NIHRDataInsights/HRCSData huggingface dataset:
Title: Epigenetic regulation of lineage competence in human pluripotent stem cells
Funder: Medical Research Council

Abstract: Pluripotency is the ability of single cells to differentiate into all somatic lineages and the germline. Two forms of pluripotency have been defined, naïve and primed, that correspond to the pre-implantation and pre-gastrulation stage epiblast, respectively. We have developed a system for conversion of naïve human pluripotent stem cells (hPSC) to the primed state in vitro termed formative transition. Remarkably, this formative transition in vitro recapitulates features of primate embryo development in vivo. During this transition hPSC acquire the ability to respond to differentiation signals, first to endoderm and then to neuroectoderm. Thus differentiation competences to these lineages are separable in time and potentially mechanistically. The molecular basis of differentiation competence is unknown; it could rely on the expression of specific transcription factors, or the epigenetic marks of regulatory elements, or a combination of both. Here, we will explore the epigenetic component of the mechanism of lineage competence in hPSC. Hypothesis: Competence for differentiation relies on certain epigenetic marks in promoters and enhancers of lineage-specific genes, which enables their activation in response to differentiation signals, once those signals appear ("epigenetic lineage priming"). We predict that epigenetic lineage priming occurs during the formative transition in hPSC. Specific aims and questions: 1) Identify the epigenetic lineage priming programmes to endoderm and neuroectoderm. 2) How are epigenetic lineage priming programmes established during the formative transition? 3) How are epigenetic lineage priming programmes activated during differentiation? The project will address the molecular mechanism of the transition from pluripotency to differentiation. Insight from our research will have far reaching implications, as it will provide a paradigm of epigenetic regulation and cell fate choice fundamental to understanding of all developing organisms.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Gene Therapy Innovation and Manufacturing Centre (GTIMC)
Funder: Medical Research Council

Abstract: Current UK facilities for manufacturing viral vectors suitable for human treatment cannot meet demand, thus seriously hindering the translation stage of moving exciting gene therapies into clinical trials. Our aim is to establish a Gene Therapy Innovation and Manufacturing Centre (GTIMC) to address key challenges facing academic groups. The GTIMC will integrate multidisciplinary partners from the Midlands, Wales and North of England with the aim to bring complementary expertise that we have identified as essential components to unravel the existing knowledge gaps focused on adeno-associated virus (AAV) manufacturing, analytics, process innovation, safety, regulatory, clinical pathways, training and commercialisation. The GTIMC includes provision of a new build state-of-the-art GMP manufacturing facility (ShefVec). This new facility, alongside the existing excellent track record and exciting initiatives in gene therapy research within the hub, will cement the hub as a leader in innovation, manufacturing and human gene therapy translational research. ShefVec, to be GMP accredited, will utilise highly efficient purification processes to generate clinical grade AAV and provide all the necessary quality assurance, regulatory certification and governance. ShefVec will enable provision of clinical grade material for human trials at Advanced Therapies Treatment Centres, the NHS hospitals Trusts within the GTIMC and the National Network. Merit, which was a key supplier for the Catapult build in Stevenage, proposes ShefVec to be constructed using a modular design. GTIMC will also develop a translational team, including a solid regulatory platform, to support further development and commercialisation of the selected projects. The hub offers opportunities for expanding training and skills through existing MSc courses in advanced therapies, ATTC training, links to the apprenticeship community, and establishing new PhD programmes in this space.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: GENERIC HEALTH RELEVANCE
Title: NHSBT Innovation Hub for Gene Therapies
Funder: Medical Research Council

Abstract: The core ambition for the NHSBT Innovation Hub for Gene Therapies (the NHSBT Gene Therapy Hub), will be to support early phase academic-led gene therapy trials and facilitate the provision of cost-effective viral vectors and plasmid DNA to stimulate the UK's gene therapy sector. Our Hub will provide viral vector manufacturing, training and support services for academic-led groups seeking Adeno Associated Viral (AAV) vectors at GMP and research-grade qualities. The NHSBT Gene Therapy Hub will be hosted within the newly-expanded NHSBT Clinical Biotechnology Centre (CBC), at NHSBT Filton, scheduled to be fully operational by end 2021. The CBC has supported UK academics through the manufacture of plasmid DNA and provision of GMP, quality and other services for more than 15 years. The expanded CBC is an ideal environment for the NHSBT Hub, with an experienced and multidisciplinary team, a variety of GMP and clean-room environments, and platforms for lentiviral (LV) and plasmid production complementing the Hub's AAV production. The NHSBT Gene Therapy Hub will play a key role in the national network of hubs, in which we will collaborate with stakeholders such as LifeArc, Cell and Gene Therapy Catapult (C&GTC) and the Centre for Process Innovation to deliver research and translation supports to UK academic-led teams. Within the Hub itself, we will produce AAVs using an innovative platform acquired via technology transfer from C&GTC, which will be GMP validated at 50L scale. A variety of batch sizes, from 10L to 50L, will be available to suit different research needs. Our GMP environments and processes will be similarly configurable. Production will be complemented by quality assurance, by training (technical, GMP, regulatory, etc.) and by translation-support services, delivered in collaboration with the wider network. Our NHSBT Gene Therapy Hub will strengthen the UK's position as an international leader in gene therapy research and innovation.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: GENERIC HEALTH RELEVANCE
Title: King's/Royal Free/UCL Gene Therapy Innovation Hub
Funder: Medical Research Council

Abstract: The King's/Royal Free/UCL Hub will provide a comprehensive capability for GMP viral vector manufacturing, addressing the primary barrier to academic-led development of gene therapies. This will include both AAV and lentivirus production for early-phase trials, alongside substantial programmes in process innovation, knowledge transfer, and training to address critical skills shortages. We are uniquely placed to deliver this vision. MRC/LifeArc investment will build on nationally leading expertise in GMP vector production - we have manufactured more lentiviral vectors for clinical trials than any other centre in Europe, and are the only academic group in the UK to have released GMP lentivirus or AAV. We have experience in gene therapy pre-clinical development and clinical trials, alongside a track record in commercialisation (inc. MeiraGTx PLC founded by Ali). We lead the Research England-funded London Advanced Therapies partnership; this, combined with strong links to other centres, places us close to the academic groups developing new gene therapies and driving demand for GMP vectors. Investment in our Hub will provide a near-immediate enhancement of UK manufacturing capacity, providing time for newer centres to come online. We will make our expertise available to support other centres directly and via the Cell & Gene Therapy Catapult. With our UCL Hub members, we will develop postgraduate training programmes for viral vector manufacturing, focusing on regulatory and technical aspects, and new on-line training modules. Viral vector manufacturing - particularly for early-phase trials - is limited by yield, scalability of technologies, and analytic standards. KCL and Royal Free Hub members will undertake a substantial programme of process innovation work to address these challenges. All these activities will link to our Hub's UK-leading early phase clinical trial activities in gene therapy, based at King's, Royal Free and UCL.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: GENERIC HEALTH RELEVANCE
Title: Building resilience: Co-designing an online rainbow wellbeing toolkit for public health systems to promote wellbeing and resilience in LGBTQ+ youth
Funder: Medical Research Council

Abstract: This project's main objective is to co-design a web-based "online rainbow wellbeing" toolkit with and for LGBTQ+ adolescents. For this project we will use the youth co-design participatory framework outlined by Hagen et al. (cited in our reference list). In addition to input from LGBTQ+ adolescents from every stage from the 'IDENTIFY' to 'USE' stages of the project (from Hagen and colleagues' co-design framework), there will also be input from key adult experts during the 'IDENTIFY', 'CONCEPT' and 'USE' stages, specifically input from: LGBTQ+ youth workers; teachers; local authority public health and healthcare providers; commissioners of health services; police; experts on bullying prevention; teachers; and, the parents/caregivers of LGBTQ+ adolescents. The second main objective for this project is to explore how the online toolkit can be used within public health systems. We will determine how the toolkit could be used by LGBTQ+ young people. We will also establish how the online toolkit can be used by others (e.g. heterosexual peer allies, family members and professionals) to assist in improving the overall social milieu for LGBTQ+ adolescents (e.g. by providing guidance for teachers around how to adequately support an LGBTQ+ youth who is being mistreated) and potentially for professionals as a form of CPD (see also letters of support - Centre for Policing & Oxon County Council). The third main objective for this project is to plan the delivery of the intervention and determine the design and measures for a future effectiveness study as well as further implementation of the toolkit. Assuming stop/go decision criteria (developed during the 'CREATE' stage) are met based on the small process evaluation conducted in the 'USE' stage (e.g. >80% of LGBT+ youth rate the online tool as acceptable), we will submit a bid for an effectiveness randomised controlled trial to NIHR - Public Health Research.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: GENERIC HEALTH RELEVANCE
Title: Co-developing an app-based intervention to increase children's consumption of vegetables
Funder: Medical Research Council

Abstract: UK children's consumption of vegetables is extremely low despite evidence that vegetable consumption is protective against numerous health risks (e.g., obesity, cancer, cardiovascular disease, type 2 diabetes). Vegetables are less accepted than fruits, and low consumption of them is more strongly related to mortality, making them a key target for intervention. Dietary habits formed in childhood track into adulthood, so it is important to intervene in the early years to promote lifelong healthy habits. Drawing on existing evidence and our previous work, which highlights the efficacy of repeated exposure, parental modelling and use of rewards for increasing children's intake of vegetables, this research aims to understand parents'/caregivers' and children's preferences about an app-based intervention to increase children's consumption of vegetables, and to develop and begin to test this app. Three work packages (WP) will be undertaken. WP1 will involve formative work to determine 25 parents'/caregivers' needs for, and the content of, a 14-day app-based vegetable intervention. WP2 aims to develop and gain initial feedback on a prototype app by conducting interviews with 20 parent/caregiver-child dyads. The app's content will be informed by WP1. Finally, WP3 will assess the acceptability of the app by trialling it with a new group of 30-40 parents/caregivers over a 14-day period, and undertaking follow-up interviews with a representative sample of 20 parents/caregivers to discover their views of using the app. Usability data and qualitative feedback will be used to finalise the intervention prior to subsequent testing in a future trial. The overarching goal of this project is to co-develop an intervention and to confirm that the intervention is feasible and acceptable to users. Ultimately, this scheme of work aims to create a public health intervention to increase children's vegetable intake and support healthy lifelong development.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: GENERIC HEALTH RELEVANCE
Title: ADMISSION UK Multimorbidity Research Collaborative on Multiple Long-Term Conditions in Hospital: from burden and inequalities to underlying mechanisms
Funder: Medical Research Council

Abstract: ADMISSION is an interdisciplinary UK Research Collaborative that will transform our understanding of the burden, causes, treatment and prevention of multiple long-term conditions in hospitalised patients. Central to the success of ADMISSION will be the creation and alignment of data across platforms, harnessing the Newcastle Hospitals Global Digital Exemplar electronic health record, the HDRUK Hub Acute Care (PIONEER, Birmingham), and the NIHR Biomedical Research Centres Health Informatics Collaborative in Critical Care (UCL) for the first time. The work is divided into five linked work packages that will: 1) use electronic health records to develop harmonised data platforms; 2) analyse these data to define clusters of medical conditions, using conventional and new cutting-edge techniques to describe the burden of multiple long-term conditions; 3) generate new knowledge of the impact of inequalities in these clusters according to differences in age, socioeconomic status and access to healthcare; 4) map these clusters of conditions against patient pathways to understand antecedent events, trajectories of care and future consequences; and 5) explore underpinning mechanisms through a combination of genetic epidemiology in large existing datasets and targeted phenotypic confirmation using existing biobanked samples linked to routinely collected data. A key feature of the Collaborative is that the researchers come from a wide range of disciplines (including data science, statistics, social science, epidemiology, genetics, primary and secondary care). Allied to strong patient partnerships and geographical reach across its centres (Newcastle, Birmingham, UCL, Manchester, Dundee), ADMISSION will offer unrivalled opportunities both to share expertise and to include comparative analyses and cross-validation within and beyond the Collaborative. This new learning, whilst of particular relevance to the UK context, will inform hospital-based care globally.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE
Title: Multimorbidity Mechanism and Therapeutics Research Collaborative
Funder: Medical Research Council

Abstract: Our research will uncover mechanisms underlying multimorbidity by triangulating relationships between medicines, drug targets and disease outcomes from electronic health records (EHRs), genetic association studies and trials. The findings will maximise treatment benefits by guiding drug indication expansion and re-purposing; reduce harm by optimising prescribing when diseases co-exist; and yield new tools for prediction and prevention of multi-morbidity.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION;6.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE
Title: Current and future temperature-related mortality and morbidity in the UK: a public health and climate change perspective
Funder: Medical Research Council

Abstract: This project will provide a comprehensive evaluation of current and future health risks associated to non-optimal outdoor temperature in England and Wales, by assessing excess mortality and morbidity at small-area level and then projecting impacts under scenarios that account for climate change, socio-economic and demographic trends, and adaptive strategies. The research proposal is structured in a detailed plan of four work packages (WPs). In the first WP, the research team will link country-wide databases of mortality and hospital admissions with high-resolution environmental measures, and will then apply advanced epidemiological designs to obtain estimate of potentially complex temperature-health associations varying across small administrative areas. The evaluation will be extended in WP2 to assess geographical and temporal differences in risks, applying cutting-edge meta-regression and machine learning models to characterise vulnerability patterns in terms of climatological, socio-economic, infrastructural, and urban setting characteristics. This information will be used in WP3 to quantify excess mortality and morbidity at small-area level in the historical period, and then to project health impacts under composite scenarios of global warming, socio-economic pathways, and potential public health policies. The last WP will create open-access documented repositories and easy-to-use web tools to extract, summarise, and display risk measures, and to perform scenario simulations. The project will provide a detailed picture of health risks associated to heat and cold, and will help identify drivers of vulnerability and resilience within the population of England and Wales. This information is critical to perform evidence-based assessments of potential benefits related to climate and public health policies, and to compare alternative mitigation and adaptation strategies to reduce the health burden of global warming at national and international level.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: EN-REACH: Every Newborn - Reach up Early Education intervention for All Children in Bangladesh, Nepal & Tanzania
Funder: Medical Research Council

Abstract: Sustainable Development Goals (SDGs) include targets for the unfinished child survival agenda, given 5.3 million deaths of children before their 5th birthday, half in the neonatal period. SDG target 4.2 aims that, by 2030, all children access quality early child development (ECD), pre-primary education and are ready for primary education. However, children most at risk of poor educational outcomes, including those with neuro-developmental delay and disability (NDD/D), are less likely to access school, including pre-school services. This proposal, co-led by Dr Jena Hamadani of iccdr,b and Prof Joy Lawn of LSHTM is called EN-REACH (Every Newborn - Reach up Early Education intervention for All CHildren) and will evaluate the impact and implementation of an adapted 'Reach Up' parenting program in in Bangladesh, Nepal & Tanzania with three objectives: Objective 1: INNOVATION: To adapt 'Reach Up' parenting package for ECD for all children, inclusive of those with NDD and disability, in three diverse low-and middle- income countries (LMIC). Objective 2: IMPACT EVALUATION: To use a quasi-experimental design to measure early child development markers for school readiness (cognition, psycho-social, etc), and child and caregiver quality of life after receiving the adapted "Reach-Up" package (delivered to 50% of the cohort, est:1000 children), compared to the other 50%. Objective 3: IMPLEMENTATION: To undertake process evaluation of implementation, including examining barriers & enablers for uptake of adapted "Reach Up" package integrated into routine health systems. EN-REACH aims to have significant impact for children and their families, at country level and on global policy for care of children with disabilities through links with global organisations such as UNICEF and WHO. This study will provide evidence on effectiveness and acceptability of a disability-inclusive and scalable parenting package in diverse Asian and African settings.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: GENERIC HEALTH RELEVANCE
Title: Improving health and development through play - Evaluation of a comprehensive ECCE programme at scale in Ghana
Funder: Medical Research Council

Abstract: A critical knowledge gap for development of effective ECCE policy is what intervention strategies are effective at scale. We aim to fill this knowledge gap through the evaluation of a holistic ECCE programme Lively Minds, implemented by the Government of Ghana at scale. The programme, shown to be effective in an efficacy trial, will be scaled to all pre-schools in 60 most deprived districts in Ghana to reach over 1 million children over 10 phases from September 2021 to May 2024. We propose to integrate a stepped-wedge cluster randomised controlled trial into this scale-up focusing on 4 phases (Sept.'21 - Sept. 23), 48 districts, randomly sampled 144 schools and 1,440 children. We will estimate the average treatment effect of the scaled Lively Minds program on child development (health, socio-emotional and cognitive) using an ANCOVA strategy. We will establish how impacts vary by child, parent, teacher and district characteristics and identify, through machine learning methods, which characteristics are associated with largest treatment effects. We will further assess heterogeneity in impacts to understand the role that degree of intervention fidelity and compliance play, to be able to advise on how the programme design can be adapted to maximise cost-effectiveness. In order to establish causal links, we will construct a counterfactual group among control areas by using baseline data to identifying those where intervention fidelity/compliance would likely be high/low. Using descriptive mediation analysis followed by structural estimation we will shed light on whether observed impacts are achieved through changes within the school and/or the children's home environments, including teacher and caregiver behaviour. We will explicitly model children's outcomes as a function of key hypothesised mediators, using an instrumental variable approach to address endogeneity of these mediators.

Lay abstract: Note - this award is managed by MRC but funded via Foreign, Commonwealth & Dev Office

Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: GENERIC HEALTH RELEVANCE