NIHRDataInsights/HRCSData huggingface dataset:
Title: Bridging the gap to translation by understanding and preventing diabetic vascular complications using human organoids
Funder: Medical Research Council

Abstract: Aims and Objectives: To (i) determine if modulation of apelin-APLNR or angiopoietin-2 signalling affects hyperglycaemia-induced damage to human vascular organoids; (ii) establish the specific role of endothelial apelin-APLNR and angiopoietin-2 signalling on the diabetic vasculature and (iii) test how human vascular organoids respond to being exposed to serum from diabetic patients with/without vascular complications. Methods: Apelin-APLNR and angiopoietin-2 signalling will be modulated using recombinant proteins, lentiviral transfections and chemical inhibitors in human vascular organoids cultured in a diabetic medium. Structural and transcriptome analysis will be performed. Novel transgenic mice to modulate endothelial apelin-APLNR and angiopoietin-2 signalling in a spatial- and temporal- specific manner will be used and the effect on the kidney diabetic vasculature explored. Finally, human vascular organoids will be exposed to serum from diabetic patients with/without vascular complications. We will then use proteomics, lipidomics and metabolomics to investigate if there are any protective factors in the serum of patients without vascular complications. Outcomes: Our proposal will bridge the gap between rodent studies and clinical trials and test the potential of manipulating angiopoietins and apelin as a therapy for diabetic vascular complications. We predict that using samples from diabetic patients with/without albuminuria will facilitate the discovery of new therapeutic targets to treat diabetic complications in the future.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CARDIOVASCULAR;METABOLIC AND ENDOCRINE
Title: Dietary patterns, microbiome, metabolome and cardiovascular disease risk in transitioning India
Funder: Medical Research Council

Abstract: The prevalence of cardiovascular disease in India is increasing rapidly. This is widely attributed to changes in dietary patterns (from traditional to western) associated with economic transition, but the molecular mechanisms by which dietary patterns specific to India (i.e. predominantly vegetarian) influence the risk of cardiovascular disease are unknown. The Andhra Pradesh Children and Parents Study is an intergenerational cohort study in 29 villages near Hyderabad city, South India. In 2010-12, detailed data on diet and cardiovascular disease risk factors were collected for ~7000 participants, and blood samples banked. The peri-urban study villages have since experienced rapid unplanned development, providing a unique opportunity for prospective investigation of mechanisms by which dietary transition may influence the risk of cardiovascular disease. We plan to re-examine the cohort in 2020-22 to collect data on dietary patterns, cardiovascular risk factors, and key hypothesised mechanisms (i.e. gut microbiome, blood metabolome, immunome and micronutrients) to address the following objectives: -Identify predominant patterns for diet, gut microbiome and blood metabolome in this transitional community, and any systematic variations in these by the level of village development -Investigate the key molecular pathways hypothesised to explain the relationship between dietary patterns and cardiovascular disease risk -Investigate the role played by the gut microbiome in the relationship between dietary patterns and cardiovascular disease risk, specifically through changes in immunological functioning and micronutrient deficiencies Findings from this study may inform dietary guidelines and food policy in India, and ultimately lead to a reduction in economic burden from cardiovascular disease epidemic in India.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR;METABOLIC AND ENDOCRINE
Title: MATCH endocrine research trial
Funder: Barts Charity

Abstract: Full title: Is Metomidate PET-CT superior to Adrenal venous sampling in predicting outTCome from adrenalectomy in patients with primary Hyperaldosteronism (MATCH): a multi-centre, randomised, within-patient comparison of diagnostic techniques. This application is for consumables costs for three years - the remaining trial costs will be met through other grants/ departmental funding.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR;METABOLIC AND ENDOCRINE
Title: Do we miss a common subset of Primary Aldosteronism in which there is cyclical or exaggerated diurnal variation in secretion?
Funder: Barts Charity

Abstract: Hypertension is a common condition affecting more than 1 in 4 adults in England. It is estimated that up to 10% have primary aldosteronism (PA). Compared with other patients with essential hypertension, patients with PA have higher risks of cardiovascular and metabolic disease. Presently, less than 1% of patients with PA are detected and treated. Of those with unilateral PA that are treated surgically by adrenalectomy, there is a low complete cure rate of 30%. In the future, radiofrequency ablation (RFA) of the adrenal gland may become a treatment option with ongoing trials (FABULAS and WAVE trials) investigating this. A recent study showed that 24h urine aldosterone measurements increases the detection of PA by two-fold.(5) Rather than a reduction in the threshold of diagnosis, the mechanism suggested was pulsatile secretion or exaggerated diurnal secretion of aldosterone. In our own studies seeking somatic mutations which cause aldosterone producing adenomas, somatic mutations of CADM1 were found in patients with apparently cyclical PA and these patients were completely cured following adrenalectomy. Transfection studies revealed biological rhythms as the most upregulated pathway.This project will aim to test the hypothesis that a number of patients with PA fail diagnosis by conventional criteria, because of cyclical, or exaggerated diurnal variation in aldosterone secretion; and to discover whether this ‘missing cohort’ includes patients with unilateral PA, whose potentially curable hypertension is due to somatic mutation of genes which influence (or are influenced by) the adrenocortical clock. My cohort will be 77 patients suspected of PA who missed conventional diagnosis. 24h urine tetrahydroaldosterone (THA) is the most sensitive urine assay for PA, revalidated in our current prospective NIHR study, MATCH. I will determine whether THA doubles the prevalence of PA, compared to conventional plasma assays, and whether the ‘extra’ patients have exaggerated diurnal variation of plasma aldosterone.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR;METABOLIC AND ENDOCRINE
Title: Genetic and molecular mechanisms of kidney stone disease
Funder: Medical Research Council

Abstract: To increase understanding of the molecular and genetic basis of kidney stone disease (KSD) I will: 1) Establish the role of coding region variants in KSD using whole exome sequencing data. I will assess for single-variant and gene-based associations with KSD in the UK Biobank and replicate findings in datasets such as FinnGen. I will search the 100,000 Genomes database for rare variants in genes of interest. Analyses will be undertaken in PLINK, GWAMA and SAIGE-GENE. 2) Identify metabolomic and proteomic biomarkers linking central adiposity with KSD and serum calcium concentrations. A) I will perform adjusted regression to identify biomarkers associated with increased waist-hip ratio (WHR), KSD and serum calcium in the UK Biobank. Biomarkers with consistent directional associations with WHR and KSD or serum calcium will be used in Mendelian randomisation (MR). B) Using publicly available genetic instruments for WHR and summary statistics from biomarker GWAS, I will test for causal links between WHR and biomarkers with MR using IVW and MR-Egger methods. Where biomarker summary statistics are not available, I will perform GWAS. C) Where biomarkers are causally linked to WHR, I will identify independent SNPs for biomarkers through conditional analyses and perform MR with summary statistics from existing KSD and serum calcium GWAS. This will identify causal links of WHR influenced biomarkers with risk of KSD or serum calcium concentrations. 3) Define potential novel therapeutic strategies for the treatment of KSD via drug target-MR studies. I will select established expression and protein quantitative trait loci as proxies of medication effects for potential therapeutic targets identified in 1 and 2. MR will be used to assess their effect on risk of KSD using KSD GWAS summary statistics. I will use targets from stages 1 and 2 in integrative network analyses to extract biological pathways and connector genes to uncover drug targets and repurposing opportunities.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR;METABOLIC AND ENDOCRINE;RENAL AND UROGENITAL
Title: Quality and Safety in Organ Donation Tissue Bank - Expansion to include Pancreas/Islets, Heart and Lungs
Funder: Medical Research Council

Abstract: The QUOD Biobank established in 2012 and funded by NHSBT until 2020, provides a unique, rapidly expanding resource comprising rich clinical data of most UK deceased organ donors; banked peri-donation blood and urine samples underpinning an 'omics' biomarker exploration / bioinformatics core; and a central tissue bank, currently including liver, kidney, ureter, and spleen biopsies from 85% of donors. A special multi-centre HTA site licence comprising 62 hospitals across the UK has been awarded to NHSBT enabling specimen removal during donation for research banking. A robust and sustainable infrastructure has been established. A bespoke 'QUOD box' is used at the donor hospital to contain all samples including blood, urine, and tissue biopsies. Bloods are collected in specific tubes to fulfil individual requirements. Tissue biopsies are preserved in buffered formalin to be processed into formalin fixed paraffin embedded (FFPE) tissue blocks for histological sectioning and analysis. Additional biopsies are collected in RNAlater and snap-frozen for banking to enable metabolic, proteomic and DNA studies. We propose expansion of sampling protocols to include collection of minimally invasive pancreas, heart and lung tissue biopsies as well as bronchioalveolar lavage samples. In addition, selected untransplanted pancreata, hearts, and lungs representing the breadth of normal, acutely stressed and chronically diseased clinical phenotypes will be transported to processing centres in Newcastle / Oxford for systematic biopsy collection, in depth phenotypic characterisation and structured pathology reporting to create searchable atlases and quantitative analyses linked to clinical data and serum proteomic biomarker library. Blocks for FFPE, frozen sectioning and EM will be stored and available for further analysis including tissue microarray, RNAScope, single cell sequencing. Live cells including intact pancreatic islets will be isolated for functional / single cell analysis.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: CARDIOVASCULAR;METABOLIC AND ENDOCRINE;RENAL AND UROGENITAL;RESPIRATORY
Title: Stochastic models to enable tailoring of medications to patients with multiple morbidities
Funder: Medical Research Council

Abstract: We propose to study three common chronic conditions: diabetes, cardiovascular disease and COPD, and their clinical guidelines. In order to find a combination of medications which result in the best outcomes for patients, we need to consider the patient's clinical history, current values and preferences, as well as have a model and treatment information for other patients with similar conditions. For the later, we propose to use Scottish EHRs, specialist disease registry data (e.g., diabetes registry), the national prescribing dataset PIS, and primary and secondary care data in Scotland. This fellowship opportunity will explore combinations of machine learning, formal modelling techniques and automated reasoning approaches commonly used respectively in Theoretical Computer Science and in Artificial Intelligence, to construct (stochastic) models from guidelines and EHRs. This will enable us to compute the optimal medication choices for a patient with one or more chronic conditions, given his/her recorded data and comparisons with similar patients. We will further investigate solutions in the presence of uncertainties and incomplete information. To evaluate the approach, we will develop and test predictive models iteratively using Scottish EHRs and replicate the processes on data from other centres involved in HDR UK, Canada and Brazil.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: CARDIOVASCULAR;METABOLIC AND ENDOCRINE;RESPIRATORY
Title: Effect of Inorganic Nitrite on Cardiac and Skeletal Muscle: Physiology, Pharmacology and Therapeutic Potential
Funder: Medical Research Council

Abstract: Until recently considered a relatively inert metabolite of nitric oxide, there is now emerging evidence that nitrite can exert very important effects, some of which occur at concentrations close to physiological levels. Amongst these, recent studies indicate that modestly increasing plasma nitrite by dietary means increases the metabolic efficiency of skeletal muscle during exercise. The mechanism responsible is unclear but may involve an effect on the mitochondrial electron transport chain. It is not known whether nitrite exerts similar effects on cardiac muscle. This programme grant comprises a series of mechanistic and clinical studies to 1. Evaluate the mechanism(s) responsible for increased metabolic efficiency in skeletal muscle when plasma nitrite is increased 2. Assess whether nitrite exerts similar effects in cardiac muscle 3. Assess the potential clinical application of these effects for therapeutic purposes. This will include the treatment of intermittent claudication (reversible ischaemia of limb skeletal muscle during exercise), stable angina (reversible ischaemia of cardiac muscle) and heart failure (a syndrome in which reduced cardiac energetic status plays an important pathophysiological role). The applicants bring together a mix of clinical, physiological, pharmacological and molecular skills and the design of the programme ensures strong integration between the clinical and mechanistic studies.


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR;MUSCULOSKELETAL
Title: Health of vegetarians
Funder: Medical Research Council

Abstract: Health of vegetarians: technical summary EPIC-Oxford is a population cohort of 65,500 men and women recruited throughout the UK in 1993-2000. The cohort comprises 34,000 meat-eaters, 10,000 people who eat fish but not meat, 19,000 lacto-vegetarians and 2,500 vegans. Participants completed a questionnaire on diet and lifestyle and gave written consent for follow-up through medical records. 20,000 participants gave a blood sample at recruitment, and 1,000 gave a second blood sample 5 years later. Follow-up questionnaires were completed 5, 10 and 15 years after recruitment. Participants are followed through record linkage to NHS data for all hospital episodes, cancers and deaths. The main dietary exposures examined will be vegetarian and vegan diets, and consumption of meat, fish, dairy products, animal protein, dairy protein, saturated fat, n-6 polyunsaturated fatty acids, n-3 fatty acids, fibre, vitamin B12 and calcium. The main disease endpoints will be: cardiovascular disease including ischaemic heart disease and stroke, skeletal health including fractures and joint replacement for osteoarthritis, and gastrointestinal disorders. The data will be analysed by standard methods for cohort studies. Repeat measures of diet and other factors will be included, and adjustments made for smoking and other relevant confounding factors. In addition to these specific research objectives, a further important part of the work proposed is to make the data from EPIC-Oxford accessible to other medical researchers, thus maximising the scientific output from the study. This will include the incorporation of the EPIC-Oxford databases into the Richard Doll Centenary Data Archive, as well as linkage to the MRC Gateway and other communications with external medical researchers.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: CARDIOVASCULAR;MUSCULOSKELETAL;ORAL AND GASTROINTESTINAL;STROKE
Title: The Interrogation of the cardiomyopathy of chronic kidney disease with advanced cardiac imaging
Funder: Chief Scientist Office, Scotland

Abstract: Patients with kidney failure have a much higher risk of heart disease compared to people without kidney failure. Cardiac MRI (CMR) is a very detailed scan of the heart and blood vessels. In this project we will use CMR to test a specialized measure of heart function, called strain, to find which patients with kidney failure are at high risk of heart disease. We will also perform CMR scans in patients before and after dialysis (a treatment for patients with kidney failure) to see whether dialysis changes the heart muscle. We will compare the pictures on CMR with another type of heart scan, called a CT scan, to see just how much damage to the heart muscle patients with kidney failure have. Finally, we will test a new way to measure hardening of blood vessels on CMR. These four studies will help us to better understand the heart and blood vessel changes that happen in kidney failure. This research will also be useful for patients without kidney failure. We hope to be able to use it in the future to see which new treatments might be able to reduce the risk of heart disease in patients with kidney failure.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR;NEUROLOGICAL
Title: Dizziness in the elderly - the role of small vessel disease
Funder: Dunhill Medical Trust

Abstract: Dizziness is one of the most common symptoms in the elderly but, in up to 50% of cases, no diagnosis can be made. We postulate that in a significant proportion of such patients the dizziness is due to an increased load of white-matter small-vessel disease (SVD). We know that SVD (as seen on MRI) increases with age and vascular risk factors and that, in advanced stages, it can cause gait dysfunction and falls. So, dizziness may be the earliest stage of this gait deterioration process. As such, early diagnosis and treatment could slow down progression. Our retrospective observations (Ahmad et al 2015, see below) support the view that “unexplained” dizziness may be caused by SVD, but a prospective study is essential to advance this hypothesis and to provide a mechanistic explanation. In this regard we postulate that SVD “disconnects” balance brain centres, which we will investigate with quantitative MRI


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR;NEUROLOGICAL
Title: Interplay between brain endothelial cells and pericytes in brain health and disease
Funder: Medical Research Council

Abstract: Many neurological disorders including Alzheimer's disease (AD) and small vessel disease (SVD) are associated with blood-brain barrier (BBB) dysfunctions. Early degeneration of brain pericytes and activation of endothelial cells are thought to be critical factors in the development and progression of common dementias. However, the molecular pathways which drive endothelial and pericyte dysfunctions are largely unknown, with no established therapies. In this fellowship, I will define the relationship between endothelial activation, pericyte degeneration, and BBB compromise, with a view to developing strategies to protecting vascular functions. The study has three goals: 1. Determine the spatiotemporal relationship between endothelial activation, pericyte function, and BBB breakdown. I will employ genetic animal models of both endothelial activation and pericyte degeneration to define the downstream consequences for the other cell type, as well as for BBB function. These investigations will involve longitudinal magnetic resonance imaging (MRI), positron emission tomography (PET), and in vivo two-photon microscopy, as well as analysis of evolving transcriptional signatures within each cell type at single cell resolution. 2. Test BBB preserving interventions in an in vitro platform composed of primary mouse endothelial cells co-cultured with pericytes. I will genetically manipulate endothelial cells and pericytes and study the impact on BBB functions. This information will help define therapeutic targets for the prevention of vascular dysfunctions. 3. Define the impact of vascular-targeted therapeutic interventions in vivo on pericyte and BBB functions in AD-/SVD-relevant models, and also downstream outcome measures including neuroinflammation and neuronal and cognitive dysfunctions. To achieve these aims, I will exploit my expertise in vascular biology, PET/MR, and optical imaging, and gain further training in transcriptomic analyses and in vitro systems.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR;NEUROLOGICAL
Title: Development of Autonomic Function Testing as a clinical & research tool to interrogate and improve neural control of the circulation
Funder: Barts Charity

Abstract: Better understanding of neural regulation of the circulation by the autonomic nervous system is key to improving healthcare delivery and outcomes for millions of patients with circulatory disorders including hypertension (15 million adults in the UK), hypotension, Postural tachycardia syndrome and, more recently, Long COVID. Our grant is intended to establish autonomic function testing as a standard of care to investigate complex circulatory disorders and provide both insights into mechanistic regulation of the circulation through evaluation of the impact of interventions (such as device therapy for hypertension or drugs to treat neurogenic orthostatic hypotension) as well as deeper phenotyping of the circulation to enable better patient management from both investigational and therapeutic perspectives. This use of the AFT lab will also result in training of the next generation of clinicians in autonomic assessment and lay the foundations for the establishment of autonomic testing as a standalone NHS facility in the Barts Heart Centre.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR;NEUROLOGICAL