NIHRDataInsights/HRCSData huggingface dataset:
Title: Using chemical biology to understand the roles of glycans in human health and disease
Funder: The Francis Crick Institute

Abstract: Glycans are among the most abundant classes of biomolecules and key to essential physiological processes. As secondary gene products, glycans are not directly genome-encoded and their biosynthesis is refractory to most current methods of quantitative biology. We develop chemical “precision tools” to probe the contribution of glycans to physiology. In our laboratory, glycosyltransferases are rationally engineered to accommodate chemically modified substrate analogues instead of their native substrates. These analogues comprise a chemical tag that is traceable by the use of bioorthogonal “click” chemistry after incorporation into cell surface glycoproteins. We demonstrate the approach on the largest human glycosyltransferase family, the polypeptide N-acetylgalactosaminyl transferases (GalNAcT). Priming abundant mucin-type O-glycosylation, the 20 GalNAcT isoenzymes are associated with tumorigenesis in an isoenzyme-dependent manner. However, redundancy in their activity hampers traditional approaches of molecular cell biology to understand isoenzyme substrate specificity. Ben Schumann has developed a strategy to deliver chemically modified nucleotide-sugar substrates to the living cell to be used by engineered GalNAcT mutants (1, 2). The approach displays complete selectivity for engineered over wild type GalNAcTs. Chemically tagged glycans retain elaboration by downstream-acting glycosyltransferases, enabling for the first time an association between glycoprotein identity, glycosylation site and glycan structure within a single experiment. Preliminary data suggests that the strategy is universal and can be applied to any GalNAcT. Currently, our research is focused on developing chemical precision tools to understand the specificities of uncharacterized, but physiologically important GalNAcTs. Together with the Proteomics Science Technology Platform, we are in the process of establishing a needed glycoproteomics workflow at the Francis Crick Institute to aid in this endeavor. Further, we are generating a library of chemically modified nucleotide-sugars to be used by certain glycosyltransferases with great specificity. Thereby, we hope to identify substrates that are specific to certain glycosylation pathways and may yield tools that do not require glycosyltransferase engineering. With our new proteomics workflow and other applications to be established at the Crick, including light microscopy and single cell knockout experiments, we will shed light on some of the most important types of protein glycosylation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Reorganization of Genomes by Molecular Forces
Funder: The Francis Crick Institute

Abstract: In order to grow and divide cells organize themselves in space and time. Three-dimensional molecular rearrangements are especially important for DNA because gene expression and repair as well as mechanisms that pass genomes from one generation to another critically depend on DNA rearrangement in space. At the molecular level, these rearrangements are driven by combination of motor and non-motor proteins that generate and respond to mechanical forces. Mutations in molecules that segregate and reorganize DNA cause developmental disorders and disease. Therefore, we aim to understand the fundamental principles underlying DNA segregation and DNA rearrangements and their physical mechanisms. In order to understand mechanisms underlying these rearrangements, we need to understand how they work at the level of individual molecules and because these mechanisms are mechanical in nature, physical forces involved in rearrangements. The progress in this field has been largely limited by tools that would allow observation of single-molecule real time dynamics and simultaneously include mechanical force as a physical parameter. To address this challenge, we use a combination of single-molecule microscopy, force spectroscopy, molecular biology and biochemistry and develop new single-molecule methods. Our research is focused in two directions: mechanisms underlying microtubule generated forces and DNA segregation. In the first area, we recently discovered that microtubule tip binding proteins can harness force generated by microtubule dynamics and lead to cytoskeleton rearrangements required for cell mating and cell division. Understanding molecular details of these mechanisms is important because tip binding proteins are implicated in key mechanistic processes such as mitotic spindle positioning, chromosome segregation, mating and cell growth. Therefore, we are investigating how tip binding proteins use forces generated by microtubules and control microtubule dynamics at single molecule level. In the second area, we investigate how DNA-DNA interactions resist forces generated by mitotic spindle. Sister chromatid cohesin is mediated by cohesin protein complex and we recently discovered that cohesin can fold DNA and unravelled the molecular mechanism, which suggested that cohesin is a molecular motor, which can compact DNA. We are investigating further physical forces associated with cohesin interacting with DNA and its conformational changes as it undergoes loading and unloading from DNA. Ultimately, we would like to discover both the mechanistic principles underlying DNA segregation and rearrangements, understand the differences in these mechanisms between different types of cells and how these are affected in disease at molecular level.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: HDR UK Site Project - Applied Analytics
Funder: Medical Research Council

