NIHRDataInsights/HRCSData huggingface dataset:
Title: Metabolic control of epigenetic stability and potential in pluripotent stem cells
Funder: Medical Research Council

Abstract: Metabolism is emerging as a key regulatory mechanism to control cellular function, potential, and state through the dynamic regulation of the epigenome. In particular embryonic development is characterised by significant metabolic, epigenetic and cellular changes associated with different developmental stages, suggesting that metabolism may play a key role in regulating cell fate decisions. But until now, the precise molecular interplay between metabolism and the epigenome remains poorly understood. The main goal of this proposal is to understand the mechanisms that link metabolism with epigenetic changes and cellular potential in pluripotent stem cells (PSCs). I plan to generate a comprehensive dataset of metabolic states in human and mouse PSCs and assess the impact of induced metabolic changes on PSC potential, histone and DNA methylation, and the relevant epigenetic enzymes. Elucidating these mechanisms will reveal molecular principles involved in the regulation of the epigenome and affecting PSC potential and state. This knowledge will form the basis for novel PSC differentiation strategies for regenerative medicine and will also contribute to our understanding of metabolic disease states and aging.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: BMI trajectories in middle to old age: methodological developments, missing data and cost-effectiveness
Funder: Medical Research Council

Abstract: Medical literature suggests that certain individuals lose muscle mass as they get older, while others continue to show a steady increase in BMI. Those who lose muscle mass experience a drop in BMI but an increase in body fat percentage (known as the obesity paradox) and could be at increased risk of comorbidities or mortality which is left unidentified due to their lower BMI. This study will use a range of growth models to estimate mean trajectories of BMI as individual's transition from middle to old age. Using latent class growth modelling, it will be possible to identify different types of individuals who are more or less likely to experience different BMI trajectories, allowing individuals at risk to be targeted by health professionals and policy makers earlier. Multiple BMI trajectories identified in this study will be linked with comorbidities and mortality in order to determine which BMI trajectories are a cause for concern. This will be particularly important if the different trajectories have very different outcomes. Again, this will allow at risk individuals to be targeted earlier with the intention of leading to better health outcomes. Missing data will be accounted for in a number of ways. These will include complete case analysis and imputation, which have been used previously in the literature as well as pattern mixture and selection models. These methods will be compared and additional methods development will be considered if appropriate. Results from the analysis described above will be used to update the existing School for Public Health Research (SPHR) diabetes prevention model. This will allow optimal subgroups of individuals to be identified for which interventions will be most cost-effective as well as producing unbiased estimates after accounting for missing data.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;8.2 HEALTH AND WELFARE ECONOMICS
Health categories: METABOLIC AND ENDOCRINE
Title: Investigating the causal associations of diet and gut microbiome in the development of metabolic disease.
Funder: Medical Research Council

Abstract: Obesity and its related conditions are leading public health concerns worldwide. Besides diet and physical activity, gut microbiota is a modifiable factor that can be targeted to prevent and treat these conditions. Indeed, alterations in gut microbiome (i.e. gut dysbiosis) have been reported in obesity and diabetes. Gut microbiome itself is affected by diet, however, the causal role of diet in gut dysbiosis, and in turn, a causal role for gut dysbiosis in the development of metabolic disease remains to be determined. Causality is difficult to assess as observational studies are subject to reverse causation and confounding bias. Mendelian Randomization (MR) is an approach that can assess causality using genetic variants, as they are randomly inherited and remain constant over life. In this project, I will begin by identifying genetic variants associated with dietary variables through genome-wide association studies (GWAS) using the UK Biobank. Next, MetaCardis cohort will be utilized to investigate the relationship between diet and gut microbial profiles during metabolic disease development. Finally, 2 sample MR will be applied using the genetic variants for dietary variables identified in step1 to the metagenomic data in step 2 to investigate whether diet causes metabolic disease via changes in the gut microbiome. These observations will also be utilized for developing health policy-related research questions in order to enhance the translational impact of the proposed work.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Research into mutations causing pituitary endocrine disorders directly or indirectly affecting growth and development
Funder: Medical Research Foundation

Abstract: Research into mutations causing pituitary endocrine disorders directly or indirectly affecting growth and development. This includes sequencing studies in patients and laboratory assessment s of the functional consequences of these gene mutations in cell lines and in transgenic animals.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Metreleptin for treating lipodystrophy [ID861]
Funder: Department of Health and Social Care

Abstract: To evaluate the benefits and costs of metreleptin within its licensed indication for treating lipodystrophy for national commissioning by NHS England.

