NIHRDataInsights/HRCSData huggingface dataset:
Title: Endothelial cell behaviours in vascular health and disease
Funder: Wellcome Trust

Abstract: At the interface between blood and tissues, vascular endothelial cells (ECs) provide signalling hubs for vascular adaptation to physiological needs. Quiescent ECs form a non-thrombotic surface that facilitates the exchange of gases, molecules and cells between blood and tissues, but they respond to hypoxia-induced signals with vascular expansion and regulate leukocyte extravasation in response to injury. Our unpublished observations indicate that the cell surface receptor neuropilin 1 (NRP1) relays signals from the extracellular environment to the endothelial nucleus to enable such context-dependent responses. Thus, we hypothesise that NRP1 integrates growth factor and extracellular matrix signalling with gene transcription programmes to balance EC behaviours that enable vascular growth and to prevent the senescent and proinflammatory endothelial phenotype common to many chronic diseases. To determine how vascular growth and homeostasis depend on NRP1-mediated pathways, we will investigate novel mechanisms by which NRP1 conveys signals for tissue vascularisation, protects ECs from premature senescence and regulates gene transcription for vascular growth and homeostasis. The knowledge gained will significantly advance our understanding of how extracellular signals are integrated with gene regulation to control EC behaviour, and will likely uncover pathways for therapeutic intervention in diseases with vascular dysfunction.

Lay abstract: Blood vessels consist of an outer protective coat, composed of muscle-like cells and fibrous substances, as well as an inner lining that is formed by endothelial cells (ECs). In healthy vessels, ECs provide a thin and smooth surface that facilitates the exchange of gases, molecules and cells between blood and tissues. However, ECs can also respond to signals from oxygen-starved tissues to expand the vessel network or promote inflammation for tissue repair and to help fight infections. These processes are perturbed in diseases such as such as atherosclerosis and diabetic eye disease. We will investigate how the cell surface molecule neuropilin 1 (NRP1) integrates signals from the environment to alter the expression of genes that balance EC behaviours important for vascular growth and at the same time prevents the poor function of ECs that is common to inflammatory diseases. The knowledge gained will significantly advance our understanding of normal EC behaviour in the healthy body and will likely uncover factors that can be targeted for therapeutic intervention in diseases with blood vessel dysfunction.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;CARDIOVASCULAR
Title: Towards a Single-Molecule Pharmacology of G-Protein-Coupled Receptors: Understanding Receptor Dynamics to Develop Innovative Drugs
Funder: Wellcome Trust

Abstract: G-protein-coupled receptors (GPCRs) mediate the effects of several hormones and neurotransmitters and are major pharmacological targets. Despite recent advances, how GPCRs work in a cell to produce specific effects remains poorly understood. My group has developed an innovative single-molecule approach to investigate GPCRs in living cells with unprecedented spatiotemporal resolution. Using this approach, we recently succeeded for the first time in visualizing individual receptors and G-proteins as they interact and signal in living cells. We discovered that dynamic interactions among receptors, G-proteins and structural elements of the plasma membrane generate nanodomains where GPCRs produce highly localized signals (“hot spots”). We hypothesize that this organization is crucial for achieving efficient and specific signalling, its alterations might be implicated in diseases like heart failure, and might be exploited to modulate GPCR signalling beyond what is possible with current drugs. In this project, we will use beta-adrenergic receptors as a model and single-molecule microscopy to provide for the first time a detailed characterization of the key protein-protein and protein-lipid interaction involved in G-protein and beta-arrestin signalling, compare their nanoscale organization in cardiomyocytes under physiological and pathological conditions and, ultimately, exploit the new information to develop innovative therapeutic strategies for cardiovascular and metabolic diseases.

Lay abstract: Cell-cell communication depends upon a specialized family of proteins called "G-protein-coupled receptors". These receptors mediate the effects of hormones and neurotransmitters, are deeply implicated in human disease and are the targets of common drugs like beta-blockers. Although long considered as simple "on-off" switches, we are now beginning to understand that G-protein-coupled receptors are far more dynamic and function through a complex series of events. This presents several critical, unanswered questions, including where and how these events take place in our cells to produce specific effects. Collecting this information will be essential to design better drugs. To achieve this, we will use cutting-edge microscopy technologies that can visualize these events in unprecedented detail and give previously unimaginable insights into G-protein-coupled receptor function. We will investigate this under normal conditions and in cell models of heart disease, with the ultimate goal of developing new therapies for diseases like heart failure or diabetes.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;CARDIOVASCULAR
Title: MRI award - Imaging
Funder: Wellcome Trust

Abstract: Prospective cohorts, such as UK Biobank, have advantages for the comprehensiveand reliable quantification of the combined effects of different types of riskfactor on disease. However, they need to involve large numbers of participantsbecause only a relatively small proportion will develop any particular condition. UK Biobank has collected extensive baseline questionnaire data, physical measures and biological samples from 500,000 men and women aged 40-69at baseline and their health is being followed by linkage to health records. Central adjudication of health outcomes will ensure that consistent definitions are used and facilitate access to the resource. It is now planned to enhance further the phenotyping of 100,000 participants with information from multiple imaging modalities involving Magnetic Resonance imaging of brain, heart, large blood vessels and abdomen, Ultrasound of carotid arteries,and Dual-Energy X-ray Absorptiometry (DXA) of bone and joints. The availability of imaging measures that quantitatively define phenotypes that are closely related to disease will provide substantial power for detecting


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: GENERIC HEALTH RELEVANCE;CARDIOVASCULAR
Title: The IV-Buddy
Funder: Innovate UK

Abstract: Whenever fluid is given into the body via a dripline, the dripline should be monitored to avoid air embolism or formation of blood clots that can block the tubing. This is conventionally done by hospital nurses and ambulance paramedics peering at the drip chambers. For catheter (thin tubes visible under X-rays) interventions in arteries, where continuous administration of fluids is important to keep the blood from clotting within the catheters, there is nothing suitable on the market to monitor flow. Interruption of flow, even for only a minute, can lead to blood clots that can result in severe disability or death. Doctors and paramedics of The Mobile Stroke Unit Charity, together with founders of Nvention, identified the need for a simple device that can be used on ambulances and in hospitals for operations in the brain and heart. Our invention, the IV-Buddy, automatically sounds an alarm if flow within a drip line into the body stops. The IV-Buddy has a novel sensor technology that leads to increased patient safety during infusions. With the IV-Buddy, valuable nursing time does not need to be spent repeatedly inspecting drip chambers. Infusion pumps could potentially be used, but they are expensive, cumbersome to handle, not readily available and not usable for catheter interventions. Our easy to use IV-Buddy will improve patient safety, especially in low-resource settings where infusion pumps are scarce. The IV-Buddy has other applications. Army medics were excited to learn of this new tool that saves lives while evacuating soldiers, or during mass casualty events. Other applications include home infusion and dialysis, blood donation or patient transport in hospitals and ambulances. With the IV-Buddy, fluid monitoring becomes possible in poorer countries where infusion pumps are too expensive. The IV-Buddy is innovative as: \* there is no such device on the market, \* it lowers the risk to patients by automatically alerting the clinician of a problem, \* it is simple to use, \* it can be low cost, making it widely affordable. This grant will fund technical design to incorporate product extensions requested by users after seeing our earlier prototype. We will also obtain information on and plan for the clinical trials (in the ambulance and catheter lab) needed to gain regulatory approval. The improved version of the IV-Buddy developed during this grant will be prototyped as part of the evaluation of its new features and tested in a simulated environment to evaluate its safety.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: GENERIC HEALTH RELEVANCE;CARDIOVASCULAR
Title: Optimising methods for measuring effects of neighbourhood environments on diet, physical activity, smoking & alcohol intake in older people in the UK
Funder: Medical Research Council

Abstract: This study will conduct a comprehensive UK-wide study of older men and women (over 65 years) to (i) develop measurement methods for quantifying the extent to which local neighbourhood environments influence patterns of diet, physical activity, smoking and alcohol behaviours, and physiological CVD risk indicators (BMI and BP), in older people in UK urban settings; (ii) identify features of neighbourhood environments which are most important in influencing health behaviours in older people, and highlight factors potentially amenable to public health or policy interventions. For the 22 study towns, we will obtain and compare three different sources of spatial data on local neighbourhood environment features potentially relevant to older people's behaviours; local environmental data from routine sources, from de novo primary environmental data collected by a robust 'street' survey tool (OPECR) developed specifically for this study, and environmental data from remote imaging (e.g google street view). Using the neighbourhood environment measures collected, we will conduct a cross-sectional analysis of the association of these measures with CVD risk factors (behaviours and physiological indicators) in older men and women across the UK. We can deliver this large, comprehensive nationwide study at a fraction of its total cost by utilising individual level data on behaviour and physiological risk indicators for 4000 women and men (over 65 years) in 22 towns already collected in 2010-2011 as part of the ongoing longitudinal studies - the British Women's Heart and Health study (BWHHS) and the British Heart Study in Men (BRHS). In addition, we will conduct a pilot study of the use of wearable GPS/ accelerometer monitors of activity and mobility in older people to explore objectively how and why older men and women move around their local neighbourhood. This will inform the study analysis.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: GENERIC HEALTH RELEVANCE;CARDIOVASCULAR
Title: AIR POLLUTION AND WEATHER-RELATED HEALTH IMPACTS: METHODOLOGICAL STUDY BASED ON SPATIO-TEMPORALLY DISAGGREGATED MULTI-POLLUTANT MODELS FOR PRESENT-DAY
Funder: Natural Environment Research Council

Abstract: There is a large and convincing body of epidemiological evidence linking short term exposure to outdoor air pollutants to adverse health effects. However, most of this evidence is derived from studies that have linked single pollutants to health in urban environments. There is increasing recognition that greater protection against the adverse health effects of air pollution could be achieved by focusing research and policy not on individual pollutants, but by a multi-pollutant approach. Furthermore, the spatial variation in pollutant concentrations and their health impacts, especially in rural areas and areas outside the larger cities where much of the UK population reside, are not-well established. Socio-economic impacts (and related issues of environmental justice) and other geographically-determined factors, including housing characteristics (indoor pollution), are also potential modifiers of exposure to outdoor air pollution. The increasing complexity of the scientific inquiry is matched by the difficulties of formulating, proving and implementing appropriate regulatory policy. This proposal builds upon an existing collaboration between researchers in the environmental and health disciplines, with the addition of investigators and practitioners from the policy and social science fields. Our proposal aims to provide new epidemiological evidence on the health impacts of exposure to multiple pollutants; to examine the implications of such evidence for regulation and control of air quality; and to assess how uncertainties in evidence affect its translation into actionable evidence-based policies and the evaluation of their costs and benefits. There are several unique innovations in our study: 1) the development of long series of high resolution (5 km) datasets for daily concentrations of a range of pollutants and weather data, linked to geo-referenced health data including daily mortality, hospital admissions and data on heart attacks; 2) an examination of the contribution of the indoor environment as a modifier of exposure to outdoor pollutants to provide an integrated assessment of the risks to health of short term exposure to air pollution; 3) an integrated assessment of the health effects of various near-term future air quality and climate policies in 2030 as well as selected emissions reduction policies for the UK; 4) the development of a 'decision analysis' tool that includes assessment of uncertainties and can be used to infer the likely outcomes of these various policy choices.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: GENERIC HEALTH RELEVANCE;CARDIOVASCULAR
Title: Molecular magnetic resonance imaging with microparticles of iron oxide.
Funder: Wellcome Trust

Abstract: We have developed a new class of agent (termed MPIO) that, when injected intravenously is able to bind to certain molecules that line inflamed or injured blood vessels. These agents are then readily identified non-invasively in mice using magnetic resonance imaging. The contrast effects are so pronounced that they lend themselves to assessment in the following applications: (1) Quantification of actual levels of molecular expression, cross-checked by measuring tissue levels of those molecules (2) identification of certain signalling molecules well in advance of the development of actual disease, but in a way that predicts the development of an anatomically distinct lesion in a given individual. (3) Measuring molecular response to treatment that would be invisible to conventional imaging approaches. The next phases of development of this promising approach will be to make more sophisticated tagging molecules that deliver MPIO to their site of interest and to make biodegradable MPI O that will dissolve harmlessly after use. Collaborators in the University of Oxford have made such particles from complex sugars. In this proposal we will test their properties in vitro and in vivo.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;CARDIOVASCULAR
Title: Causal inference in large datasets using genetic instrumental variables: extending Mendelian randomization techniques.
Funder: Wellcome Trust

Abstract: Mendelian randomization is a technique for assessing cause-effect relations from observational data. Without direct experimentation, which is often impractical, it is usually impossible to distinguish between a factor which is truly responsible for increasing the risk of disease, and one which merely indicates that an individual is at increased risk. In Mendelian randomization, we take advantage of the random allocation of genes to exploit a natural experiment in the population. Under the assump tion that a genetic variant is specifically associated with the factor of interest, the variant mimics the random allocation of a treatment in a clinical trial, allowing assessment of the causal effect of the risk factor in an observational setting. While methods exist for the simple case of a single genetic variant, a single risk factor and disease outcome, we would like to go beyond this. My research comprises extensions to Mendelian randomization to cover situations where there are large n umbers of genetic variants, multiple risk factors, and data from a variety of sources. We want to understand networks of relationships between various potential risk factors using all available data. The overall aim is to better understand mechanisms which cause disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE;CARDIOVASCULAR
Title: Phase 1 Randomised Clinical Trial of the First-in-Class KMO inhibitor KNS366
Funder: Innovate UK

Abstract: Our company, Kynos Therapeutics Ltd., is developing a new kind of medicine to treat diseases caused by inflammation, especially kidney damage after major open heart surgery, and that may also have a use against cancer. This new medicine affects the metabolism of cells and tissues, and especially how cells of the immune system function. Our new medicine has all the characteristics required to be developed into a successful drug for patients, and has been extensively safety-tested in experimental models.\r\n\r\nIn order to continue the new medicines development process, we need to now make sure that this new medicine is safe for human use. In this project, which is a clinical trial recruiting healthy volunteers, we will carefully measure the safety of the new medicine by giving a very low dose of the new medicine and gradually increasing the dose across different groups of volunteers, ultimately reaching a dose level that we expect will be the dose used in patients. Throughout all of this process, the safety of the volunteers will be our foremost priority.\r\n\r\nIf our project is successful and the medicine is safe in humans, and blood tests show that the medicine changes metabolism in the way we expect it to, we will have made a game-changing leap forward and opened the door to follow-on clinical trials involving patients, initially to trial whether the medicine can prevent kidney damage after major open heart surgery.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE;CARDIOVASCULAR;CANCER AND NEOPLASMS
Title: Chronicity and Care in African Contexts
Funder: The British Academy

Abstract: My research programme, themed Chronicity and Care in African Contexts, will contribute to global initiatives addressing Africa’s disproportionate burden of chronic diseases through a “whole-of-society” approach, and to UCL’s Grand Challenge of Global Health and forthcoming London Strategy. Blending research and public engagement, I will conduct a longitudinal social psychological study on chronic illness experiences and systems of care among London’s West African communities, and establish a multilingual-multimedia website and annual international multi-stakeholder workshops on the programme theme. The programme will inform my graduate teaching, supervision and research collaboration at UCL and broader networking activities with my current collaborators in the UK, US, Netherlands and West Africa. I will disseminate research results through academic, policy, and popular press publications, and promote the British Academy Global Professorship through my research networks and participating in Psychology, African Studies, Medical Humanities and Global Health conferences.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE;CARDIOVASCULAR;METABOLIC AND ENDOCRINE;RESPIRATORY
Title: The Whitehall II study: A Core Resource for Ageing Research
Funder: Medical Research Council

Abstract: The aim of our proposal is to maximise the potential of the Whitehall II study as a source of discovery and replication for research on aetiology and prognosis of age-related conditions, such as dementia, cardiometabolic diseases and multimorbidity. We seek MRC support to ensure arrangements for sustainable long term biosample/data storage and ease of access for future studies; to enrich the dataset by annual update of linkage to electronic health records, including hospital admissions (diagnoses and treatments), cancer, cause of death, use of mental health services (including dementia) and primary care data; to ensure the opportunity to re-contact participants for further data collection, and to continue and increase sharing of the data to the research community in the UK and elsewhere. Whitehall II is a prospective cohort study of 10,308 women and men, aged 35 to 55 years at study inception in 1985-88, followed up with 7 repeated clinical examinations up to 2016. Biorepository includes 334,137 stored blood, urine, and hair samples; data from clinical examinations are anthropometry, blood pressure, electrocardiogram (ECG) and a range of physical and cognitive functional tests. The data are enriched by genotyping from the Illumina Metabochip (200K SNPs); the new Illumina Human Drug Core Array, which has a whole genome SNP scaffold with enhanced coverage with 200,000 custom markers in 4,500 drugged/druggable genes; serum NMR metabolomics profiling of 233 lipids, lipoproteins and metabolic intermediates; and, for a subsample, proteomic profiling based on SOMAScan multiplexed assay for >4000 proteins. During the grant period (by 2023), the cumulative number of cases from electronic health records will be 1316 for dementia, 1028 for cardiometabolic multimorbidity, and 717 for stroke, providing future studies with >95% power to detect a 1.3-fold relative risk for top compared to bottom tertile in midlife risk factors in relation to old-age disease outcomes.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: GENERIC HEALTH RELEVANCE;CARDIOVASCULAR;NEUROLOGICAL