NIHRDataInsights/HRCSData huggingface dataset:
Title: Spatiotemporal dissection of vascular heterogeneity
Funder: Wellcome Trust

Abstract: Endothelial cells (ECs) are essential for organ development, homeostasis and regeneration, yet we still know relatively little about the early steps of their formation. I have shown that ECs from different embryonic lineages preferentially contribute to distinct parts of the vasculature; paraxial mesoderm (PXM) is the major source of lymphatic ECs, but its contribution to blood vessel endothelium is restricted to certain organs. This finding establishes a new model of how the vasculature is formed, however the underlying molecular mechanisms are unknown. Here I propose experiments to test the hypothesis that EC heterogeneity is underpinned by an intrinsic molecular memory established during differentiation from distinct embryonic sources. Building on my recent findings, we will the use the formation of lymphatic (PXM-derived), liver (partial PXM contribution) and coronary ECs (no PXM contribution) as paradigms to dissect the impact of lineage history on EC heterogeneity. Specifically, we will decipher the transcriptional and epigenetic mechanisms that control EC differentiation from distinct embryonic sources, and determine the impact of lineage history on the regenerative/fibrotic response of ECs. These analyses will provide insight into what makes ECs from distinct lineages different, and determine whether these differences impact organ development, function or regeneration.

Lay abstract: The cardiovascular and lymphatic systems deliver nutrients and remove waste products from every cell in the body, allowing our brains to process information, our hearts to beat and our muscles to move. The innermost layer of blood and lymphatic vessels is formed by a specialised cell type known as endothelial cells. These cells are important for normal organ function and tissue repair, and contribute to the development of pathologies that include heart disease and cancer. Yet despite their importance, we still do not fully understand how endothelial cells are formed. By studying the development of endothelial cells in animal models, our research will reveal how blood and lymphatic vessels are made. In the future, we hope that an improved understanding of these processes will allow us and others to develop new strategies to target endothelial cells, which will lead to improved treatments for a range of diseases.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CARDIOVASCULAR;GENERIC HEALTH RELEVANCE
Title: Developing cardiac electrophysiology models for drug safety studies
Funder: Wellcome Trust

Abstract: Simulations of the effect of multiple ion channel block on cardiac electrophysiology have become a key part of proposals to replace the ThoroughQT clinical study with more accurate preclinical tests. Success depends on having accurate mathematical models of both baseline cellular electrophysiology and drug-induced changes. Mathematical models include both ion channel kinetics (and drug effects on these) as well as action potential electrophysiology with appropriate expression levels of each ion channel type. We will extend and refine a new approach we have developed that uses shorter, more information-rich, experimental protocols for developing cell-specific mathematical models of ion channel and cellular electrophysiology, then predict drug responses with these models and validate against experiments. To make models that are ready for safety-critical use the problem of model selection (selecting the most appropriate set of equations) will also be addressed, as will model discrepancy – assessing, quantifying and predicting the difference between the model and reality. We will include uncertainty in our models and their inputs in a probabilistic framework, such that our predictions take the form of probability distributions. We will continue close collaboration with pharmaceutical companies and drug regulators to test and roll-out improved models.

Lay abstract: The heartbeat is co-ordinated by proteins that bind together in cell membranes and allow electrically-charged ions to pass through them - structures known as ion channels. When new drugs are developed they can interfere with the heart’s rhythm because they interact with ion channels. This unwanted side effect can be fatal in some cases. We research why and how certain drugs cause these problems by interacting with various types of ion channels in various ways. The aim is to have an accurate picture of safety for each new drug before patients are given it in the clinic. To do this we use mathematical models for electrical activity of heart cells to integrate data from safety tests and predict overall risk. We are designing new experimental approaches to get more information for building our models more accurately and in less time, with the aim of making better predictions from easier-to-perform experiments.

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR;GENERIC HEALTH RELEVANCE
Title: RegsWizard - Simplifying the Complex World of Medical Device Regulation
Funder: Innovate UK

Abstract: **The** **Challenge** The world of Medical Device Regulation ("MDRegs") is extremely complex and difficult to navigate. Even seemingly simple questions like, "is my product a Medical Device ("MD")" are riven with interpretive complexity and nuance. This is even more the case in the emerging world of Digital Health which is contributing significantly to the increase in the number of Software as a Medical Device ("SAMD"). The guidance available to product owners ("Product-Owners") looking to navigate this space, is limited to generic 'static' advice and information provided by relevant industry bodies (i.e. regulators or approved assessment bodies like BSI/TuvSud) or very specialist consultancy support from rare and costly experts. This limited guidance is exacerbated by a lack of transparency or clarity over the precise interpretations to be applied - particularly in the SAMD space - and the associated requirements that Product-Owners need to take into account to ensure compliance. The full impact of this is to be found in the raft of products that do not - intentionally or otherwise - meet these key regulatory requirements (a recent ORCHA survey illustrated a potential none compliance rate in the Digital health space of over 50%), but also huge inefficiency and delay for those Product-Owners who attempt to navigate through the complexities. **The Concept** This project brings together a hugely complimentary and multi-disciplinary team, lead by ORCHA to address this critical issue through the development of an intuitive, interactive and intelligent tool (the "RegsWizard"), that can provide Product-Owners with tailored, personalised and reliable advice and guidance at a fraction of the cost of traditional 'expert' consultancies. The RegsWizard is a ground breaking concept in this space - although ORCHA have developed similar constructs in the broader Digital health regulatory environment. It will revolutionise the navigation of products through the MDRegs landscape and ensure that reliable advice and guidance is available to all Product-Owners at an affordable price. At the heart of the RegsWizard concept is an intuitive interactive tool that enables Product-Owners to accurately identify the likely status of their product under MDRegs in the UK (UKCA mark) and EU (MDR CE mark) and which generates a tailored checklist of compliance requirements that flow from that status and which will be necessary to meet the demands of the relevant regime. The RegsWizard will also identify or map to relevant externally maintained Nomenclatures with a specific focus on SNOMED and GMDN.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: CARDIOVASCULAR;GENERIC HEALTH RELEVANCE
Title: Multi-User Ultra-High Field Clinical Imaging Research Centre for London
Funder: Wellcome Trust

Abstract: Using Magnetic Resonance Imaging and Spectroscopy (MRI/S) to study patients can provide unparalleled anatomical, functional and biochemical information completely non-invasively without using ionising radiation. Most clinical and research scanners operate with 1.5T or 3T magnets. This proposal will fund an ultra-high field MRI system with a stronger (7T) magnet that produces larger MRI/S signals, the properties of which change so that they can be more informative. The signal increases allow higher resolution imaging and the signal changes can allow detection of subtle disease properties. This offers enormous potential for research and clinical investigation, but is very demanding technically, so integrated teams of doctors, biologists, physicists, engineers and computer scientists are needed to make best progress. We will create a collaborative MRI/S Research Facility to be located at St Thomas’ Hospital as a regional resource to be used by clinical researchers drawn from the major London Universities (King’s, Imperial and University College), the Institute of Cancer Research and other leading institutions. This will place the latest MR technology in the hands of a world leading multi-disciplinary group, enabling them to tackle major scientific questions and clinical challenges. This will substantially increase understanding of disease processes and ultimately enhance patient care.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR;GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS;NEUROLOGICAL
Title: King's College London Medical Engineering Centre of Research Excellence
Funder: Wellcome Trust

Abstract: 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.

Lay abstract: No Data Entered

Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: CARDIOVASCULAR;GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS;NEUROLOGICAL
Title: Physical and mental health multimorbidity across the lifespan (LIfespaN multimorbidity research Collaborative (LINC)).
Funder: Medical Research Council

Abstract: One in two individuals with mental health disorders have poor physical health and, conversely, one in three of those with physical health disorders have mental health disorders. The social and economic cost of this physical and mental health multimorbidity (PMH MM) is substantial. Targeted interventions to reduce this risk are needed urgently. A particularly common example of PMH MM is Internalizing disorders (anxiety and depression) co-occurring with CardioMetabolic diseases (ICM MM). Internalizing and cardiometabolic disorders typically originate in childhood. Yet the role in ICM MM development played by risk factors that are present from an early age onwards (genetics, neurodevelopmental disorders (NDDs) and adverse childhood experiences (ACE)) remains unclear. To examine PMH MM across the lifespan, we have established the LIfespaN multimorbidity research Collaborative (LINC) comprising a multidisciplinary team, and an incredible resource of five large longitudinal population-based cohorts, with rich data on health and social environment, early-life factors and genomics. Our resource includes three young cohorts and four adult cohorts and is ethnically and socioeconomically diverse. We will examine the effects of key shared genetic and environmental factors on the development of ICM MM. For genetic factors, we will include polygenic scores for relevant traits as well as rare variants (Copy Number Variants and Rare Coding Variants). We will investigate the role of NDDs and environmental risk factors, including ACE (deprivation, maltreatment). We will examine effects of sex and ethnicity heritage on ICM MM development. Our findings will provide insights to inform tailored interventions. We will disseminate rapidly to the research community, and work in concert with policymakers to develop multiple-stakeholder interventions to better support those at elevated risk of ICM MM.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: CARDIOVASCULAR;GENERIC HEALTH RELEVANCE;MENTAL HEALTH
Title: Food for added life years: Putting research into action (Food4Years)
Funder: Medical Research Council

Abstract: The UK national population trajectory forecasts that by 2050, one in four people will be aged 65 years+. However, increases in life-span appear to be surpassing increases in health-span. Incidence rates for chronic diseases are increasing with treatments allowing people to live for longer with their disease. There is good evidence to support changes to lifestyle to maintain or improve body composition, cognitive health, musculoskeletal health, immune function and vascular health in older adults. Much research has been done which has produced significant support for foods and nutrients that contribute to improved health span. Yet two major barriers remain. Firstly, older adult consumers are not meeting current UK recommendations for macro and micronutrients yet this would provide benefits to health and quality of life. Secondly, the UK-specific recommendations may not be sufficient to support the aging population, particularly for nutrients with key physiological roles. More needs to be done to improve intakes of specific foods, diets and nutrients by older adults, through a variety of mechanisms including improved clarity of information, appropriate marketing, "nudge" strategies and policy changes to enable incentives. More research is needed to explore how to build consumer awareness about the importance eating for healthy ageing and co-produce and co-create diets and foods that meet the ageing populations needs. This message needs to be supported by policy makers and national guidelines. The current market offer of real food solutions for older adults is modest; despite the food industry recognising the need to address the challenges of designing and marketing high-quality foods and meals for the older adult consumer. The aim of the Research Network is to build a Community that is absolutely committed to the development, integration and communication of healthy, affordable foods and specific diets for all older adults across our food landscape.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;3.3 NUTRITION AND CHEMOPREVENTION
Health categories: CARDIOVASCULAR;GENERIC HEALTH RELEVANCE;METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL;STROKE
Title: Addressing Gaps in Men's Health Literacy and Health Seeking in Mozambique: A Case for Differentiated Care for HIV and CVD
Funder: Medical Research Council

Abstract: Men are more likely to disengage with health services than women in Southern Africa, a gap worsened with the rise of non-communicable diseases (NCD) and complex patterns of co-morbidity. There is little regional data on men's health literacy, health-seeking behaviour, and experiences of receiving care in health systems. Using the tracer of cardiovascular disease (CVD) in HIV+ men in Mozambique, this project aims to strengthen the evidence base for differentiated health systems strategies to promote men's health literacy and health-seeking in Southern Africa. Mozambique has a high burden of infectious diseases (ID) with steady increase in NCD since the early 2000s. Retention of men in HIV care remains challenging; emerging evidence indicates that men have lower levels of awareness, control, and uptake of treatment for NCDs including CVD risk factors. Our mixed-method observational and cross-sectional study will is based in a large urban district of Maputo and has four phases: 1) A scoping review and mapping exercise will examine current approaches to men's health; 2) facility-based observations and interviews with health providers and male patients will situate illness trajectories within social, structural, and systems context; 3) a community-based survey and a nested qualitative study will triangulate data on health literacy, self-perceived health and household influences on men's health seeking behaviour and 4) participatory systems modelling techniques and stakeholder consultation will inform potential strategies to strengthen men's engagement with HIV and CVD services. We expect to deliver timely insights for the systems response to HIV/CVD co-morbidity in men. The partnership will further generate a solid interdisciplinary platform for the development of a larger proposal that can implement and evaluate health systems strategies to address the chronic health needs of male migration and mobility across borders in the Southern African region.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: CARDIOVASCULAR;INFECTION
Title: CARDINNATE: Variation in innate immune activation and cardiovascular disease risk as drivers of COVID19 outcome in South Asians in UK and India
Funder: Medical Research Council

Abstract: In the UK, individuals of South Asian heritage have a higher COVID-19 mortality rate than other ethnic groups, even after adjusting for age and social factors. This is driven by a greater risk of in-hospital death rather than an increased rate of admissions, in part related to a higher prevalence of cardiovascular disease (CVD) and diabetes which are recognised risk factors for severe COVID-19. By contrast, mortality rates for COVID-19 in India are markedly lower than the UK. Severe COVID-19 is associated with profound systemic immune dysregulation, haemodynamic and thrombotic complications. Multiple lines of evidence suggest that innate immune mechanisms, specifically variation in the regulation of the type 1 interferon (IFN) response and the subsequent dysregulation of cellular innate and adaptive immunity, may be very important determining factors in COVID-19 pathogenesis. Hence these mechanisms are good candidates for underlying increased mortality risk in UK South Asians and set a platform for understanding why the situation is different in India. Our multi-disciplinary UK and India team will elucidate the inter-relationship among innate immune mechanisms, pre-existing CVD/diabetes and environment (India versus UK). Differences in innate immunity, which provides a first line of defence to infection, are captured by the term "trained immunity", reflecting its conditioning in part via IFN, by exposure to endemic environmental pathogens, diet, and inflammatory conditions including CVD/diabetes. Hence, evident differences in these factors for South Asians in India versus the UK may profoundly affect the speed and strength of first-phase immune responses to SARS CoV2, as well as attendant cardiovascular damage and dysfunction, to collectively drive systemic immunopathology and the differences in COVID-19 mortality between the UK and India.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: CARDIOVASCULAR;INFECTION
Title: Opportunity-Led Dr Tranjit Singh Rai - Senescence biomarkers for predicting risk in Covid-19 patients
Funder: Public Health Agency, NI

Abstract: Among the risk factors for death in Covid-19, age, underlying health conditions such as heart disease, hypertension, diabetes, obesity come on top. Some heart patients are at extremely high risk of severe illness from coronavirus. As we age, the cells in our bodies change and some proteins related to ageing also change. We hypothesize that some of these proteins are elevated in Covid-19 patients and may predispose them to heart attacks prematurely. Currently, there is no reliable blood test to predict which Covid-19 patients with/without heart disease are at most risk of dying or debilitating disease. In this project we will test if some of these proteins are elevated in Covid-19 patients with severe form of the disease. We have developed a simple blood test that can measure the amount of some of these ageing proteins and these can accurately predict who is at risk of a heart attack (IP protection sought by Ulster University). Since age is the biggest risk factor for both Covid-19 and for heart disease we hypothesize similar combinations of these age associated proteins might stratify Covid-19 patients in need for urgent monitoring. By innovatively targeting these proteins, we may turn back the tide on Covid-19.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR;INFECTION