Abstract: This work is funded by the UKRI Medical Research Council, UKRI Engineering and Physical Sciences Research Council, UKRI Economic and Social Research Council, National Institute for Health Research (England), Chief Scientist Office (Scottish Government), Health and Care Research Wales, Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome Applied Analytics: We will match expert knowledge of new analytical tools such as machine learning and artificial intelligence with large-scale health datasets to demonstrate the power of these approaches to inform health and care delivery. Led by Professor Chris Holmes, HDR UK Health Data Science and AI Lead The challenge There are innovators in the NHS, universities and business with great ideas to improve patient outcomes, experience, and efficiency of healthcare services. However, innovators often find it unnecessarily difficult to access health data, whereas the people who are accessing the data, often don’t have the skills or support to innovate. In cases where this disconnect has been fixed, the arrangements don’t always stream the benefits back into the NHS as much as they should. Our approach We are facilitating people with the right skillsets to develop useful and reliable medical apps for the public, doctors and healthcare centres to use to enhance use of services and outcomes for patients. We are helping them to gain access to the data they need to do this, in a way that protects that data, maintains the anonymity of patients, and allows innovation. We make sure that the innovations we support directly benefit the NHS and have UK-wide reach across the four nations. We’ll create an environment that empowers innovators to the UK population healthier though the creative and secure use of health data. Our output High-quality, useful and reliable apps for the public, doctors and health centres (e.g. hospitals, GP surgeries) to use to improve healthcare and outcomes in the NHS.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: HDR UK Site Project - Better Care
Funder: Medical Research Council

Abstract: This work is funded by the UKRI Medical Research Council, UKRI Engineering and Physical Sciences Research Council, UKRI Economic and Social Research Council, National Institute for Health Research (England), Chief Scientist Office (Scottish Government), Health and Care Research Wales, Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome Better Care: Health Data Research UK's Better Care programme aims to improve people’s lives by equipping clinicians and patients in the UK with the best possible data-based information to make decisions about their care. Led by Simon Ball, HDR UK Better Care Lead in Birmingham Our approach We support the development of learning healthcare systems that integrate clinical practice, large scale data and advanced analytics in a cycle of continuous improvement by: • Systematically gathering real-world data about patients’ treatment, experience and outcomes within the setting of routine care • Collating and providing access to large scale data in a format that is analysis-ready • Using advanced analytics to derive generalisable evidence and provide critical insights into healthcare delivery • Developing data-driven tools that make these insights actionable by clinicians and patients when they are making decisions about their care • Implementing tools to support personalised decision making by clinicians and patients at the point of care • Gathering data to manage the quality, safety and efficiency of care delivery, underpin research, and generate new insights that can continuously improve decision-making by clinicians and patients Our focus is on answering the research questions necessary to achieve these goals and seeking solutions that can be implemented at scale across the health and care system.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: HDR UK Site Project - Human Phenome
Funder: Medical Research Council

Abstract: This work is funded by the UKRI Medical Research Council, UKRI Engineering and Physical Sciences Research Council, UKRI Economic and Social Research Council, National Institute for Health Research (England), Chief Scientist Office (Scottish Government), Health and Care Research Wales, Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome Human Phenome: HDR UK will drive forward The Human Phenome project – applying the science of measurement to robustly and reproducibly characterise all aspect of human health and disease. Led by Professor Cathie Sudlow, HDR UK Scotland, and Professor Harry Hemingway, HDR UK London Unlike other research disciplines that have taken advantage of the power of large scale data – be that the Human Genome Project or particle physics enabled by CERN – the study of human health characteristics (the phenome) is significantly hindered by the lack of a well-curated resource for researchers and clinicians to deposit algorithms, tools, methods and training material required to reproducibly interpret complex health data. To address this, HDR UK will create a critical mass of data scientists, engineers and health data researchers to develop an online open-access, standards-driven library of complex health and disease characteristics (phenotypes) from diverse health data. This will significantly reduce duplication of effort and will be essential to the delivery of health research at scale.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Study of queuosine salvage and function in eukaryotes; a forgotten micronutrient
Funder: Medical Research Council

Abstract: Queuine is the only micronutrient that directly affects translation efficiency and accuracy in eukaryotes, with roles in metabolism and healthy-aging of the brain (Fig. 1). It is a precursor of the tRNA modification Queuosine (Q) and is exclusively retrieved from ingested food or provided by the gut microbiota1. The Q modification is found at the wobble base (position 34) of cytoplasmic and mitochondrial tRNAs for the amino acids Tyr, Asp, Asn and His. Absence of Q in tRNAs of mice or human HepG2 cells lowers biopterin (BH4) pools and leads to serious tyrosine metabolic defect and eventually death2, highlighting the importance of Q in mammalian physiology. Cognisant of the fact that tRNA of rapidly-proliferating cells is hypomodified with respect to Q, chemical analogues have been developed that induce complete remission of multiple sclerosis in an animal model3. The realization that tRNA modifications are associated with neurological and mitochondrial diseases4–6 has led to renewed interest and in the biosynthesis and function of Q1. A common goal of the Crécy and Kelly laboratories is to characterize the Q synthesis pathways and explore the functional importance of this modification in all kingdoms of life, leading to 15 publications and laying the groundwork for this proposal. The bacterial Q synthesis pathway and the human tRNA Q addition enzyme, tRNA-guanine transglycosylase (hTGT), are well characterized7,8. However, many gaps in knowledge of eukaryotic Q metabolism remain1. These include unknown transporters, hydrolases and sugar transferases. The lead PIs have gathered a multidisciplinary team taking advantage of the US-Ireland R&D Partnership, where funds are provided by each jurisdiction for their investigations (see commitment letters), to identify the “missing” human players in Q biosynthesis and elucidate the biologicalrole of this overlooked micronutrient in metabolism and neuronal function.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: The Avon Longitudinal Study of Parents and Children (ALSPAC): A multi-generation, longitudinal resource
Funder: Medical Research Council

Abstract: "ALSPAC is a multi-generation (G0/G1/G2), prospective cohort based in the UK [1-4] (supplementary information, Figure 1). This proposal seeks support to: - Maintain the existing samples and data resources. - Enhance visibility and access to data and samples. - Maximise linkage opportunities through broad and innovative use of administrative records. - Expand the resource by maximising recruitment and retention, and collecting new data and samples on original parents (G0), index participants (G1) and the next generation (G2). Work will be delivered via an efficient operational and governance infrastructure. We will deploy a combination of face-to-face assessment, biosample collection and analysis, remote data collection and administrative record linkage where the value of this activity is substantially enhanced by existing resources. All proposed work has been designed according to the overarching principles of (i) scientific utility and (ii) engagement/recruitment/retention. Study activities draw on experience from previous ALSPAC activity and consultation with participants and academics through bespoke workshops. Scientific focus reflects ALSPAC strengths and our target science areas, namely: The antecedents of cardiometabolic/cognitive/mental health, cross-generation contributions to health and era specific contributions to health, well-being and society."


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Nucleic Acid Therapy Accelerator (NATA)
Funder: Medical Research Council

Abstract: The Nucleic Acid Therapy Accelerator (NATA) was funded to unlock the potential of precision genetic medicines by enabling state-of-the-art interdisciplinary research partnerships to solve critical issues in the development of these drugs. This will be an internationally unique resource, bringing together world-leading academic expertise with innovative businesses in carefully targeted public-private partnerships. NATA will capitalise on the UK’s industrial and research centres to create partnerships between academia, large pharma, biotechs, and firms with disruptive physical science technologies. The partnerships will exploit cutting-edge physical science technologies to discover and test viable ways of delivering high reward nucleic acid therapy. Located on the Harwell Campus near Oxford, NATA Hub will exploit, and contribute to, the local world class scientific talent and scale-up ecosystem. The long-term objectives and anticipated effects of the NATA programme centre around: a) Promote the development of nucleic acid therapies b) Catalyse industry engagement and leverage investment in the area of nucleic acid therapies The initial investment in the Nucleic Acid Therapy Accelerator (NATA) is funded in the region of £30m in total. With some of the funds assigned to the Hub and at least two research funding calls where we will work with academia and commercial entities.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: UKRI trusted and connected Data and Analytics Research Environments, Phase 1
Funder: Medical Research Council

Abstract: The UK Trusted and Connected Data and Analytics Research Environments, Phase 1 project involves an extensive scoping phase (""Design and Dialogue"") to define the socio-technical requirements for a novel national federated digital infrastructure to establish the next generation of Trusted Research Environments (TREs) (i.e. secure, cloud-enabled environments for advanced analytics) - where researchers can safely: • store (as and when required), but mainly process, link and analyse potentially identifiable/sensitive data (generally, unconsented ‘FAIRified’ data from different modalities/sources) at UK scale; and • have programming access to bring advanced analytical algorithms (e.g. AI/ML algorithms) to the data; but also, export software/algorithms and analyses results developed and produced within this environment.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Developing a Modular Train-the-Trainer Programme for Open Research Practices
Funder: Medical Research Council

Abstract: Open research is an increasing feature of science across the biomedical disciplines. However, there is as yet no common training in open research available across MRC-funded Units and Centres. We will deliver a train-the-trainer course in open research practices for experimental and observational research, which would allow the delivery of harmonised training across MRC Units and Centres. The MRC IEU (Marcus Munafò), MRC CBU (Rik Henson), and the MRC LMB (Madeline Lancaster) have extensive experience of promoting open research practices. This project will bring together this expertise via a remotely delivered train-the-trainer course offered across the MRC portfolio of Centres and Units, augmented by brief animations and other online materials. The course will be structured around the five primers on open research practices already developed by the UK Reproducibility Network (www.ukrn.org) We will extend these with a consultation across the MRC Portfolio of Centres and Units to identify the training needs of researchers across the disciplines supported by the MRC.


Research activity codes: 8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: MRC/NIHR guidance on Natural Experimental Evaluations (NEEs) for researchers and End-Users
Funder: Medical Research Council

Abstract: The applicants propose to refresh the MRC Guidance for Natural Experimental Evaluations (NEEs) to cover the design and planning NEEs (including horizon scanning for NEE opportunities, assessing the viability and value of a potential NEE, including methods for theorising intervention effects, evaluability assessment, etc.). Guidance will include novel quantitative NEE methods (e.g. synthetic controls, ‘multiverse’ and related approaches), economic evaluation methods applied to NEEs; and mixed methods (e.g. NEEs involving qualitative methods or systems thinking/science approaches, such as systems mapping or simulation modelling), Throughout, we shall illustrate the guidance with detailed, worked examples and provide a range of tools to support its use with a focus on policy makers and researchers as the key audience


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: GENERIC HEALTH RELEVANCE
Title: PIONEER - Health Data Research Hub for Acute Care
Funder: Medical Research Council

Abstract: PIONEER is the Health Data Research Hub for Acute Care, led by the University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, in partnership with West Midlands Ambulance Service, the University of Warwick, and Insignia Medical Systems. Acute care is the provision of unplanned medical care; from out of hours primary care, ambulance assessment, emergency medicine, surgery and intensive care. Demand for acute health services are currently unsustainable for our national healthcare resource. Despite this, there has been less innovation in acute care than in many others health sectors, in part due to siloed information about patients with acute illnesses. The PIONEER Hub collects and curates acute care data from across the health economy, including primary, secondary, social care, and ambulance data. PIONEER uses this data to: provide accurate, real-time data for capacity planning and service innovation support learning healthcare systems including better use of current/novel investigations, treatments and pathways map innovation need Ultimately, PIONEER enables stakeholders to develop, test, and deliver new ways of caring for acutely unwell people, supported with expert patient, health care professional, and compute/analytic services. out a framework for further investment from UKRI, to be spent within the 21/22 financial year.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Developing cross-population Mendelian randomization for generalizing evidence on drug targets: the MRC Cross-Population Mendelian Randomization Network
Funder: Medical Research Council

Abstract: The overarching aim of the MRC Cross-Population Mendelian Randomization Network is to integrate research expertise and resources across four MRC Units with expertise in cross-population genetic epidemiology to explore the use of Medelian randomization (MR) to evaluate generalisability of existing drugs and target drugs to specific sub-populations. The network will implement pilot studies focused on specific established drug targets (e.g. CETP, HMGCR) to investigate how differences in genetic architecture between populations affect estimates of efficacy. In parallel we will explore how differences in environmental interactions between populations (including public health policy such as folate supplementation) alter MR estimates of efficacy of such supplementation (using MTHFR as the instrument). The network will focus on the development of both cross-ancestry and ancestry-specific genetic instruments for MR and investigate how genetic colocalization with molecular targets (metabolomic, proteomic and transcriptomic) vary across populations.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE