NIHRDataInsights/HRCSData huggingface dataset:
Title: Identifying the mechanisms of persistent mTORC1 in senescence
Funder: Wellcome Trust

Abstract: Cellular senescence is an established mediator of cellular and organismal ageing and clearance of senescent cells can extend healthspan and lifespan in mouse models. Senescence is defined as an irreversible exit from the cell cycle; these cells however maintain robust activation of the master growth regulator, mTORC1. My previous work identified that mTORC1 becomes unresponsive to the removal of nutrients in senescence, supporting increased cell size and production of inflammatory cytokines. My project aims to identify new insights into nutrient-dependent mTORC1 signalling and how it is altered in senescence. I will specifically test the hypothesis that mTORC1 is supported by amino acids liberated via an increase in lysosome activity. Inhibition of mTORC1 and lysosomal degradation can cause senescent cell death suggesting the rewiring of cellular metabolism is essential for cell survival. A better understanding of the biology of senescence could therefore help identify new interventions to eliminate these cells and promote healthy ageing.

Lay abstract: Due to improvements in diet, sanitation and medicine, we are living longer, healthier lives. However, our ageing population represent some of the most significant biomedical, social and economic challenges in Western society. Understanding how we age is essential to develop interventions improve healthy ageing. Most cells are constantly growing and dividing but over time, as a result of stress and damage, there is an accumulation of non-dividing cells, called senescent cells that contribute to ageing. Growth pathways are still active in senescent cells making them bigger and producing inflammatory proteins and this is because they lose the ability to sense the availability of nutrients. My project aims to use senescence to better understand how healthy cells sense and respond to nutrients, how it goes wrong in ageing and whether we can use this knowledge to eliminate senescent cells and improve healthspan.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: The INSPIRE network: Building a data science platform
Funder: Wellcome Trust

Abstract: 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.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: Chromatin re-organisation at the transition from mitosis to G1: how phospho-switches regulate the process in space and time
Funder: Wellcome Trust

Abstract: Reversible protein phosphorylation is the most used regulatory mechanism adopted by cells and cell division (mitosis) heavily relies on this. Protein phosphatases are inactivated at the beginning of mitosis and must be re-activated at its end to produce viable products. My study will focus on Protein Phosphatase1 (PP1) complexes: Repo-Man/PP1, PNUTS/PP1 and Ki-67/PP1. This choice has been made based on studies conducted in my laboratory where we have identified the complexes important for nuclear structure and chromatin organisation in mitosis. The aim of this investigation is to provide the first integrated picture of the role of PP1 at the Mitosis-G1 transition, thereby filling crucial knowledge gaps in the field of mitotic exit. By combining genetic, biochemistry and cell biology, I will identify the main substrates of these complexes during mitotic exit, how they modify chromatin architecture and their mitotic and non-mitotic roles. The data obtained from this project will generate essential information on the G1 nucleus re-establishment network. The identification of substrates, their de-phosphorylation order and biological consequences, will pave the path towards modeling the cascade of events that drive mitotic exit execution and explain how cellular homeostasis is maintained.

Lay abstract: To support the wellbeing of an organism and the perpetuation of life, cells must conduct specific tasks in a very controlled manner. Lack of these controls will generate either birth defects or diseases. One way used by cells to execute these controls is via transient changes in the behaviour of molecules. One example of these changes is the addition/removal of phosphates (phosphorylation/de-phosphorylation) where a molecule will be functioning or non-functioning according to this modification. My research will identify how the molecules that remove these phosphates (called phosphatases) can change the behaviour of the genome during cell division. Besides representing a major advance in cell biology, it will also provide translational potential. For example, some of these phosphatases are emerging as important candidates in different diseases; the knowledge of their mechanism and site of action could be used for designing drugs in specific conditions linked to their dysfunction.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Global Health Chemical Diversity Library V2
Funder: Wellcome Trust

Abstract: The Drug Discovery Unit, University of Dundee, UK (DDU) is working with Wellcome, the Bill & Melinda Gates Foundation and other partners including AMG (library selection), Enamine (virtual compound design, synthesis), and DNDi, MMV (triaging known pharmacophores), to build a high quality diversity library of 30,000 novel compounds to initiate drug discovery projects. Multiple organizations are constantly seeking new chemical matter to screen against priority pathogens, due to low hit rates and high attrition following up screening campaigns. This library selected from Enamine’s REAL (REadily AccessibLe™, https://enamine.net/compound-collections/real-compounds) 21 billion virtual compounds, will add to the ongoing process. This set’s advantage is that all the library structures will be novel and shared, unlike many screens using donated compound sets, so all structures can be used to analyse the resulting data and are available without reach through for exploitation by partners carrying out screens.


Research activity codes: 5.1 PHARMACEUTICALS;5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: GENERIC HEALTH RELEVANCE
Title: Orphan drugs: high prices, access to medicines and the transformation of biopharmaceutical innovation
Funder: Wellcome Trust

Abstract: "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?

Lay abstract: "Orphan drugs" are a class of medicines that treat rare diseases. They are growing rapidly, highly profitable, attracting massive investment from the biopharmaceutical industry and stimulating new business models based on high cost products for niche markets. The very high price of some orphan drugs has led several countries, including the UK, to refuse to pay for them. This has provoked controversy and growing political concern that patients are being denied access to life saving therapies due to cost. A major international debate on how best to improve access is ongoing. This project is innovative in developing a new concept, “orphanisation”, to understand the technical, political and regulatory changes associated with orphan drugs. It will ask to what extent is orphanisation occurring in the UK and USA, how is it being shaped by different technologies, institutions and stakeholders, and what are the implications for industry, health policy and patients?

Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Endosomal sorting: deciding the fate of surface membrane proteins
Funder: Wellcome Trust

Abstract: Membrane proteins destined for lysosomal degradation are ubiquitinated within the endosome and then sorted into intralumenal vesicles (ILVs), to form the multivesicular body (MVB). This critically important process is exemplified by the sorting of EGF receptor (EGFR). MVB sorting requires ESCRTs (Endosomal Sorting Complexes Required for Transport). ESCRTs collectively recognise ubiquitinated EGFR on the cytoplasmic face of the endosome and capture it within ILVs, whilst they escape. Towards understanding how ESCRTs overcome this topological problem, we will reconstitute the process. We have identified all those ESCRTs that drive EGFR sorting, and how they bind each other. We will now reconstitute MVB sorting, using proteoliposomes containing EGFR and exploiting our full complement of baculovirus-expressed ESCRTs. We will use site-directed photo-crosslinking to map the entire process biochemically, and will complement this with further in vitro analysis of the molecular architecture within the developing ILV. Key conclusions will be verified in cells. Current ideas suggest ubiquitination is the determining factor for EGFR sorting. However, we believe instead that EGFR signalling-dependent activation of ESCRTs is decisive. We will systematically identify ESCRT post-translational modifications (PTMs) that map with MVB sorting, and test using both reconstituted proteoliposomes and in cells how these PTMs control the pathway.

Lay abstract: Plasma membrane proteins destined for degradation are internalised, enter the endosome, and then transit to the lysosome. Many crucial proteins follow this pathway, with epidermal growth factor receptor (EGFR) an exemplar because of its biological and biomedical importance. EGFR transport to the lysosome requires a crucial event; the receptor is ubiquitinated and then enters membrane vesicles that bud into the lumen of the endosome, to form the multivesicular body. The molecular machinery that drives multivesicular body formation must overcome a complex topological problem: it recognises ubiquitinated EGFR on the cytoplasmic face of the endosome, generates vesicles that capture EGFR inside the endosome, but escapes itself. How this works remains mysterious, but we aim to solve it. We will reassemble the machinery from its component parts on artificial endosomes, and dissect biochemically how it envelops EGFR. We will also examine how the machinery is activated by EGFR, ensuring EGFR’s efficient capture.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Optimising pharmacometric assessment in phase 2 studies of Chagas disease
Funder: Wellcome Trust

Abstract: 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.

Lay abstract: We aim to develop and validate a methodology for phase 2 assessments of new drugs to treat Chagas disease based on parasite clearance dynamics estimated from serial qPCR. This will provide a platform for the assessment of new drugs currently in development in the HIT NTD Wellcome flagship. The use of parasite clearance as a phase 2 endpoint and the utility of antibody and other biomarker measurements will be validated through meta-analysis of all available long-term follow-up studies in Chagas disease. The major components and aims of the project are: 1. Build a data platform to facilitate meta-analysis of all existing clinical trial on short-term and long-term drug efficacy; 2. Characterise the major determinants of long-term cure in Chagas disease; 3. Develop a within-host pharmacodynamic model of infection that can be used to infer dose-response curves in phase 2 trials from serial qPCR measurements of circulating parasite densities; 4. Optimise the PCR sampling and pilot the use of serial qPCR to determine dose-response curves in adults and children, with proof-of-concept applied to the three main drugs with known anti-parasitic activity: benznidazole, nifurtimox and posaconazole; 5. Characterise the utility of deep sequencing to assess cure and distinguish reinfection from recrudescence in endemic areas. This work will be carried out by a multi-disciplinary group of experts in clinical Chagas disease research, clinical pharmacology, mathematical modeling and genomics.

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE
Title: The Biosocial Lives of Birth Cohorts
Funder: Wellcome Trust

Abstract: 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.

Lay abstract: Research that follows participants and their families throughout their lifetimes, known as birth cohort studies, are important for understanding how human biology and our environment – including social experiences and exposures to substances in our environment – interact, and how they affect our health or well-being. Researchers refer to this as biosocial research. This four year project will be one of the first social science studies to examine birth cohorts across different national contexts, including the UK, Europe and Latin America. I will examine (a) how and why birth cohorts are sites of biosocial knowledge, (b) the practices that produce birth cohorts and biosocial science and (c) the meaning and consequences for cohort research participants. Findings from my project will help to better understand the role of birth cohort studies for science in diverse national contexts, and to develop new ways for social, medical and life scientists to work together.

Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: LivingBodiesObjects: Technology and the Spaces of Health
Funder: Wellcome Trust

Abstract: 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.

Lay abstract: LivingBodiesObects is a project that asks how health research is undertaken: what are the assumptions that govern how the work proceeds?; who decides how to start, and where and when?; why are certain ideas privileged and who gains from this? Leadership and Management: we want to address the above by moving away from the usual top-down model through which research is often led and managed. Instead, we want to share the design and participation between academic researcher and our project partners, This will give us a better understanding of how health research happens. It will also be more equal for all involved and help participants in thinking about their own health experiences. Vision: our plan is to explore the above questions by setting up physical and virtual spaces in which academics and non-academics come together to share and investigate ideas and opinions on health, using new technologies in particular.

Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS;1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Mitochondrial DNA maintenance, propagation and disease
Funder: Wellcome Trust

Abstract: Thousands of copies of the mitochondrial genome (mtDNA) are maintained by each cell. Their replication and equal distribution around the cell is required for the generation of functional respiratory chains. Failure of these processes results in impaired energy transduction, leading to human metabolic disease. The molecular mechanisms of mtDNA replication termination and subsequent segregation are an unexplored field of research, with my recent work having identified the first factor involved, Top3alpha. My proposed project aims to understand how DNA is separated and segregated in human mitochondria, and how this impacts upon bioenergetics and mitochondrial disease. My first aim is to study how mtDNA replication is terminated, by biochemically determining the identity and genomic location of the resolution structure. My second aim is to identify the machinery that resolves replicated mtDNAs using proximity biotinylation, immunoprecipitation and mass spectrometry. The roles of these factors may then be characterised. The third aim is to reconstitute this reaction in vitro in order to dissect the resolution process biochemically. Mitochondrial genetic diseases frequently exhibit mtDNA instability and clustering of mitochondrial genomes, suggesting that mtDNA segregation defects contribute to disease states. My fourth aim is to study the contribution of mtDNA segregation to human mitochondrial disease.

Lay abstract: Human cells contain two sources of DNA: the nucleus and the mitochondrial genome (mtDNA). mtDNA is essential to life, as it is required for the respiratory chain, which produces the vast majority of the cell's utilizable energy. A cell requires thousands of identical copies of mtDNA, which must be replicated, separated, and distributed evenly around the cell. Defects in either mtDNA replication or distribution impair respiration, leading to human mitochondrial diseases. I aim to understand the molecular mechanisms of mtDNA replication termination in human cells: how mtDNA is resolved, and how this leads to efficient distribution around the mitochondrial network. I will study how, and when, mtDNA molecules are untangled during replication, and identify the factors involved. I will also study the contribution of mtDNA segregation to mitochondrial diseases and the formation of mtDNA deletions. These studies aim to link together basic mechanisms of mitochondrial genetics, bioenergetics, and human disease.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE