NIHRDataInsights/HRCSData huggingface dataset:
Title: Do mitochondria-targeted hydrogen sulfide (H2S) donors prevent and / or reverse diabetic endothelial dysfunction?
Funder: Medical Research Council

Abstract: We will examine whether our novel mitochondria-targeted H2S donors (mtH2SD) can be used to treat diabetic endothelial dysfunction. Diabetic angiopathy is characterised by an inability of the vascular endothelium to respond to endogenous vasodilators caused by hyperglycaemia (HG), oxidative stress, mitochondrial dysfunction and endothelial damage. Thus, interventions to prevent/reverse endothelial damage caused by diabetic insult could offer a novel treatment option for diabetic angiopathies. Our previous data suggest that therapeutic administration mtH2SD (e.g. AP39 and AP123) may fulfil this role; we showed a significant loss of plasma H2S in diabetes (animals and humans) which was associated with vascular dysfunction and importantly have shown that AP39/AP123 prevents hyperglycaemia-associated metabolic changes and toxicity to the endothelium. Thus, we will firstly synthesise esterase-resistant derivatives of AP39 and AP123 and determine the pathways by which they generate H2S. We will next examine, using cellular and animal vessels, the mechanisms by which mtH2SD protect the endothelium from diabetes-associated degradation and their in vivo therapeutic potential. We will then use cultured vascular endothelial cells and examine the effects of mtH2SD on detrimental HG-induced cellular signalling and determine whether mtH2SD can reverse endothelial damage in vivo by using isolated blood vessels from in diabetic mice treated with (and without) mtH2SD.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR;METABOLIC AND ENDOCRINE
Title: Inorganic nitrate, nitric oxide and energy metabolism in humans
Funder: Medical Research Council

Abstract: The concepts of metabolic and vascular ageing as opposed to chronological ageing form a novel research paradigm useful to ascertain the observed between-subject variability in the association between ageing and cardiovascular and metabolic health outcomes. Older subjects show a greater impairment of endothelial function and control of vascular tone, which are both closely linked to the bio-availability and activity of nitric oxide (NO). The study of genetic, bio-molecular and physiological mechanisms linking ageing and NO metabolism as well as the identification of novel nutritional and lifestyle factors influencing NO synthesis is topical to maintain or restore a healthy ageing phenotype. The overall aims of the proposed research programme will determine: a. The association of ageing with NO synthesis and whether it is modified by eNOS polymorphisms b. The effects of inorganic nitrate supplementation on resting energy expenditure, dietary-induced thermogenesis and absorptive fuel oxidation in the elderly c. The effects of inorganic nitrate supplementation on mitochondrial respiration in muscular and adipose tissue and changes in core pathways involved in glucose and fat oxidation. The projects will use advanced, state of the arts methods for the measurement of endothelial and metabolic functions. These include a non invasive measurement of NO production using stable isotopic tracers, and, for the first time, a measurement of the effects of inorganic nitrate on dietary induced thermogenesis and substrate oxidation using indirect calorimetry. These physiological measurements will be coupled to detailed biomolecular investigations of mitochondrial efficiency in muscular and adipose tissue.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR;METABOLIC AND ENDOCRINE
Title: Diet-induced Arrangement of the gut Microbiome for improvement of Cardiometabolic health
Funder: Medical Research Council

Abstract: To effectively tackle cardiometabolic diseases (CMD) it is crucial to understand interplays between dietary and microbial factors that promote or inhibit transition from early metabolic symptoms to cardiovascular complications. CMD are associated with dysbiotic microbial ecosystems in the gut, that is, alterations in the composition and function of the microbiota. Diet is a prime influencing factor of both the intestinal milieu and risks for developing CMD, but knowledge about the reciprocal interaction between dietary components and microbial populations is scant. The proposal will investigate interactions between diet and the gut microbiota, and the potential of modulating these interactions for prevention of metabolic dysfunction and cardiovascular complications in humans. This would enable novel nutritional strategies for prevention of CMD. The work programme is based on: (i) state-of-the-art prospective and genetically well-characterized human cohorts to gain detailed insight into associations between dietary habits, the gut microbiome and cardiometabolic health parameters; and (ii) targeted nutritional and microbiota interventions to study causal relationships between specific diet-responsive microbial taxa and related metabolites and the development of metabolic syndrome as risk factor for cardiovascular diseases. The work is underpinned by established pipelines for assessment of 16S rRNA gene diversity and composition, as well as state-of-the-art shotgun metagenomics, metabolomics and data integration platforms. Hence, the complementary use of large scale and targeted strategies, explorative and interventional approaches, as well as standardization innovative assessment of the gut microbiota within the DINAMIC consortium will deliver penetrating insights into nutritional strategies to develop and validate practices for modulation of the intestinal microbiome to promote metabolic and cardiovascular health.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.4 METHODOLOGIES AND MEASUREMENTS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: CARDIOVASCULAR;METABOLIC AND ENDOCRINE
Title: Sex differences in the vascular consequences of diabetes: big data analyses to inform prevention and treatment
Funder: Medical Research Council

Abstract: Vascular disease is the major cause of death and disability in people with diabetes. Compelling evidence has shown that the relative risks of major macrovascular diseases conferred by diabetes are considerably greater in women than in men. The factors underpinning these sex differences are largely unknown. I aim to create a leading programme of research that aims to further understand the sex differences in the vascular consequences of diabetes. Since diabetes is defined based on an arbitrary level of a continuous trait, i.e. measures of glyceamia, such as fasting blood glucose or glycated haemoglobin (HbA1c), my objectives are to assess: 1. the sex-specific effects of glyceamic levels on the relative risks of micro- and macrovascular outcomes 2. through Mendelian Randomisation analyses, whether the sex-specific effects of glyceamic levels on vascular disease risk are likely to be causal 3. which biological factors contribute to the sex-specific effects of glyceamic levels on vascular diseases 4. whether differences in health service delivery contribute to the sex-specific effects of diabetes on vascular diseases This research will utilise individual participant data from large contemporary datasets with extensive phenotypic and genotypic detail: UK Biobank (Obj. 1 and 3), linkages of multiple national electronic health records (Obj. 1 and 4) and summary-level data from large international genome-wide association studies (GWAS) consortia (Obj. 2). This project provides new insights in why there are sex differences in the vascular consequences of diabetes. This could inform the development of new interventions, and will inform policy makers in the designing sex-specific guideline recommendations for prevention and treatment of diabetes and vascular diseases. This could help ensure that women are not disproportionately affected by the vascular consequences of diabetes and will help reduce the burden of diabetes and vascular disease in both


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;7.3 MANAGEMENT AND DECISION MAKING
Health categories: CARDIOVASCULAR;METABOLIC AND ENDOCRINE
Title: Methods to improve genetic understanding of cardiometabolic traits through multiple traits and diverse population studies
Funder: Medical Research Council

Abstract: Many trait-associated genetic variants have been identified, but the underlying biological mechanisms behind the genetic effects are unknown and the lists of potential causal variants behind these effects need refinement. The molecular underpinnings of cardiometabolic diseases may be better understood by examining how metabolism is affected by genetic variation via the association analysis of biochemical measures, including metabolites. To improve detection power and fine-mapping, I will develop multi-trait methods, as well as trans-ethnic multi-trait methods, for which methods currently do not exist. To meta-analyse across diverse ancestries, I will construct an adaptable approach to trans-ethnic meta-analysis that balances between combining effects over cohorts without the loss of ethnicity-specific signals. This involves the use of a measure for the degree of genetic architecture overlap at each SNP to partition the SNPs according to heterogeneity and then adapting two approaches: a high-powered trans-ethnic meta-regression approach to detect associations in the presence of allelic heterogeneity due to ancestry and a powerful meta-analysis method in a Bayesian framework. Few methods are applicable to hundreds of traits, as from metabolomics assays. For such data, I will develop an analysis approach that merges factor analysis and multiple regression. For multi-trait fine-mapping, I propose a Bayesian approach that takes advantage of the relatedness between traits by assigning a higher prior probability to joint models with shared variants between the traits. I will also adapt this approach across diverse ethnicities to capitalise on the differences in linkage disequilibrium between them. Further improvements will be sought by integrating external biological data. I will assess method performance via simulation studies and apply the methods to unique datasets to which the outcomes will assist in understanding the aetiology of cardiometabolic diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR;METABOLIC AND ENDOCRINE
Title: Opportunity-Led Research Proposal: Medication adherence in long-term conditions - leverage of the NICOLA study
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: The primary aim of this study is to quantify the level of adherence (using dried blood spot technology) to a range of medications used to treat chronic illness. In this project, type 2 diabetes, hypertension, dyslipidaemia and cardiovascular disease have been selected for study. Having achieved this goal, a further aim is to combine these data with clinical outcome data gathered as part of the latter NICOLA study to evaluate the effect of medication non-adherence on health statis among this patient cohort. The key research questions are: (i) What is the level of adherence to medications used to treat chronic illness in the population in N. Ireland? (ii) Is there differential adherence rates to dofferent medications? (iii) What are the attributes of patients (including socio economic circumstances) and their treatments which lead to non-adherence? (This information will inform primary care intervention strategies). (iv) To what extent is non-adherence corelated with poor clinical outcomes in the study population?


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: CARDIOVASCULAR;METABOLIC AND ENDOCRINE
Title: Human blood-derived endothelial colony forming cells as a new cell therapy for chronic non-healing wounds
Funder: Medical Research Council

Abstract: Chronic non-healing wounds are a major socioeconomic burden worldwide and remain a therapeutic challenge. Some cell therapies based on MSCs and BM-MNCs are being tested to accelerate the wound healing process. A critical factor to achieve wound closure is effective angiogenesis and the majority of chronic wounds, including diabetic ulcers, exhibit impaired neovascularisation. Therefore, we propose a cell therapy based on vasoreparative endothelial progenitor cells known as endothelial colony forming cells (ECFCs) to promote vascular repair that will facilitate wound healing. Our published evidence demonstrates that ECFCs are a highly pure subpopulation of endothelial progenitors isolated from human blood and defined as CD31+CD105+CD14-CD45- cells with clonogenic potential and unequivocal endothelial phenotype. ECFCs contribute directly to angiogenesis by de novo vessel formation and by direct incorporation into pre-existing capillaries. Importantly, we have shown that ECFCs contribute to vascular repair in ischaemic tissues using mouse models for hind limb and retinal ischaemia. This project will harness the vasoreparative properties of ECFCs as a new therapy for chronic wounds. We will use a well-established and clinically-relevant model of diabetic wounds i.e. the mouse silicone-splinted excisional wound model to demonstrate feasibility and efficacy of ECFCs in diabetic wounds. In addition, we will validate a 3D Matrigel-based in vitro tube formation assay as a potency assay for quality control of ECFCs when considered a cell therapy product. This is a legal requirement for ATMPs to ensure consistency in the performance of cells as therapeutics.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CARDIOVASCULAR;METABOLIC AND ENDOCRINE
Title: Image-Derived Enzymatic Adrenal Lateralisation of Primary Hyperaldosteronism (IDEAL)
Funder: Medical Research Council

Abstract: Aim: to develop a highly selective aldosterone synthase (CYP11B2) PET tracer as a diagnostic tool to better identify and stratify patients with primary hyperaldosteronism (PHA) for surgery. Hypertension is a leading cause of premature morbidity and death globally. Although most hypertension can be treated with life-long medication, some patients have "secondary" hypertension due a specific cause, the detection of which is important as it allows more targeted medication or a curative procedure. The commonest secondary cause of hypertension is PHA, characterized by excessive aldosterone production by the adrenal gland/s. PHA occurs in 5-10% of the 12 million patients with hypertension in the UK, and 15-25% of those with treatment resistant hypertension, however, in most cases this cause remains undetected. In cases with a demonstrable unilateral cause - typically an aldosterone producing adenoma (APA) - adrenalectomy substantially reduces blood pressure and medication requirements, and may result in a complete cure (30-60% of cases). Thus, although a unilateral APA is the most common, curable cause of secondary hypertension, less than 300 patients per year undergo adrenalectomy for APAs in the UK. This reflects the inefficient and often inconclusive series of tests currently used to identify APAs (screening, confirmative tests, CT scans and adrenal vein sampling (AVS)). AVS is challenging, invasive, has a poor success rate and is often not feasible as it requires patients with severe hypertension to stop medication for several weeks. Imaging of CYP11B2 can provide a non-invasive readout of aldosterone production in each of the adrenal glands, and allow patients with suspected PHA to be stratified for surgery with a single PET/CT scan, without the need to stop medication. We have developed [18F]UCB2 as the first highly selective CYP11B2 PET tracer. The diagnostic potential of the tracer is substantial and will be evaluated in patients with PHA using PET/CT.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR;METABOLIC AND ENDOCRINE
Title: Innovating behaviour and health surveillance for cardiovascular disease prevention in Malaysia
Funder: Medical Research Council

Abstract: We propose a combination of new data collection, secondary analysis of SEACO cohort data, metabolic analysis of blood and urine samples, methodological innovation using urinary biomarkers and wearable sensors to measure diet and physical activity. We will generate detailed data on diet, physical activity and intermediate cardiometabolic risk factors from 1500 children aged 7-17 years. We will collect objective physical activity data using a wrist-worn accelerometer worn for 7 days. Newly collected blood samples will be analysed using an automated high-throughput serum nuclear magnetic resonance (NMR) to estimate quantitative molecular information >150 metabolites. A targeted assay designed to measure selected putative food biomarkers relevant to Malaysian diets will be applied to n=750 urine samples. Machine learning will be applied to labelled motion sensor data (n=150) to identify eating events and if robust the model will be applied to wrist-worn accelerometer data (n=1500). We will then explore associations of objective measures of physical activity and diet with metabolic health using linear and logistic regression.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CARDIOVASCULAR;METABOLIC AND ENDOCRINE
Title: CHArMING - Control of Hypertension and diAbetes in MINas Gerais
Funder: Medical Research Council

Abstract: In Brazil, the prevalence of hypertension is near 35%, while diabetes is self-reported in 6.2% of adults. Treatment of hypertension and diabetes can avoid complications and death, but, in Brazil and most low- and middle-income countries, blood pressure and glycohemoglobin control rates are still low. The aim of the study is to develop and implement an integrated multidimensional strategy using digital health to be widely used in the PHC setting for the management of patients with hypertension and diabetes, leading to better adherence to glycohemoglobin and blood pressure measurement and decreased glycohemoglobin and blood pressure levels. The intervention consists of a multidimensional strategy with multidisciplinary approach, including: (a) telehealth tools: teleconsultations, telediagnosis and short message service (SMS); (b) a web system for health professionals including a decision support system; (c) continued education, including web courses and in-person activities; (d) group activities for health professionals, as Balint groups; and (e) educational and groups for hypertensive and diabetic patients. This study is a partnership among the University of Southampton, Brazilian Federal Universities of Minas Gerais and of Vales do Jequitinhonha e Mucuri and Einstein Hospital. The study will be conducted in the Mucury Valley, in the northeast region of the Minas Gerais state. The 1st phase will consist in a before-and after study, combined with a qualitative study. The 2nd phase is a cluster randomized controlled open label trial in which 34 PHC units will be randomized to receive or not the intervention. We will recruit hypertensive and diabetic patients from 30 to 80 years-old, 150 per centre, with an expected total sample of 5264 persons. The overall goal of our application is to build a sustainable model for diabetes and hypertension management, embedded in the Brazilian public health system, aiming to reduce the present and future burden in the country.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: CARDIOVASCULAR;METABOLIC AND ENDOCRINE
Title: RESET: REmission of diabetes and improved diastolic function by combining Structured Exercise with meal replacemenT and food reintroduction.
Funder: Medical Research Council

Abstract: Background: Early onset type 2 diabetes (T2DM) is associated with an aggressive disease phenotype and a magnified lifetime risk of cardiovascular disease. Although diabetes remission can be achieved through low energy diets (LED) incorporating meal replacement products (MRP), our research suggests that such approaches do not lead to anticipated improvements in diastolic function or cardio-respiratory fitness, whilst lean mass is lost. Aim: To establish a UK (Leicester)-Canada (Montreal, Edmonton) team of experts to investigate whether combining MRP with structured exercise leads to T2DM remission in younger adults over 24 weeks, whilst also improving diastolic function, cardiorespiratory fitness and supporting lean mass preservation. Design: Prospective, randomized (2 arm) open-label, blinded-endpoint trial. Participants: Obese individuals with T2DM (3 months-6 years), aged 18-40. Control: Standard T2DM care. MRP plus EX: LED with total and partial MRP (900kCal/day) for first 12 weeks followed by individualised food reintroduction (weeks 13-24); combined with supervised aerobic and resistance exercise (weeks 3-12), transitioning to home-based exercise (weeks 13-24). Primary outcomes: Diabetes remission (A1c<6.5% without antihyperglycemic medication). Key secondary outcomes: MRI-defined measures of cardiac function/structure including circumferential peak early diastolic strain rate (diastolic function); peak VO2; visceral/hepatic fat (MRI); body composition, blood pressure; objectively assessed sleep, sedentary time and physical activity; depression, anxiety and quality of life; process evaluations. Sample size: With a conservative 45% remission rate in the intervention group and 5% remission rate in controls (power=90%, alpha=<0.05, 30% dropout), we will recruit 80 individuals (40 UK,40 Canada). Importance: This work will establish whether diabetes remission is possible with early onset T2DM whilst also optimising whole body and cardiovascular health.


Research activity codes: 6.7 PHYSICAL
Health categories: CARDIOVASCULAR;METABOLIC AND ENDOCRINE
Title: A global approach to prevent secondary microvessel complications in diabetes
Funder: Medical Research Council

Abstract: Objective 1: To establish the structural changes in e-Glx at retinal endothelial cell clefts, caused by HS loss, that are associated with increased solute flux. i. Human retinal endothelial cells: HS will be disrupted by enzymatic removal (heprainase III) or knock down (shRNA to the HS biosynthesis enzyme, Ext1). Solute permeability will be assessed across monolayers using electrical cell impedence sensing (ECIS) and labelled albumin passage. E-Glx structure and junctional cleft parameters will be assessed by electron microscopy (EM). ii. Rat retina: E-Glx HS will be removed using an i.v. bolus of heparinase III. Retinal solute flux will be assessed by sodium fluorescein angiography (NaF). HS removal and albumin leak will be confirmed by immunofluorescence on retina. E-Glx structure and junctional cleft parameters will be quantified by EM. Objective 2: To establish structural endothelial glycocalyx HS changes in retinal endothelial cells in diabetes Adult male Wistar rats will receive a single dose of streptozotocin (STZ, 50mg/Kg) or vehicle. Retinal NaF will be measured at 2wk and 4wk post STZ. Urine albumin creatinine ratios (uACR) will be determined at baseline and endpoint. HS removal, retinal albumin leak, e-Glx structure and junctional cleft parameters will be confirmed as in aim 1ii. E-Glx HS immunofluorescence and heparanase activity will be carried out on healthy versus diabetic retina from human donor eyes. Objective 3: To protect e-Glx HS and reduce microvascular permeability in experimental diabetes. Diabetes will be induced in rats as in aim 2. A heparanase inhibitor will be administered i.p. daily for the last 2wk in cohort 1: 4wk post-STZ and cohort 2: 12wk post-STZ. E-Glx HS changes will confirmed by immunofluorescence on fixed retina and glomeruli. E-Glx structural and junctional cleft parameters in the retina and glomerulus quantified as above. Functional microvascular changes will be confirmed by NaF angiography and uACR.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR;METABOLIC AND ENDOCRINE