does dysregulated translation lead to altered synaptic function in Fragile X Syndrome (FX), the most common monogenic cause of ASD/ID? And (2) How are specific mRNAs translated to support opposite changes in synaptic strength?
I will test the predictions that reduction of ribosome production can correct neurological phenotypes in the Fmr1-/y mouse model of FX, and that mRNAs translated to support synaptic strengthening (LTP) and weakening (LTD) are differentially regulated by ribogenesis. To do this I will use Translating Ribosome Affinity Purification (TRAP) and RNA-seq along with electrophysiological and behavioral assays. These studies will identify the link between excessive protein synthesis and synaptic disruption in FX and explain how translation is specified to support opposing changes in synaptic strength.
|
| 03/12/2019 |
£2,200,879 |
IMPERIAL COLLEGE LONDON |
While emerging antimicrobial resistance is widely recognised in bacteria, the emergence of fungi that are resistant to antifungal drugs is underappreciated yet is compromising our ability to treat these serious diseases worldwide. The most widely used class of chemicals, the azoles, are driving the evolution of fungal multidrug resistance through their dual-use in both agricultural and clinical settings. However, we lack critical insights into how these antifungal chemicals are leading to changing patterns of disease in humans. We focus on Aspergillus fumigatus, an environmental fungus to which all humans are exposed causing disease in millions, and which is rapidly evolving resistance to azole antifungal drugs worldwide. Our project aims to understand the risk that azole-resistant aspergillosis presents to public health by identifying the extent to which patients are acquiring resistant infections from environmental sources. We will explore whether the emerging spectrum of mutations that confer drug resistance come with a fitness cost, how these mutations impact upon the global population of A. fumigatus with respect to undesirable phenotypes such as virulence and infectivity. The science that our study produces will be focused on tackling this pandemic in order to retain the efficacy of essential current, and incoming, clinical antifungal drugs.
|
| 03/12/2019 |
£1,905,114 |
UNIVERSITY OF EDINBURGH |
Liver fibrosis is a major global healthcare burden. Iterative liver damage, secondary to any cause, results in progressive fibrosis, disrupted hepatic architecture and aberrant regeneration, defining characteristics of liver cirrhosis. Currently, treatment options for patients with chronic liver disease are limited to removal of the underlying cause, if possible, or liver transplantation. However, demand for transplantation greatly outweighs donor organ supply. Therefore, effective antifibrotic therapies are urgently required. To enable true precision medicine-based therapies, we need to significantly increase our understanding of the cellular and molecular composition of the fibrotic niche across the different forms of human liver fibrosis, and therefore this application is deliberately human disease-focused. In this proposal, we will define and interrogate the interactome of the human liver fibrotic niche using cutting-edge single-cell transcriptomic approaches including single-cell and single-nucleus RNA sequencing, spatial transcriptomics and machine learning, and single-cell epigenomics. These studies should greatly advance our understanding of how the fibrotic niche operates across different forms of human liver fibrosis, generating aetiology-specific, relevant and potentially druggable therapeutic targets to treat patients with liver fibrosis. By the end of this Fellowship, if awarded, we aim to have multiple therapeutic targets entering Phase I clinical trials.
|
| 03/12/2019 |
£1,700,629 |
UNIVERSITY OF LEEDS |
Remodelling of the heart is linked to a poor prognosis for patients with cardiac disease. While the mechanisms underpinning this process are only poorly understood, changes in the microstructural architecture of the myocardium are considered to play a key-role. Cardiac diffusion tensor imaging (cDTI) has enabled insights into the microstructure non-invasively through the assessment of the diffusion of water molecules in the myocardium. cDTI provides quantitative diffusion metrics such as Fractional Anisotropy, Mean Diffusivity and Helix Angle, which can serve as biomarkers of disease. Nevertheless, cDTI is technically challenging due to its sensitivity to motion, strain and perfusion. Moreover, the diffusion tensor is an oversimplified representation of the underlying tissue structure. More realistic tissue models as developed for the brain are presently prohibited by MR scanners hardware limitations, particularly magnetic field gradient strength. The aim of this project is to establish cardiac diffusion MRI on the Connectome scanner, which features gradients 4x stronger than those available on clinical scanners, in order to develop next generation MRI techniques for the non-invasive, microstructural characterisation of the beating heart in humans, with the ultimate aim to detect subtle remodelling of cardiac tissue earlier, and with higher accuracy than ever before.
|
| 03/12/2019 |
£1,600,709 |
UNIVERSITY OF ABERDEEN |
In low-income countries, rodents have very significant impacts on health and well-being. Annually cereals lost to rodents could feed hundreds of millions of people, whilst rodent-borne infections (RBI) kill thousands. A major research challenge is developing holistic rodent management strategies that deliver both improved food security and reduced disease burdens, and are sustainable for communities. I will work with health and agricultural stakeholders and communities to fill key knowledge gaps and adapt and test innovative management techniques developed in the agricultural sector, primarily in Asia, to other ecological and socio-cultural contexts. Working in Madagascar, I will combine empirical and modelling studies to explore how localised control impacts on the risk from a range of RBI with contrasting transmission routes, determining in what circumstances control increases or decreases risk. I will test the cost-efficiency of different strategies, using an approach that incorporates agricultural losses, disease burdens and management costs. With communities I will explore the impacts of socio-cultural practices, identifying opportunities and constraints for community-led control. To optimise management strategies, adaptive research experiments will be co-developed and evaluated with communities and stakeholders. Active engagement with national and international stakeholders throughout the project will facilitate scaling up and policy impact.
|
| 03/12/2019 |
£3,027,479 |
UNIVERSITY OF OXFORD |
The movement of proteins within eukaryotic cells is an essential process that maintains internal organelle integrity and underpins normal cell function. Despite the identification, several decades ago, of the receptors controlling protein trafficking, the molecular mechanisms of selective retention and export of ER and Golgi resident proteins still remain poorly understood. However, this recently changed when our study on the KDEL receptor revealed the structural basis by which a trafficking receptor can signal across a membrane to cytoplasmic coat protein complexes to initiate retrograde trafficking. We now aim to determine the mechanisms that underpin protein trafficking by other receptors within the early secretory pathway. We have developed an integrated approach involving cell biology and structure-based methods, including lipid-based crystallisation and single particle cryo-electron microscopy coupled with advanced protein engineering, super resolution light microscopy, and multiscale molecular dynamics analysis of trafficking complexes. Specifically, we will determine the mechanism for several cargo-receptor systems that control anterograde and retrograde protein sorting and address how sorting receptors recognise cargo proteins, and the mechanism(s) by which these receptors signal across membranes. Ultimately, we expect to understand the molecular basis for cellular trafficking, providing fundamental insights into crucial pathways involved in human protein folding diseases.
|
| 03/12/2019 |
£2,061,387 |
UNIVERSITY OF GLASGOW |
The proposed research aims to (i) build fundamental understanding of mechanisms of immune evasion by helminth parasites, (ii) explore helminth modulation of the intestinal tissue niche; and (iii) to develop a new strategy towards vaccination to prevent infection. Helminths exploit a key immunological pathway within the immune system to induce suppressive regulatory T cells, and dampen innate effector cells. We have discovered a key player to be a novel parasite mimic of TGF-beta (TGM), which we will analyze structurally and funtionally on (i) immune cells and (ii) intestinal epithelium. The intestinal environment will be modelled through organoids (enteroids) in which parasites can modify stem cell differentation and therefore epithelial composition; we will investigate whether this is caused by TGM or an unrelated mediator. To promote immunity to infection, we focus on extracellular vesicles (EVs) released by parasites, which we have shown inhibit innate cell activation but can be neutralised by specific antibodies. In this model, antibodies to EVs direct them to uptake by phagocytes and lysosomal degradation, abolishing the inhibitory effect on immune cells. Taken together, the research will define how helminths may modify host signals and pathways, and how we may best interrupt this process to achieve protective immunity.
|
| 03/12/2019 |
£1,917,147 |
THE FRANCIS CRICK INSTITUTE |
The DNA replication checkpoint senses perturbation of DNA replication forks by a wide variety of agents. We know the protein components and the overall architecture of the checkpoint pathways, but we do not understand how very different fork stalling events can signal via a common pathway. The first aim of this proposal is to use the fully reconstituted DNA replication system we have developed together with purified checkpoint proteins and defined DNA templates to elucidate in molecular detail the mechanisms by which the checkpoint pathway is activated.
One of the main functions of this checkpoint is to prevent irreversible replication fork arrest (IRFA). From a whole genome siRNA screen, we have recently found that loss of the HLTF DNA translocase suppresses IRFA. Furthermore, we have found evidence that HLTF generates a toxic recombination intermediate and that this is conserved in yeast. Our second aim is to use genetics in human cells along with biochemistry with yeast proteins to understand how IRFA is generated and how the DNA damage checkpoint protects forks from IRFA.
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| 03/12/2019 |
£2,844,723 |
UNIVERSITY OF OXFORD |
I aim to understand how the brain represents the relationships between objects and events in the world, and how these representations can be generalised to allow flexible behaviour in new situations. By combining modelling with experiments in human and macaque, I will investigate these computations at both the cellular and systems level. We have developed models that abstract relational knowledge and predict detailed neuronal representations in rodent hippocampal-frontal circuitry. I will ask whether these building blocks can be extended to explain the sophisticated abstractions and inferences commonplace in primate behaviour. In primates, such abstractions compound hierarchically, and can be combined together, allowing deep inferences. To study these computations, I will develop novel tasks that are high-dimensional, yet amenable to mathematical description. I will use state-of-the-art techniques in humans, validated by high density cellular recordings in macaques, to study representations underlying abstraction, generalisation and inference in medial temporal and frontal cortices. In doing so, I will build new bridges between human and animal neuroscience, between biological and artificial intelligence, and new analytical and experimental tools for integrating across scales of neural activity. Developing such tools is important to bridge the precision of modern neuroscience to humans and thence clinical populations.
|
| 03/12/2019 |
£2,097,551 |
UNIVERSITY OF OXFORD |
IBD affects over 1.5 million and 2 million people in North America and Europe respectively. A significant proportion fail to respond to current treatments. In IBD genetic, environmental and intestinal barrier defects combine to precipitate dysregulated immune responses in the mucosa that manifest in disease. Recently we have utilized single cell technologies to chart the behaviour of diverse cell types making up the mucosal barrier in health and early diagnosis IBD. This has demonstrated the nature of cellular remodeling occurring in the human colon in inflammation revealing trajectories of differentiation, the connectedness of different cell states together with describing novel epithelial, mesenchymal, T, B and myeloid cell states that hallmark disease. In this work we will build on these findings to explore functional pathways and barrier cell relationships revealed by this analysis that maintain commensal symbiosis in health but lead to breakdown in tolerance driving inflammation in IBD. Specifically, we will focus on defining how the colonic epithelia remodels to lose cell intrinsic barrier protective function, how the supporting mesenchyme fuels inflammation and how heterogenous colonic myeloid cells handle commensal bacteria in health and IBD to drive aberrant adaptive responses.
|
| 03/12/2019 |
£4,041,766 |
UNIVERSITY OF CAMBRIDGE |
Primary Immunodeficiency (PID) has a devastating impact on the lives of patients and their families, and management is aided by genetic diagnosis. 80% of PID patients have no overt family history, and thus have been intractable to gene discovery. Our recent pilot study explored whole genome sequencing (WGS) to enhance diagnosis in PID, and found only 8% of such patients carried disease causing mutations in known PID genes. By applying new Bayesian analytical techniques, we identified multiple new PID-associated genes; causative deletions in regulatory regions; and interplay between novel high-penetrance monogenic and common variants, beginning to explain the variable penetrance of PID. We will expand this WGS PID cohort, already the world’s largest, and develop additional specialised statistical tools to incorporate deep clinical, immunophenotyping and antigen receptor repertoire data to enhance WGS analysis techniques. We will use genetic association data from immune-mediated diseases to increase power, and use genetic information to characterise the clinical features predictive of PID and enhance diagnosis. This collaborative effort will enhance understanding of PID biology, define phenotypic variability, discover new disease associated genes, increase diagnostic yield - but importantly develop mechanisms for WGS-based gene discovery in cohorts of sporadic patients, applicable beyond PID.
|
| 03/12/2019 |
£1,740,984 |
UNIVERSITY OF MANCHESTER |
Tissue morphogenesis is associated with dramatic changes in cell morphology. Whilst these cell shape changes may define final tissue form, how they impact and/or direct other key morphogenetic processes remains unclear. I aim to redefine our understanding of the role of cell shape in tissue formation by revealing that, far from simply a structural feature, cell shape encodes critical instructive information that directs diverse morphogenetic events. Using the vasculature and neural crest as morphogenetic models and combining zebrafish live-cell imaging, in-vitro micropatterning and computational modelling, this proposal will investigate (1) if acquisition of specific cell geometries in interphase determines whether cells will divide symmetrically or asymmetrically to direct post-mitotic cell fate, (2) whether signal-induced cell shape changes create positive-feedback that amplifies signal to expedite fate decisions, and (3) how local cell shape remodelling, driven by polarised mRNA targeting and translation, functions to orient motile cell polarity and tissue movements. As such, this work will determine if cell shape unexpectedly encodes diverse morphogenetic cues that direct fundamental decision-making processes underpinning tissue building. Considering that cell shape change is an inherent feature of almost all forming tissues, mechanisms uncovered here may be broadly conserved and of therapeutic relevance in numerous tissue contexts.
|
| 03/12/2019 |
£1,758,388 |
UNIVERSITY OF CAMBRIDGE |
I first identified mutations in the anion transporter SLC26A7 as a novel genetic cause of human and murine congenital hypothyroidism (CH), but its molecular role in thyroid hormonogenesis remains unclear. I will investigate SLC26A7 function in cultured primary thyrocytes, initially evaluating its role in pH regulation, seeking new insights into thyroid hormone biosynthesis.
The incidence of CH with a normally-located gland-in-situ (GIS CH) is increasing, but its determinants are poorly defined. In a case-control study, I will investigate the roles of genetic variants, micronutrients (iodine, selenium, iron) and endocrine disruptors (perchlorate, thiocyanate and nitrate), in the pathogenesis of permanent and transient GIS CH. Confirmed involvement of environmental factors will have public health ramefications and mandate future trials of micronutrient supplementation for treatment or prevention of CH. The study will also provide insights into the aetiology of transient CH, a clinically important entity for which the cause is largely unknown.
DUOX2/DUOXA2 mutations impair thyroidal H2O2 production, often causing transient CH. I will investigate whether maternal heterozygosity for DUOX2/DUOXA2 mutations in association with increased gestational demand for thyroid hormone biosynthesis, causes hypothyroidism during pregnancy. Gestational thyroid dysfunction would mandate future studies of childhood neurodevelopmental outcome and levothyroxine treatment in such patients.
|
| 03/12/2019 |
£2,158,990 |
UNIVERSITY OF CAMBRIDGE |
Filopodia are finger-like actin rich projections from cells that are ubiquitously present during cell movement, are involved in cell connectivity, and are hijacked for internalization by pathogens. We established a cell-free system of filopodia-like structure formation using supported lipid bilayers and frog egg extracts, which has generated hypotheses about where and when filopodia form. My first aim is to discover how endocytosis and phosphoinositide lipid metabolism contribute to the time and place of filopodia formation and suppression in retinal ganglion cell neurons. We will examine the timing and contributions of neurotrophic factor signalling through PI(4,5)P2, PI(3,4,5)P3, PI(3,4)P2 and PI(3)P to membrane deformation and filopodial protrusion. We will explore filopodia in axon guidance, terminal arborization and synaptogenesis, and recovery from neuronal injury. My second aim is to identify the proteins needed for formation of filopodia-like structures to increase our understanding of the molecular mechanisms that determine filopodia function in cells. Where filopodia form determines the direction of cell movement, their length determines the extent of signal sensitivity and their lifetime determines the strength of signaling or duration of migration and adhesion. Our molecular and cellular studies may also give us information needed to manipulate actin regulation therapeutically.
|
| 03/12/2019 |
£1,947,412 |
UNIVERSITY OF CAMBRIDGE |
Peptide presentation on MHC-I molecules is central to mounting effective antiviral and antitumoral immune responses. However, we currently lack full insight regarding how peptides are selected onto these extremely polymorphic molecules. Following our discovery that TAPBPR is an MHC-I peptide editor which shapes the final antigen repertoire displayed for immune recognition, we have recently identified that polymorphism in MHC-I significantly impact on their ability to be edited by TAPBPR. Our findings question the concept that all MHC-I molecules undergo peptide selection via a largely identical manner. Our overarching aim is to gain insight into how polymorphisms in MHC-I influence the mechanism by which they gain peptide.
We will focusing on three aspects:
What impact do polymorphisms in MHC-I and TAPBPR have on the molecular mechanism of peptide selection?
What is the specific biological function of TAPBPR?
Can further molecular dissection of the presentation pathway reveal new insight into MHC-I biology and novel therapeutic targets?
This work will enable deeper insight into how peptides are selected onto MHC-I. It will help uncover why specific MHC-I alleles are associated with particular disease. Furthermore, it will help in the development our novel TAPBPR-based therapeutics and maximise their full potential in cancer immunotherapy.
|
| 03/12/2019 |
£2,251,660 |
UNIVERSITY OF CAMBRIDGE |
The mechanisms that regulate cell fate promise fundamental insights into the pathways that promote tumour growth. Through advances in genetic lineage tracing and single-cell profiling, the functional identity, lineage relationships and fate behaviour of stem and progenitor cells have begun to resolve. Applied to epithelial tissues, these studies have challenged prevailing models, emphasizing the role of stochastic renewal programmes, fate priming and the flexibility of cell states during regeneration. Using a novel lineage tracing strategy based on variants of the multicolour Confetti reporter system, we will use quantitative modelling-based approaches to target the cellular and molecular mechanisms of epithelial cell fate, and how these programmes become subverted following the activation of oncogenic mutations. With a focus on columnar and squamous epithelia, where a foundational understanding of associated signalling pathways and transcriptional programmes is in place, we will define at clonal resolution the changes that take place in cell fate following the acquisition of oncogenic mutations, targeting tumour cells and the reaction of surrounding normal tissue – the tumour microenvironment. As prominent sites of disease, we will contrast tumour cell dynamics in the closed glandular arrangement of the intestinal epithelium and the open organization of the interfollicular skin epidermis and oesophagus.
|
| 03/12/2019 |
£2,286,425 |
UNIVERSITY OF OXFORD |
Bacteria need to control import/export of charged molecules across their relatively impermeable membrane(s) which also house many nano-machines critical for motility and hence infection. These processes are often driven by harvesting the energy stored in ion gradients across the inner-membrane by ion flow through inner-membrane resident channels.
Unpublished work from my group has demonstrated that bacterial inner-membrane ion channels which couple ion flow to protein secretion, nutrient import and bacterial motility unexpectedly share a common architecture within their membrane domains. The architecture revealed unexpectedly suggests rotation between components may be mechanistically important and this application seeks to test this hypothesis. The question will be assessed by a series of structural and mechanistic studies that will seek to determine what commonalities in mechanism underlie this shared architecture and how this is adapted to perform the very different biologies achieved. Specifically, what adaptations allow coupling of uni-directional ion flow to achieve work on both sides of the inner-membrane. Using structural and functional tools developed in my group we will study the ion channels in more native contexts both in terms of the membrane bilayer and in terms of the protein interactions that couple ion flow to work to tease out molecular mechanisms.
|
| 03/12/2019 |
£1,439,158 |
UNIVERSITY OF OXFORD |
Understanding the factors determining the occurrence of de novo mutations (DNMs) in the human genome is central to genetic disease and genome biology. DNMs arise predominantly in the male germline and increase in frequency with paternal-age. Despite the fact that germline mutation rates are intimately linked to spermatogenesis, very little is known about testicular homeostasis in humans. This proposal aims to address this gap in knowledge by focusing on a new disease-mechanism whereby pathogenic DNMs are preferentially transmitted because they hijack the mechanisms controlling spermatogenesis. This selfish selection process relies on principles similar to oncogenesis to explain why some paternally-derived mutations occur spontaneously up to 1000-fold more frequently than background.
Exploiting our current knowledge of selfish selection, this proposal will deploy novel methodologies to describe mutations/genes/pathways subject to this phenomenon, including (1) cataloguing DNMs at single-seminiferous tubule resolution, in geographically-mapped testicular biopsies and in sperm; (2) modelling clonal DNM distribution in tubules to describe spermatogonial dynamics; (3) mining large DNM databases from family trios to detect mutational enrichment. We will also investigate 'selfish mitotic drive', a novel mechanism of mutation enrichment.
Together these approaches will allow us to assess the significance of selfish selection for human disease and genome evolution.
|
| 03/12/2019 |
£2,475,352 |
UNIVERSITY OF CAMBRIDGE |
Heritability has traditionally been thought to be a unique feature of the genetic material of an organism, notably its DNA sequence. However, from studies of a variety of organisms, it is now clear that non-DNA sequence-based inheritance exists from microbes to mammals. The molecular mechanism(s) operating in humans remain opaque. However, understanding the impact of non-DNA sequence-based mechanisms is likely key to a full appreciation of heritability in health and disease. Here we will take ground-breaking steps towards understanding non-DNA sequence-based inheritance mechanisms and consequences. For this work we will focus on the imbred C. elegans model where we have the advantage of extensive genetic tools, a three day generation time and large numbers. In addition, we have identified the African Rift Lake cichlid radiation as a unique opportunity to dissect the contribution of epigenetics to plasticity, adaptation and heritability of phenotype in a vertebrate. While C. elegans gives us the ability to discover new mechanisms de novo we now also have developed paradigms to investigate the role of epigenetic inheritance on the plasticity and adaptivity in C. elegans and in cichlids. The latter is an important step towards a better understanding of inclusive inheritance in vertebrates more generally.
|
| 03/12/2019 |
£715,470 |
UNIVERSITY OF BRISTOL |
Platelets are essential for haemostasis and play critical roles in innate immunity, angiogenesis and tissue repair. They are derived from megakaryocytes, each of which generates several thousand platelets. A major goal is to generate platelets in vitro, to address shortage of platelet supply for transfusion, and to enable fundamental discovery of gene function. To date, however, only very small numbers (approximately 10 per megakaryocyte) of platelets can be made in vitro.
We propose a step change using novel in vitrosystems, to increase generation efficiency by 1-2 orders of magnitude. We will use two in vitrosystems (mouse lung vasculature and microcirculation microfluidics) using forward-programmed iPSC-derived megakaryocytes. Our new data show that passage of megakaryocytes through lung vasculature ‘educates’ them to undergo a sequence of changes: reversible deformation, enucleation and abscission to release platelets. We aim to understand the detailed biology of these processes using CRISPR-edited megakaryocytes. We also show we can make human platelets in our novel microfluidic system and will optimize this to bioengineer large quantities of cells, by learning from the biology of the ex vivolung preparation. This is potentially transformative for fundamental understanding of human platelets and megakaryocytes, and for their bioengineering for clinical uses.
|
| 03/12/2019 |
£593,451 |
UNIVERSITY OF CAMBRIDGE |
Platelets are essential for haemostasis and play critical roles in innate immunity, angiogenesis and tissue repair. They are derived from megakaryocytes, each of which generates several thousand platelets. A major goal is to generate platelets in vitro, to address shortage of platelet supply for transfusion, and to enable fundamental discovery of gene function. To date, however, only very small numbers (approximately 10 per megakaryocyte) of platelets can be made in vitro.
We propose a step change using novel in vitrosystems, to increase generation efficiency by 1-2 orders of magnitude. We will use two in vitrosystems (mouse lung vasculature and microcirculation microfluidics) using forward-programmed iPSC-derived megakaryocytes. Our new data show that passage of megakaryocytes through lung vasculature ‘educates’ them to undergo a sequence of changes: reversible deformation, enucleation and abscission to release platelets. We aim to understand the detailed biology of these processes using CRISPR-edited megakaryocytes. We also show we can make human platelets in our novel microfluidic system and will optimize this to bioengineer large quantities of cells, by learning from the biology of the ex vivolung preparation. This is potentially transformative for fundamental understanding of human platelets and megakaryocytes, and for their bioengineering for clinical uses.
|
| 03/12/2019 |
£3,803,801 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
Conflict-affected populations across the world are vulnerable to alcohol misuse and psychosocial distress. This is a direct consequence of exposure to war, violence, and ongoing stressors in their new areas of settlement such as impoverishment, unemployment, and discrimination. Alcohol may be used as strategy to cope with adversities which refugees and internally displaced people might face, and may cause or result from psychosocial distress. Despite the major health, social and economic consequences of alcohol misuse, there is a notable absence of interventions addressing alcohol use disorders (AUD) among conflict-affected populations. This proposal seeks to complement a WHO evidence-based psychological intervention for people living in adversities ("Problem Management Plus" (PM+)) with strategies to reduce alcohol misuse, thereby developing an intervention which prioritises alcohol misuse but also addresses other underlying mental health problems of conflict-affected populations. We will develop our intervention called PM+/AUD through a comprehensive formative research process, and evaluate the final intervention through two independent randomised controlled trials among South Sudanese refugees living in Uganda, and internally displaced persons in Ukraine. Our project will include social science research on implementation and scaling-up, and will produce guidelines for the treatment of AUD among conflict-affected populations.
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| 03/12/2019 |
£2,832,201 |
UNIVERSITY COLLEGE LONDON |
Hearing is critical to human communication and intelligence. The cascade of neuronal processes that enable hearing remain poorly understood, particularly in computational terms. These gaps in knowledge limit our ability to design treatments for hearing impairment. The proposed research has three goals. First, to develop new computational models that can account for human perceptual abilities and neuronal responses. Second, to reveal representational transformations within auditory cortex that contribute to auditory recognition. Third, to use these models to develop auditory prostheses that augment human hearing. The overarching hypothesis is that the functional organization and tuning properties of the auditory system are constrained by ecologically important tasks (speech recognition, sound localization etc.), such that task-optimized models may converge to the structure of the auditory system. We will leverage deep learning to develop new neural network models of auditory computation. These models will be evaluated for their matches to behavior and brain data using sound synthesis methods introduced by the PI. Candidate hearing aids will then be derived by backpropagating recognition errors through the model to optimize a front-end audio transformation. Such audio transformation should restore model performance given an impaired model cochlea. We will then test their benefits for hearing-impaired listeners.
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| 03/12/2019 |
£1,166,334 |
IMPERIAL COLLEGE LONDON |
Multicellular organisms use systemic signals to transmit biological information across tissues in order to co-ordinate responses to stress or infection. Discovering such signals, how they spread and what responses they trigger is therefore of paramount importance for organismal development. We have previously introduced the first tractable animal system to investigate a diverse group of eukaryotic pathogens, the oomycetes, which cause deadly infections in humans, as well as the model organism Caenorhabditis elegans. We have now discovered that C. elegans is able to sense these pathogens in neurons and mount a protective transcriptional response, the hallmark of which is the induction of conserved chitinase-like proteins in its epidermis. We propose to use comprehensive molecular genetics, cell biology, biochemistry, metabolomics and developmental imaging to determine the host response underlying pathogen recognition and elucidate the molecular gene network underlying the mounting of this response via neuron-to-epidermis signal exchange. Studying intercellular signalling requires a system-wide approach and, to this end, C. elegans offers a great opportunity to investigate this fundamental problem at the whole organism level. The proposed work will expand our knowledge on core cell and developmental biology mechanisms of intercellular signal exchange and immune response in the context of oomycete recognition.
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| 03/12/2019 |
£1,902,595 |
UNIVERSITY OF CAMBRIDGE |
Glycosphingolipids (GSLs) are specialised lipids enriched in the outer leaflet of the plasma membrane (PM) and defects in GSL metabolism underlie a range of devastating diseases. I have shown for the first time a direct link between GSL metabolic defects and changes in the abundance of disease-associated PM proteins. Changes to the cell surface abundance of these proteins are driven by trafficking defects and gene expression changes: pathways that may be mechanistically linked. My preliminary work highlights that the role of GSLs in membrane trafficking has been under-appreciated. I now seek to define the molecular mechanisms that link GSL abundance to disease pathways: how do specific GSL-protein interactions direct membrane trafficking; and what are the consequences of this mistrafficking? We will target specific enzymes in GSL metabolic pathways, monitor lipid and protein changes using quantitative mass spectrometry and visualise co-ordinated protein trafficking from the endoplasmic reticulum using an innovative fluorescence-based secretory assay. Using high-resolution structural techniques we will determine how the specificity of GSL-protein interactions is defined and exploit these insights to feedback into our cell-based assays. My research proposal implements a multidisciplinary strategy that will reveal crucial new insights into how this important class of lipids influence cell fate.
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| 03/12/2019 |
£2,400,000 |
UNIVERSITY OF OXFORD |
We will define the extent of RNA polymerase II (Pol II) transcription units (TUs) across mammalian genomes, both protein coding (pc) and long noncoding (lnc). For each TU class, termination sites and mechanisms will be scrutinised, especially by definition of XRN2 "torpedo" entry sites at positions of co-transcriptional endonuclease cleavage. Multiple endonucleases will be investigated including CPSF-73, Drosha and Integrator-S11. For lncRNA their mechanism of transcriptional initiation will also be investigated, especially R-loop dependant promoters. Pilot experiments show that R-loops promote antisense lncRNA particularly at pc-gene promoters and enhancers, so defining a new class of Pol II promoter that we intend to fully characterise at a molecular level. Histone genes represent an unusual, ubiquitous Pol II pc-gene class. We will also characterise the termination mechanism for these genes and in particular the role of the novel endonuclease MBLAC1. Finally, we will study the particular case of the H2AX gene that employs both a histone like, poly(A)- termination mechanism as well as a poly(A)+ mechanism. Overall, we will characterise mechanisms that define gene TUs across mammalian genomes to better inform gene function in the rapidly expanding repertoire of genomic sequences being generated for normal and pathogenic human cells.
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| 03/12/2019 |
£1,979,621 |
UNIVERSITY OF GLASGOW |
Allodynia and hyperalgesia occur in neuropathic and inflammatory pain states, and depend on circuits involving dorsal horn excitatory interneurons. Recent studies have identified several neurochemical/transcriptomic populations among these cells. We will use a multi-disciplinary approach, involving molecular-genetic targeting of these populations, to investigate their involvement in pain mechanisms at circuit and behavioural levels. We have found that neurons expressing gastrin releasing peptide receptor (GRPR) correspond to vertical cells, which transmit information to lamina I projection neurons, and are implicated in both neuropathic and inflammatory pain. We will use anatomical, electrophysiological and behavioural approaches to determine whether the GRPR cells fulfil this role. If not, we will investigate another population defined by expression of neuropeptide FF. Cells with PKCgamma are critical for neuropathic allodynia, but these can be assigned to two populations that express neurotensin or cholecystokinin. We will determine whether these are functionally different, and whether both contribute to allodynia. Finally, we will establish whether any other excitatory interneurons are interposed between PKCgamma cells and vertical cells in the pathway for tactile allodynia. The study will provide important information about synaptic circuits for pain, and the roles of different interneuron populations.
Keywords: pain, spinal cord, neuronal silencing, chemogenetics, optogenetics
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| 03/12/2019 |
£1,495,073 |
NEWCASTLE UNIVERSITY |
The main goal of this research is to develop and apply advanced statistical methods to help elucidate the biological mechanisms and causal pathways underpinning the correlations seen between genotype and phenotype in complex genetic disorders, with specific emphasis on liver and kidney disease. This will allow us to better understand the biological processes leading to disease development, thus enabling the development of potential therapies and cures. Identifying genes and their protein products which alter disease risk will point to potential new drug targets and allow opportunities for re-purposing of existing drugs.
We will use measurements of genetic factors and potential intermediate processes like gene expression, DNA methylation and protein levels, available through long-standing collaborations with clinical colleagues. A key goal of our research is to develop methods that integrate these different data types with one another and with similar data from external sources.
We will expand the data available through UK-PBC (SNP-genotypes and gene-expression profiling in 100 pre-treatment cases plus 50 controls), by adding CpG-methylation and serum proteomics, enhancing our ability to identify causal pathways in disease development/progression.This will inform disease biology, subsequent treatment response, and the extent to which it can be predicted from baseline measures.
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| 03/12/2019 |
£1,533,479 |
UNIVERSITY OF DUNDEE |
To maintain genetic integrity, eukaryotic cells must properly segregate sister chromatids to opposite spindle poles during mitosis. This process has important medical relevance because chromosome mis-segregation plays causative roles in human diseases such as cancers and congenital disorders, which are often characterized by chromosome instability and aneuploidy. For proper chromosome segregation, it is vital to establish correct kinetochore–microtubule interaction in early mitosis, prior to segregation. We will investigate how kinetochores initially interact with microtubules on the mitotic spindle and how errors in kinetochore–microtubule interactions are resolved to establish correct interactions. In particular, we will address the following questions:
A) What are the molecular mechanisms regulating the kinetochore–microtubule interface during early mitosis?
B) What are the mechanisms resolving errors in kinetochore–microtubule interactions and stabilising correct interactions in a tension-dependent manner?
To address evolutionarily conserved mechanisms, we use budding yeast as a model organism because, in this organism, a single microtubule attaches to a single kinetochore in metaphase – this considerably simplifies our analyses. We use methods in cell biology, molecular genetics, biochemistry and computer simulation, and address not only molecular mechanisms but also the biological significance of step-by-step development in the kinetochore–microtubule interaction.
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| 03/12/2019 |
£1,944,579 |
UNIVERSITY OF CAMBRIDGE |
Obesity is strongly associated with common metabolic diseases (T2DM, fatty liver and cardiovascular disease) which collectively account for a huge global health burden. Insulin resistance underpins this association and our goal is to understand, and reverse, its molecular pathogenesis.
Having worked on rare monogenic lipodystrophies, almost all of which are associated with the metabolic diseases typically seen in obesity, for ~20 years, we have recently convincingly shown that subtle forms of lipodystrophy are a major factor in common insulin resistance/metabolic disease. Specifically we showed that SNPs associated primarily with reduced hip (femorogluteal) fat, are as strongly associated with T2DM and cardiovascular disease risk as variants associated with central adiposity.
We will build on this step-change in understanding by:
Deepening understanding of the molecular mechanisms by which adipocytes form and then store surplus energy in unilocular lipid droplets
Performing an experimental medicine intervention study designed to demonstrate the clinical and molecular impact of alleviating energetic overload using a very low energy diet in patients with partial lipodystrophy.
Investigating the source and action of two hormones (GDF15 and FGF21) which we hypothesize to be stress signals released in response to sustained overnutrition. Both of these molecules represent exciting therapeutic opportunities.
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| 03/12/2019 |
£1,361,584 |
UNIVERSITY OF DUNDEE |
Human life utilises hundreds of cell types with massive diversity in function defined largely by which proteins they express. We will determine how regulation of the mRNA cap modification coordinates the gene expression required in different cell types. The cap protects mRNA from degradation and recruits processing and translation factors. The enzymes which catalyse cap formation were perceived as acting on all genes, in every cell. Our research reveals that the capping enzyme complexes are differentially expressed in different tissues and have gene-specific impacts. During cell differentiation, we demonstrate that changes in capping enzyme complexes result in coregulation of gene families, which we hypothesise co-ordinates the gene regulation required for new cell identities to emerge.
Key goals are to determine:
mechanisms governing capping enzyme gene-specificity
how co-factors influence capping enzyme functionality
the impact of mRNA cap regulation in differentiation
In pluripotent cells, the components of mRNA capping enzyme complexes will be characterised and their impact on enzyme kinetics, cap formation and sequence-specific RNA selection determined. During differentiation, how mRNA capping enzyme regulation impacts on enzyme function and gene expression will be investigated. This project will determine the dynamic impact of mRNA capping enzyme regulation.
Keywords: gene regulation; mRNA; cell function
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| 03/12/2019 |
£2,042,009 |
UNIVERSITY OF EDINBURGH |
Meiotic cell division is defined by a unique and highly dynamic programme of events that results in homologous chromosome segregation following crossover formation. In mammals, the telomeric ends of chromosomes become tethered to the nuclear envelope by the meiotic telomere complex (MTC), where they undergo rapid movements, driven by microtubule forces transmitted by the LINC complex, that facilitate the identification and alignment of homologous chromosome pairs through recombination. Once established, homologue chromosome pairs become synapsed along their length by the zipper-like assembly of the synaptonemal complex (SC), which provides the unique three-dimensional architecture necessary for recombination intermediate resolution and crossover formation. We will uncover the structure, assembly mechanism and recombination function of the SC, the mechanistic basis of nuclear envelope tethering by the MTC and the mechanism of force transduction by the LINC complex. This will be achieved through a structural biology approach of biophysics, crystallography and cryo-EM, coupled with collaborative structure-directed mutation in mouse meiosis. Our work will result in unprecedented molecular understanding of how the mammalian SC, MTC and LINC complex operate together as an integrated molecular machine to achieve their essential functions of mammalian meiosis, and crucially how their dysfunction leads to human infertility, miscarriage and aneuploidy.
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| 03/12/2019 |
£1,843,933 |
UNIVERSITY COLLEGE LONDON |
The cerebral vasculature and glial cells play crucial but poorly understood roles in initiating Alzheimer’s disease (AD) and related dementias, contributing to cognitive decline via a loss of synapses and neurons. We have shown that:
(i) a major reduction of cerebral blood flow occurs early in human AD because oligomeric amyloid beta (Aß) evokes constriction of brain capillaries by contractile pericytes;
(ii) the blood flow reduction in AD may reflect microglia controlling pericytes;
(iii) microglia-mediated phagocytosis, which removes both Aß and synapses, is regulated by ion channels and receptors;
(iv) decreased blood flow and AD alter node of Ranvier length in myelinated axons, which will change axonal conduction speed and thus neural circuit function.
Now, focusing on Aß and decreased blood flow, we will investigate how vascular and glial function contribute to dementia, by:
(A) defining the mechanisms underlying Aß-evoked capillary constriction, and developing therapeutic approaches to restoring blood flow;
(B) characterising how microglia and astrocytes remove Aß and synapses, and investigating how to control this;
(C) studying how Aß and decreased blood flow damage myelin and nodes of Ranvier, and how to prevent this.
Together, this work will identify novel non-neuronal therapeutic targets for treating dementia.
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| 30/11/2019 |
£764,996 |
UNIVERSITY COLLEGE LONDON |
Across much of sub-Saharan Africa, pneumococcal disease (otitis media and pneumonia) and malaria are leading causes febrile illness, and therefore drivers of both appropriate and inappropriate antibiotic use. Prevention through vaccination has the potential to influence antimicrobial resistance (AMR) both directly and indirectly. We are in a unique position to leverage two large funded cluster-randomised vaccine evaluations in Malawi: 13-valent pneumococcal conjugate vaccine (PCV13) schedule change (3+0 to 2+1; extending immunity and potentially herd protection); and RTS,S malaria vaccine introduction. We will ask what are the direct and indirect selective effects of pneumococcal and malaria vaccines on antibiotic resistance, febrile illness and antibiotic usage in young children in Malawi? We will determine whether in children S. pneumoniae carriage isolates; the upper respiratory tract resistome; and stool carriage of extended spectrum beta-lactamase (ESBL) E. coli or Klebsiella. We will assess whether the pneumococcal or malaria vaccines alter the frequency of febrile illness and antibiotic use in children
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| 30/11/2019 |
£177,986 |
WASHINGTON STATE UNIVERSITY |
We are initiating a CDC-funded study of antimicrobial-resistant bacteria in the western highlands of Guatemala. This study is in collaboration with investigators at Washington State University (WSU, USA), University de Valle de Guatemala (UVG), the Guatemalan Ministry of Health and Social Assistance (MSPAS), and the Central America Regional Office of the Centers for Disease Control and Prevention. The goal of this two-stage randomized, cross-sectional study (n=577 households) is (1) to estimate the prevalence of three groups of antimicrobial-resistant bacteria and Group A Streptococcus at the community-level, and (2) to identify risk factors for carriage of the target organisms including antibiotic use and hygiene variables. If funded, the current proposal will add 326 households (with participants Enterobacteriaceae. All vaccinations will be considered, but with the proposed design we hypothesize that we will detect a statistically significant vaccine effect relative to rotavirus and-or pneumococcal vaccinations. Findings from this study will inform the MSPAS vaccination efforts and will be shared with the local, national and international communities (e.g., PAHO and WHO).
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| 30/11/2019 |
£267,005 |
EMORY UNIVERSITY |
Rotavirus is the most common cause of severe gastroenteritis in infants and young children. The primary benefit of rotavirus vaccination is prevention of severe diarrheal disease and hospitalizations have been reduced dramatically since vaccine introduction. Rotavirus vaccination may impact antibiotic prescribing and resistance by two mechanisms. First, bacterial agents of gastroenteritis are often treated with antibiotics. Since aetiology is usually not known at the time of the medical encounter, antibiotics are frequently prescribed for viral gastroenteritis even though they are not recommended. Second, antibiotics, whether prescribed for gastroenteritis or infection at other sites, may disrupt the enteric microbiome. This may in turn lead to other secondary bacterial infections, mainly Clostridium difficile infection (CDI). C difficile is inherently resistant to most groups of antibiotics, such as aminoglycosides, penicillins, cephalosporins, and fluoroquinolones, hence treatment options are limited. In this study, we aim to 1) estimate the effect of rotavirus vaccination on antibiotic prescribing 2) estimate the effect of rotavirus vaccination on CDI. We will conduct a large retrospective cohort study constructed from MarketScan databases. Analysis will be performed using longitudinal, individual-level data. These findings can provide evidence for national and international bodies for vaccine decision-making and antimicrobial resistance control strategies.
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| 30/11/2019 |
£232,239 |
HARVARD T.H. CHAN SCHOOL OF PUBLIC HEALTH |
Prioritizing vaccine development to focus on pathogens that drive the most antibiotic prescribing will have multiple advantages: reducing the burden of disease, reducing the extent of antibiotic use, and thus reducing the selective pressures driving antimicrobial resistance. In this proposal, we will (1) test the hypothesis that recent declines in outpatient antibiotic prescribing in the US are associated with reductions in pneumococcal disease attributable to PCV13 uptake and (2) estimate the antibiotic prescribing attributable to the most common pathogens and variation by age, demographic, and geography. To do so, we will use large representative nationwide datasets from the US, including insurance claims, public health surveillance, and a national immunization survey. The deliverables from this project will include estimates of the impact of PCV13 on outpatient prescribing and quantification of the expected reductions in antibiotic prescribing given vaccines for common pathogens. We expect that the results from these studies will establish (1) robust estimates of the reductions in outpatient antibiotic prescribing achieved by PCV13, as an exemplar of what vaccines can accomplish; and (2) priorities for vaccines to target in terms of impact on antibiotic prescribing and thus on antimicrobial resistance.
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| 30/11/2019 |
£237,892 |
UNIVERSITY OF LIVERPOOL |
Vaccination should reduce antibioticl prescribing (AP), the driver of antimicrobial resistance. Looking for reductions in Randomised Controlled Trials of vaccine is problematic as they are usually powered for large effect sizes of specific end-points. An alternative approach is to undertake observational studies using large routine data sources. The problem with this approach is ensuring major confounding is identified and accounted for when linking vaccine status and outcome and, demonstrating a causal relationship.
We will conduct an observational study using the Clinical Practice Research Datalink (2007-2019) and The Health Improvement Network (THIN) (2007-2019) from the United Kingdom. Our primary aim is to measure AM prescribing in adults over 65 and children under 5 by frequency of influenza vaccination.
We will use three complimentary approaches and different methods to adjust for confounding:
1 A Self-controlled case series – comparing annual AM prescribing within individuals by annual receipt of influenza vaccine and vaccine/pathogen match.
2 A Cohort study - balancing comparator populations using propensity scoring to control for major determinants of health care utilisation and underlying health status.
3 An Interrupted time series analyses – investigating paediatric influenza vaccine uptake (September 2013) and AM prescribing
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| 30/11/2019 |
£201,273 |
UNIVERSITY OF MANCHESTER |
Antimicrobial resistance (AMR) threatens public health and individual patient care. Gonococcal (GC) infection incidence has been increasing year on year for the last decade in the UK. AMR in GC infection is relatively low in the UK, but it has been increasing too.
We propose to develop, simulate and parameterise a model for Neisseria gonorrhoeae and Neisseria meningitidis circulation. Control of gonorrhoea is likely to become increasingly difficult due to widespread antibiotic resistance. While vaccines are routinely used for N. meningitidis, no vaccine is available for N. gonorrhoeae. Recent studies where meningococcal B (MenB) vaccine is given to adolescents reported a reduction in incidence rates of GC in those vaccinated, as the vaccine potentially offers some cross protection. Counterfactual scenarios can be investigated with a model (with potential uncertainty in outputs) to consider appropriate health economic evaluation.
Goals:
Develop a transmission model of GC and MenB infection for the UK
Investigate the cost-effectiveness of MenB vaccine in infants, adolescents and targeted at-risk populations in reducing MenB and GC infection incidence and AMR.
Investigate the potential impact in areas of low, medium and high incidence of GC infection and low and high level AMR in GC.
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| 30/11/2019 |
£678,619 |
AMSTERDAM INSTITUTE FOR GLOBAL HEALTH AND DEVELOPMENT |
Rotavirus is the most common aetiology of serious gastroenteritis in young children. Despite antibiotics not being indicated in its treatment, gastroenteritis remains a very common cause for antibiotic prescribing in low-income settings. We hypothesize that effective rotavirus vaccination can reduce diarrheal episodes and thereby unnecessary antibiotic usage in young children in low-income settings.
This study aims to evaluate the impact of rotavirus vaccination on antibiotic usage. Specifically, the study will quantify how differences in rotavirus vaccine efficacy impact days of prescription and non-prescription antibiotic usage in the first 2 years of life among two large cohorts of children in Zambia and Ghana.
The key goal is to understand the effect of rotavirus vaccine efficacy on antibiotic usage and household antibiotic costs. This will generate evidence needed to inform policy-makers seeking to introduce new rotavirus vaccines into national vaccination programmes, ofpotential, and often under-appreciated, secondary effects of rotavirus vaccine implementation on antibiotic usage.
This proposal will be conducted within a planned phase III randomised controlled trial comparing the efficacy of a new parenteral trivalent P2-VP8 subunit rotavirus vaccine to the oral live attenuated vaccine, Rotarix®, against severe rotavirus gastroenteritis in the first 2 years of life in Zambia and Ghana.
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| 30/11/2019 |
£179,852 |
UNIVERSITY OF NEW SOUTH WALES |
In high income countries the greatest use of antibiotics is in community (primary care) settings in the context of acute respiratory tract infections. Within these settings, both the very young, the very old and those with respiratory conditions such as asthma and chronic obstructive pulmonary disease are known to be the greatest antibiotic users. While there are a number of vaccines routinely provided that protect against acute respiratory tract infections, there is limited empirical data quantifying the potential benefit of vaccines to reduce antibiotic use for respiratory tract infections, particularly in adult populations.
In this project we will use a large-scale database of electronic general practice records to quantify, in older adults, the effectiveness of influenza, pertussis and pneumococcal vaccines in reducing primary care presentations for acute respiratory tract infections and subsequent antibiotic prescribing. We will focus on high risk groups defined by age and/or co-morbidity (asthma and chronic obstructive pulmonary disease). We will use these estimates of vaccine effectiveness to model the absolute reductions in antibiotic use that could be obtained by increasing vaccine coverage in different adult sub-groups. This evidence will enable policymakers to better prioritise strategies to increase uptake of these vaccines.
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| 30/11/2019 |
£404,673 |
MURDOCH CHILDREN'S RESEARCH INSTITUTE |
PCVs prevent pneumonia and invasive pneumococcal disease (IPD). The serotypes contained within PCV are those which carry most antimicrobial resistance (AMR). PCVs reduce the carriage of PCV serotypes, and also limit the use of antibiotics by preventing pneumococcal infections. In the US, the 13-valent PCV (PCV13) reduced childhood IPD AMR by > 75%. Despite a high pneumonia burden in Asia, very few countries have adopted PCV into their national immunisation programs. PCV may have a substantial role in reducing AMR and it is vital that the role of PCV in reducing AMR in this region is determined.
PCV introduction has also led to serotype replacement with serotypes that are not included in the vaccine (NVTs). It is therefore important to define pneumococcal population changes and identify emergent clones in the post-PCV era. In 2013, we commenced pneumococcal carriage surveillance in Laos in children aged 2- 59 months with acute respiratory infection (ARI). Our proposed study in Laos will:
a) determine the PCV13 effectiveness against AMR in pneumococcal carriage isolates;
b) determine the AMR and virulence of emerging NVTs; and
c) investigate using a life-like system the recombination frequency for the acquisition of resistance genes, and secondary chromosomal insertions, in pneumococcal NVTs.
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| 30/11/2019 |
£429,266 |
HARVARD T.H. CHAN SCHOOL OF PUBLIC HEALTH |
Vaccines against viruses can reduce antibiotic prescribing by reducing the incidence of viral infections that are inappropriately treated with antibiotics, as well as by reducing the incidence of secondary bacterial infections caused by viral infections. We will estimate the magnitude of this effect for influenza vaccination and the potential magnitude for Respiratory Syncitial Virus (RSV) vaccination and enhanced influenza vaccination. First, we willestimate the antimicrobial prescribing attributable to RSV and influenza in the Kaiser Permanente population in Northern California, USA, in total and by drug class and age group. Next, we will estimate the antimicrobial prescribing currently averted by influenza vaccination by comparing antimicrobial prescribing in (1) persons who have not received influenza vaccine vs. (2) persons who have, controlling for age and location within northern California, in aggregate and stratified by age and antimicrobial class. Using these results, we will estimate the number and proportion of antimicrobial prescriptions that may potentially be averted by improved influenza vaccines and (separately) by RSV vaccines that are now investigational, assuming various possible levels of coverage and effectiveness. Notable features of our analysis will be extensive measures to avoid confounding and an examination of waning of influenza prescribing effects with time since vaccination.
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| 30/11/2019 |
£239,190 |
UNIVERSITY OF VIRGINIA |
Diarrhoeal disease, caused by leading aetiologies of Shigella and rotavirus, is a major contributor to antimicrobial resistance (AMR) due to increasing incidence of drug-resistant episodes and frequent treatment with antibiotics. We propose to quantify the comprehensive impact of enteric vaccines in combating AMR by preventing drug-resistant diarrhoea episodes and reducing antibiotic use using data from the MAL-ED study, a longitudinal birth cohort conducted in 8 low-resource sites. Specifically, we will: 1) quantify the incidence of antibiotic use and of antibiotic exposure to subclinical enteric infections that is attributable to the treatment of aetiology-specific diarrhoea episodes, 2) estimate reductions in the incidence of aetiology-specific diarrhoea and antibiotic exposure achievable by vaccines against Shigella, rotavirus, and other enteric pathogens, and 3) estimate the worldwide impact of enteric vaccine introduction on aetiology-specific diarrhoea, antibiotic use, and antibiotic exposure to subclinical infections using data from Demographic Health Surveys and Multiple Indicator Cluster Surveys. These results will generate precise estimates of enteric vaccine impact, most importantly for Shigella vaccines, which have been prioritized for development, and for rotavirus vaccines, which continue to be adopted globally. These quantitative estimates will inform advocacy efforts for continued support and provide relevant data for comprehensive analyses of cost-effectiveness.
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| 30/11/2019 |
£193,863 |
UNIVERSITY OF SHEFFIELD |
Typhoid fever is a common cause of non-specific febrile illness in low-resource settings. Empirical treatment for typhoid may be a major driver of AMR in typhoid-endemic communities, where estimates suggest that up to 25 additional cases receive antimicrobial treatment for each one confirmed. Harare in Zimbabwe has experienced a major increase in typhoid since 2016, with recent emergence of ciprofloxacin-resistance. In February 2019 a mass typhoid vaccine campaign was performed, targeting infants and children living in 9 affected suburbs with the new typhoid conjugate vaccine (TCV). In work being performed at primary health clinics in these densely-populated suburbs as part of the FIEBRE study, which aims to assess the causes of febrile illness in low-resource settings, we have already identified a significant reduction in typhoid in vaccinated children. In this project our key goals are to investigate the impact of the 2019 mass TCV campaign on antimicrobial resistance in S. Typhi and on antimicrobial prescribing and related practices in community clinics. Defining these effects will have major policy implications for TCV use, both locally, in determining the benefits of further routine/repeat vaccination, and internationally to inform estimates of the direct and indirect impacts on AMR infection and antimicrobial use.
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| 30/11/2019 |
£193,504 |
BIOMEDICAL RESEARCH & TRAINING INSTITUTE, HARARE |
Typhoid fever is a common cause of non-specific febrile illness in low-resource settings. Empirical treatment for typhoid may be a major driver of AMR in typhoid-endemic communities, where estimates suggest that up to 25 additional cases receive antimicrobial treatment for each one confirmed. Harare in Zimbabwe has experienced a major increase in typhoid since 2016, with recent emergence of ciprofloxacin-resistance. In February 2019 a mass typhoid vaccine campaign was performed, targeting infants and children living in 9 affected suburbs with the new typhoid conjugate vaccine (TCV). In work being performed at primary health clinics in these densely-populated suburbs as part of the FIEBRE study, which aims to assess the causes of febrile illness in low-resource settings, we have already identified a significant reduction in typhoid in vaccinated children. In this project our key goals are to investigate the impact of the 2019 mass TCV campaign on antimicrobial resistance in S. Typhi and on antimicrobial prescribing and related practices in community clinics. Defining these effects will have major policy implications for TCV use, both locally, in determining the benefits of further routine/repeat vaccination, and internationally to inform estimates of the direct and indirect impacts on AMR infection and antimicrobial use.
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| 30/11/2019 |
£453,415 |
UNIVERSITY OF EDINBURGH |
Vaccines can, in principle, alleviate antibiotic resistance by preventing infections and reducing the need for antibiotic use. However, the impact of pneumococcal conjugate vaccines (PCVs) on antibiotic resistant disease is unclear because resistance in non-targeted serotypes is increasing and we do not understand the mechanisms driving this phenomenon. To overcome this issue , we have assembled a multidisciplinary team to leverage an ongoing three-year Phase IV cluster-randomised PCV trial in Vietnam which will provide unparalleled predictive power to calculate the long-term consequences of PCV on resistant infection. First, we will develop a suite of novel bioinformatics tools to determine antibiotic susceptibility using deep sequence data that will allow us to evaluate both the dynamic changes in antibiotic resistance in the three years following PCV introduction and, for the first time, the frequency of resistant–sensitive strain co-colonisation. Second, we will analyse surveys to evaluate the longitudinal impact of PCV on antibiotic use. Third, we will integrate these results into a mathematical modelling approach to disentangle the mechanisms driving pneumococcal resistance. We will use this calibrated model to predict the long-term effect of PCV on pneumococcal resistance. Our results will, for the first time, accurately predict the wider health impact of PCVs.
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| 30/11/2019 |
£31,008 |
WELLCOME TRUST SANGER INSTITUTE |
Vaccines can, in principle, alleviate antibiotic resistance by preventing infections and reducing the need for antibiotic use. However, the impact of pneumococcal conjugate vaccines (PCVs) on antibiotic resistant disease is unclear because resistance in non-targeted serotypes is increasing and we do not understand the mechanisms driving this phenomenon. To overcome this issue , we have assembled a multidisciplinary team to leverage an ongoing three-year Phase IV cluster-randomised PCV trial in Vietnam which will provide unparalleled predictive power to calculate the long-term consequences of PCV on resistant infection. First, we will develop a suite of novel bioinformatics tools to determine antibiotic susceptibility using deep sequence data that will allow us to evaluate both the dynamic changes in antibiotic resistance in the three years following PCV introduction and, for the first time, the frequency of resistant–sensitive strain co-colonisation. Second, we will analyse surveys to evaluate the longitudinal impact of PCV on antibiotic use. Third, we will integrate these results into a mathematical modelling approach to disentangle the mechanisms driving pneumococcal resistance. We will use this calibrated model to predict the long-term effect of PCV on pneumococcal resistance. Our results will, for the first time, accurately predict the wider health impact of PCVs.
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| 26/11/2019 |
£209,673 |
LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE |
The aim of the public engagement programme is to improve youth engagement with health services and to have them as active partners in design and delivery of health interventions. We aim to utilize a crowdsourcing approach where a large group of individuals attempt to solve a problem, and share solutions with the public, to identify solutions to overcome barriers to engagement with health services. We will organize a national contest for 16-24 year olds in Zimbabwe, soliciting entries in three artistic categories: 1) music 2) drama and 3) visual images, specifically themed on how to improve engagement of youth with health services. We will hold a national festival where entries will be showcased. Winning entries will then be implemented within my Wellcome Trust funded trial (CHIEDZA) that is evaluating community-based provision of HIV and sexual and reproductive health services for youth. We also run a Youth Researcher Academy to train youth researchers who will then conduct mentored research projects to evaluate the CHIEDZA intervention. Findings will help improve the configuration and delivery of the intervention.
The project will be delivered in partnership with local community-based organisations and other key stakeholders. Our team combines expertise in research with youth, leaders in the arts in Zimbabwe and experts in crowdsourcing and process evaluation. The project will be evaluated and lessons learnt will be shared with stakeholders through a variety of channels. The project will provide a framework for youth engagement that can be used in other areas of health and research.
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| 26/11/2019 |
£189,632 |
IMPERIAL COLLEGE LONDON |
An estimated 1.07 million people in Vietnam are infected with hepatitis C virus (HCV). In the ‘VIETNARMS’ trial, we are investigating the efficacy of HCV treatment strategies that could be used to treat underserved populations (e.g. ultrashort or intermittent therapy). Should these strategies have efficacy as hoped, it will be crucial to develop innovative ways to engage with underserved populations. We propose a ‘bottom up’ approach using community based participatory research (CBPR) to explore barriers to HCV care and to determine what actions must be taken to improve engagement with these populations at risk for HCV.
In this project, we will first conduct stakeholder mapping of organizations working with populations at risk for HCV and create two advisory groups, one at the NGO level and the second at the community level. Next, we will conduct CBPR with 3-5 communities in Ho Chi Minh City over the course of one year. Using CBPR methods, we will work with communities to identify barriers, facilitators, and health priorities related to HCV, as well as design and implement strategies to overcome the problems identified in each group. We will hold dissemination meetings in the communities where CBPR took place, with the local advisory groups, and with regional stakeholders to determine how to integrate dialogues from underserved communities at risk for HCV into larger policy conversations centering on HCV care and treatment. The questions raised and strategies implemented in the communities could also inform future operational research questions within our context.
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| 26/11/2019 |
£11,900 |
INTERNATIONAL CENTRE OF INSECT PHYSIOLOGY AND ECOLOGY |
The Research Enrichment activity will involve a participatory health education to increase awareness and encourage good practices related to the prevention and control of malaria and other vector-borne diseases in Samia sub-county, Busia County in western Kenya. Activities will be coordinated by the International Centre of Insect Physiology and Ecology (icipe) in collaboration with local health and education authorities. Activities will start with engaging school teachers, community health volunteers and parents in open space meetings to discuss and explore community perceptions and issues related to vector-borne diseases, and suggestions for improved control. Participants in open space meetings will be purposively selected from communities where the on-going study is implemented. Issues raised in open space discussions will inform development of action plans for the health education targeting children aged 12-15 selected from at least 12 schools from the study area. Practical demonstrations will include the use of traps for vector surveillance, dippers in aquatic habitats and screening for malaria parasites. Initially, children will be taught about biology of common vector-borne diseases, their prevention and control, using fun and interactive approaches. The participatory health education will culminate into World Mosquito Day on Thursday, 20 August 2020, where the children will participate in the dissemination of information related to prevention and control of vector-borne diseases using entertaining techniques. In groups, the children will develop their own relevant disease-themed projects, such as drama, for presentation. This exercise is aimed at encouraging participants to be messengers of good practices to improve control of vector-borne diseases.
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| 26/11/2019 |
£18,596 |
CARDIFF UNIVERSITY |
Gwyddoniaeth wrth y tân (Fireside Science) aims to promote open dialogue and mutual understanding between non-clinical NHS staff and academic scientists in Wales. Welsh NHS staff are a vital link between the kind of projects funded by Wellcome and translational outcomes in the clinic. However, the 37,000 non-clinical Welsh NHS staff are not directly involved in research and may question any investment therein when the NHS is under-resourced.
This project draws on the traditional Welsh culture of storytelling, using it as a means to facilitate conversations between non-clinical NHS staff and scientists about their working lives. A 2-day workshop for 20 scientists and NHS staff will teach transferable communication and storytelling skills. The workshop will culminate with 20 short 10-minute conversational recordings between, a scientist and a member of NHS staff.
Audio content will be disseminated via three routes: for time-poor NHS staff, podcasts will be available to the general public on standard podcast platforms, promoted via NHS newsletters and targeted social media. Audio recordings will also be released to the Welsh Community Radio Network. Finally, audio recordings will be used in a travelling installation hosted in hospital atria and National Museum sites across Wales. The installation will be themed around a traditional Welsh miner’s front room, with two armchairs using speakers in the headrests to deliver audio, alongside a fireplace and a lamp. The concept will engage NHS staff with human stories about science and healthcare in Wales in a comfortable and welcoming environment.
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| 26/11/2019 |
£66,550 |
BOOTS UK LTD |
Boots Archives would develop a well-researched, high quality travelling exhibition to promote awareness of this now publicly accessible collection. Located in Boots stores this display would engage with new audiences and challenge people's perceptions of the relevance of corporate archives. The exhibition would appear in 25 flagship Boots stores across the country during a seven month tour. The installation would use material from the archive to illustrate changes in community pharmacy. By using the Boots collection as a discussion tool, I aim to show that the value of corporate archives goes beyond their originating organization, providing a long-view on social issues. The exhibition, in illustrating the developments in pharmacy services, would seek to understand people's attitudes towards the role which community pharmacy plays in providing healthcare services in the UK today. Content would be drawn from recent research and I would work with an academic and museum professionals to create a visually engaging and stimulating display. The exhibition would aim to draw comparisons between the role of Victorian pharmacists and the current NHS positioning of retail pharmacists as the first point of contact for minor ailments. By demonstrating the extent to which pharmacist diagnosis was common practice prior to the inauguration of the NHS in 1948, it is hoped that this installation will raise questions and gauge opinions on the current and future role of community pharmacy.
Additional events would be held in Nottingham which would include a community screening of pharmacy related archive footage and public talks.
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02076118888
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Giving is Great