Lay abstract: Lipodystrophy is a rare, heterogeneous group of syndromes characterised by the complete or partial loss or absence of subcutaneous adipose tissue. Without sufficient adipose tissue the hormone leptin can become deficient and the body’s system for regulating energy use and storage is disrupted, resulting in lipid accumulation in abnormal sites, such as the liver and muscle. Lipodystrophy is often accompanied by metabolic abnormalities including insulin resistance with resultant hyperinsulinemia and diabetes mellitus, hepatic steatosis or steatohepatitis, dyslipidemia and severe hypertriglyceridemia. It can therefore have a substantial effect on quality of life. Despite progress in identifying the molecular basis of many lipodystrophy syndromes, it is often diagnosed late in the course of the disease or remain undiagnosed. Lipodystrophy is generally classified on the basis of the extent or pattern of fat loss (generalised or partial) and whether the disease is genetic or acquired. There are 4 major subtypes: Generalised: ? congenital (inherited) generalised lipodystrophy ? acquired generalised lipodystrophy Partial: ? familial partial (inherited) lipodystrophy ? acquired partial lipodystrophy The prevalence of lipodystrophy varies from approximately 1 to 2 per 1,000,000 population depending on the subtype. Applying the prevalence estimates to the population of England for 2016 (1) suggests there are approximately 200 people with lipodystrophy in England. There are no licensed treatments in the UK for generalised or partial lipodystrophy. The disease is currently managed with lifestyle modifications: such as a low fat diet and exercise; cosmetic surgery; and medications to manage the metabolic disturbance associated with leptin deficiency, including lipid lowering drugs (fibrates and statins) and medications for diabetes (metformin, insulin, sulphonylureas, and thiazolidinediones). A single National Specialist Service for people with lipodystrophy was established in 2011 at Addenbrooke’s Hospital in Cambridge. References 1 Population of England (2016) https://www.ons.gov.uk/peoplepopulationandcommunity/populationandmigrati on/populationestimates Accessed October 2017

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Diabetes
Funder: Department of Health and Social Care

Abstract: Our strategy is to improve biomedical and psychosocial outcomes for people with and at risk for diabetes and its complications by improving access to and uptake of strategies of proven benefit, optimising these to engage people more widely. We focus on groups in the local community with underserved needs for treatment and prevention and documented poorer outcomes: local adults with established T1DM and suboptimal diabetes control and children at high risk of obesity and T2DM.


Research activity codes: 8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: METABOLIC AND ENDOCRINE
Title: Dapagliflozin for type 1 diabetes [ID1478]
Funder: Department of Health and Social Care

Abstract: To appraise the clinical and cost effectiveness of dapagliflozin within its marketing authorisation for treating type 1 diabetes.

Lay abstract: Type 1 diabetes results from the body’s own immune system destroying the cells that make insulin. The inability to secrete insulin leads to high blood glucose levels (that is, hyperglycaemia) and other metabolic abnormalities, which have short and long-term health consequences. Long-term complications include blindness, kidney failure, foot ulceration, amputation, premature heart disease, stroke and death. The risk of developing complications can be reduced by limiting tissue damage with insulin treatment that lowers blood glucose levels to as near normal levels as possible. However, insulin may increase the risk of hypoglycaemia (that is, low blood glucose levels) and weight gain. In addition, some people on insulin may still not meet blood glucose targets. In England in 2017, about 3.1 million people had diabetes (1), of which around 10% had type 1 diabetes (2). The management of type 1 diabetes in adults includes structured education, dietary control, physical activity, self-monitoring of blood glucose levels, insulin therapy, hypoglycaemia control, ketone monitoring, control of cardiovascular risk and treating complications. The NICE clinical guideline on the diagnosis and management of type 1 diabetes in adults (NG17) recommends flexible basal-bolus insulin regimens. This involves self-injecting multiple daily doses of longer-acting insulin to keep blood glucose levels stable during periods of fasting, and short-acting insulin to prevent increases in blood glucose levels after meals. NICE technology appraisal 151 recommends continuous subcutaneous insulin infusion (‘insulin pump’) therapy for people on multiple daily injections who have disabling hypoglycaemia, or when average blood glucose concentrations remain high (haemoglobin A1c, HbA1c levels are 69 mmol/mol or higher). The clinical guideline also recommends consideration of adding metformin, which does not currently have a marketing authorisation in the UK for treating type 1 diabetes, to insulin therapy in some circumstances. References 1. Diabetes UK (2017) Diabetes Prevalence 2017. Accessed August 2018. 2. Diabetes UK (2018) Facts & Figures. Accessed August 2018.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Forensic detection of steroid abuse - Online hydrotreatment as an elegant preparative step - Resubmission
Funder: Science and Technology Facilities Council

Abstract: Detection of drug abuse is essential for safety and fairness in sport. Steroid hormones are the most commonly abused drugs in athletics but confirming steroid abuse can be difficult. One highly accurate method is to look inside the carbon atoms of steroid to measure the ratio of their non-radioactive isotopes (carbon-12 to carbon-13). The carbon isotope ratios of natural human steroids and those used by drug cheats are recognizably different. However, measuring carbon isotope ratios requires good sample preparation steps and steroids can be problematic for the instruments used. Existing preparation techniques lag behind the powerful capabilities of modern mass spectrometer detectors. STFC research has produced a rapid on-line method that can be used to treats steroids with hydrogen to leave only the carbon skeleton intact - the perfect preparation step for carbon isotope ratio analysis. This grant will commercialize the method by demonstrating its advantages relative to existing techniques and by producing a prototype system that will allow the method to be used by technical staff in forensic laboratories world-wide. The commercialization will benefit from partnership with a major UK provider of drug testing services.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: METABOLIC AND ENDOCRINE
Title: A bio-inspired artificial pancreas for Type 1 diabetes
Funder: Wellcome Trust

Abstract: The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive management of type 1 diabetes reduced complications by 50-76 per cent compared with conventional therapy. This was achieved at the expense of increased hypoglycaemia, especially when HbA1c levels <7.5 per cent were achieved. A closed loop system provides the potential to improve HbA1c levels while avoiding hypoglycaemia. Professor Christofer Toumazou and Dr Pantelis Georgiou at the Institute of Biomedical Engineering together with Professor Desmond Johnston and Dr Nick Oliver at the St Mary's Hospital of Imperial College London have received a Translation Award to develop a bio-inspired artificial pancreas that will be used for closed loop control of type 1 diabetes. They aim to develop and clinically trial a microchip that will be used in conjunction with clinically approved glucose sensors and pumps to control blood glucose. The overall system will replicate the concentrations between 4 and 8mM and will therefore be the world’s first bio-inspired artificial pancreas.A film of Dr Nick Oliver and Dr Pantelis Georgiou talking about the device is available to watch on the YouTube channel of Imperial College London.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: METABOLIC AND ENDOCRINE
Title: Aetiology and Mechanisms of Diabetes and Related Metabolic Disorders of Later Life
Funder: Medical Research Council

Abstract: The overall aim of this programme is to use epidemiological methods to investigate aetiological pathways to type 2 diabetes and to translate that knowledge into preventive action. The descriptive epidemiology of type 2 diabetes (T2DM) and its variation in time, place and person suggests that it arises from a complex interplay between innate susceptibility and lifestyle behavioural factors. Although global hypotheses have been put forward to explain these variations, the detailed mechanisms and pathways that underlie them are largely unknown. This programme aims to investigate the basis of these interactions by studying the genetic aetiology of obesity, T2DM and related metabolic disorders, the association between lifestyle factors such as diet, nutrition and physical activity, and lastly to study how the interplay between these various factors leads to disease. These goals are studied using a range of different epidemiological study designs including large case-control and case-cohort studies and population-based cohorts with detailed quantitative metabolic characterisation. The study of gene-lifestyle interaction requires a synthesis of data from a range of different studies including a large prospective case-cohort study nested within an existing cohort (EPIC-InterAct) and detailed metabolic phenotype cohorts with objective assessment of key lifestyle behaviours (Fenland study). Specific objectives are currently to (i) Investigate the genetic basis of T2DM (ii) Study the genetics of intermediate quantitative traits in order to identify and validate potential modifiable pathways to diabetes risk and (iii) Study the basis for gene-lifestyle interactions in the causation of T2DM and related quantitative traits.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: METABOLIC AND ENDOCRINE
Title: Mechanisms of insulin resistance in South Asians (MIRSA): the roles of skeletal muscle microvasculature and mitochondrial metabolism
Funder: Medical Research Council

Abstract: South Asians (SA) have 2-4 fold higher risk of type 2 diabetes and develop the disease at lower body weights and younger ages than white Europeans. Lower cardiorespiratory fitness and capacity for muscle fat oxidation contributes substantially to SAs' greater insulin resistance, the extent to which this can be improved by exercise training is unclear. In this randomised controlled trial, we will investigate the effects of a 12-week exercise training intervention on insulin sensitivity (hyperinsulinaemic-euglycaemic clamp) in South Asian adults (22 intervention, 22 control). We will also explore the mechanisms within skeletal muscle which mediate these changes by evaluating exercise-training induced changes: in basal and insulin-stimulated microvascular blood volume (using contrast-enhanced ultrasound); skeletal muscle mitochondrial function (Seahorse); and lipid droplet morphology and spatial interaction with mitochrondria, muscle fibre capillarisation, endothelial content of key enzymes controlling dilation/constriction and GLUT-4 translocation (using novel confocal immunofluorescence microscopy and transmission electron microscopy methods). Thus, this work will integrate physiological and molecular data to determine the extent to which exercise training can improve insulin sensitivity in SA and the mechanisms underpinning this improvement. This knowledge is important for optimising diabetes prevention interventions in SAs and identification of potential novel therapeutic targets.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Regulation of pancreas organoid plasticity: new strategies for diabetes
Funder: Medical Research Council

Abstract: We hypothesize that increasing the stability of Ngn3/Pdx1/MafA and targeting the right subpopulation of cells within pancreatic organoids will result in more efficient beta cell generation and more functional beta cells. Using a multidisciplinary approach integrating molecular and cellular studies with advanced imaging techniques, NGS, FACS and proteomics, we will leverage basic biology to improve beta cell generation. In Aim 1, we will characterise the Fbw7:Pdx1/MafA and Ngn3-Huwe1 axes (coIP, ubiquitin assays, mapping critical residues, Fbw7 and Huwe1 loss of function experiments, identification of novel interactors). In addition, the functional role of both axes in organoid differentiation into beta cells will be evaluated. In Aim 2, a comprehensive characterization of the role of the lysosome on the regulation of the proendocrine factors and in the differentiation process will be assessed. We will inhibit lysosome function using pharmacological agents (Lysosome inhibitors, NH4Cl, Leupeptine) or loss of function strategies (lysosome components). We will test glucose challenge-induced insulin release, calcium measurements, and qPCR and IF analysis of beta cell markers (glut2, pck1/3, insulin, gck) to assess the efficiency of differentiation upon perturbation of the lysosome pathway. In Aim 3, we will perform Genomix 10X single cell RNAseq analysis (3000 cells/sample) in mouse adult organoids using differentiating and undifferentiating conditions. Comprehensive bioinformatics analysis will be focused on the identification of novel FACS-sortable markers for the subpopulation which is permissive to differentiate to beta cells and we will address whether the lysosome and huwe1 signature could explain the organoid heterogeneity. Functional validation of the identified populations will be assessed as in aims 1 and 2.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: Aldosterone regulation in aldosterone-producing cell clusters and its impact on medical management of primary aldosteronism
Funder: Medical Research Council

Abstract: Background: 25% of the adult population has hypertension and, in 10% of those people, the cause is primary aldosteronism (PA). Despite its prevalence, <1% of cases are discovered and cured due to challenging investigations and low cure rate after definitive surgery; 50%. The recent discovery of microscopic clusters of aldosterone producing cells (APCC) indicates that they are a likely precursor to APA and a possible cause of persistent PA after surgery. Aims: To develop an understanding of APCCs and their role in PA, identify molecules whose measurements can guide optimal management of PA and offer targets for a medical cure. The objectives are 1- mechanistic; to a) find which selectively-expressed molecules of APCCs regulate aldosterone secretion b) find out if SLC35F1 is a nicotinamide transporter, and 2- translational; to identify components of adrenal blood, and treatment responses to e.g. ultra-low ACTH, which predict treatment outcomes and/or the presence of APCCs. Methodology: Conditioned cell culture with subsequent aldosterone assay and qPCR for CYP11B2 will be performed on H295R cell line and human adrenal. Transfection with a 3rd generation lentivirus vector will be used to investigate proteins acting within the cell. Tissue slices will be used to investigate conditions in which cell-cell communication is important. Small experimental studies include the measurement of target molecules in adrenal vein blood and correlation with surgical outcomes. Outcomes: Understanding the cell biology of APCCs, which is of great interest in identifying the frequency, pathogenesis and therapeutic targets of PA. Adrenal vein molecular markers of APCCs could be used as a predictor of surgical outcome. The novel methodologies proposed will enable adrenal researchers to model the in-vivo pathophysiology of adrenal glands.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE