NIHRDataInsights/HRCSData huggingface dataset:
Title: Genes and Environment in Diabetes Mellitus : A multi-species approach
Funder: Medical Research Council

Abstract: Aims: The aim of this project is to understand the biology of the DEXI gene which has been associated with susceptiblity to multiple autoimmune diseases including type 1 diabetes (T1D), multiple sclerosis and primary biliary cirrhosis. The specific questions of the functional impact of this gene in the context of the immune system and the microbiome will be addressed. Objectives: The first objectives of this study are to evaluate the impact of DEXI knockout on diabetes suceptibility, the microbiome and the function of the immune system. Additionally, this project will generate novel monoclonal antibodies to facilitate study of DEXI protein across species, including humans. This project will also endeavour to evaluate the client-owned domestic pet dog, which also suffers from spontaneous diabetes, as a potential spontaneous model for study of the microbiome in T1D. Methodology: Gene knockdown has already been achieved using CRISPR-Cas9 technology in the non-obese diabetic (NOD) model. Immunological and phenotypic studies will include evaluation of cytokine production and activation status in response to a range of stimuli and single cell RNA-Seq of selected cell types. Microbiome analysis will be undertaken on DNA extracted from faeces in the NOD and in spontaneously diabetic pet dogs undergoing veterinary treatment. Microbiome transfer experiments will also be undertaken in the NOD model in the presence and absence of Dexi. Scientific and medical opportunities: Discovery of novel pathways in autoimmune disease susceptibility offers new opportunities for therapeutic or preventative intervention.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Remodelling of corticotroph excitability in chronic stress: an integrated physiological and modelling analysis
Funder: Medical Research Council

Abstract: Chronic stress (CS) is a major risk factor for development of a wide range of human disorders including diabetes, obesity, cardiovascular function as well as neurological and behavioural deficits. CS is typically associated with hypersensitivity of the hypothalamic-pituitary-adrenal (HPA) axis with escape from glucocorticoid negative feedback. The anterior pituitary corticotroph has been proposed as a major locus for CS-induced changes in HPA axis function, however the mechanisms are not defined. We have recently identified that chronic stress promotes extensive remodelling of the corticotroph ion channel landscape, including channels critical to the control of 'basal' and hypothalamic CRH- and AVP-evoked ACTH secretion. Importantly, these data suggest that CS controls corticotroph hypersensitivity primarily by altering calcium-dependent signalling responses to CRH and/or AVP rather than through effects on ACTH content or availability for release. To address this, we will take an integrated hybrid experimental and mathematical modelling approach to define both in vivo and ex vivo: altered regulation of ACTH secretion by secretagogues and modification of glucocorticoid feedback following CS; the underlying mechanisms leading to altered corticotroph ion channel expression; and the reversibility of ion channel mediated corticotroph dysregualtion following either cessation of CS or pharmacological manipulation of intracellular signalling pathways. Taken together we will unravel the molecular mechanisms by which chronic stress controls HPA axis function at the level of the anterior pituitary corticotroph and define mechanisms and targets for potential therapeutic strategies to limit the deleterious effects of sustained stress for validation in future translational studies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Targeting GLP-1 receptor trafficking to improve therapies for type 2 diabetes
Funder: Medical Research Council

Abstract: The glucagon-like peptide-1 receptor (GLP-1R) is an important target in type 2 diabetes (T2D) as GLP-1R agonists stimulate beta cell insulin release and promote weight loss. The GLP-1R undergoes rapid agonist-mediated endocytosis, leading us to question whether desensitisation limits GLP-1R agonist treatment effectiveness. We have tested this hypothesis by generating modified versions of the GLP-1R agonist exendin-4. One of these, Ex-phe1, displays a sharply reduced propensity for receptor internalisation, is a more potent insulin secretagogue, and provides enhanced glycaemic control in diabetic mice without increasing nausea, a common side effect of GLP-1R agonists. Ex-phe1 exhibits a distinct pharmacological profile to the parent compound, including fast receptor dissociation kinetics and biased signalling, with beta-arrestin-2 (barr2) recruitment selectively reduced. Here, we will elucidate the molecular mechanisms linking biased GLP-1R activation and trafficking to insulin secretion and examine the therapeutic benefits of biased GLP-1R agonism in a humanised T2D model. Specifically, we will: 1) identify the structural basis for biased GLP-1R activation and trafficking using molecular modelling, reciprocal receptor mutagenesis and a GLP-1R conformational biosensor; 2) determine biased agonist-specific kinomic and transcriptomic responses and changes to interactions with endocytic trafficking regulators in beta cells; 3) confirm the role of barr2 in beta cell responses to GLP-1R agonism both in beta cell-specific barr2 knockout mice and by silencing barr2 in human islets; and 4) establish the long-term effects of biased GLP-1R agonism in a humanised mouse model with human islets implanted into diabetic mice eyes, an approach that uniquely allows serial imaging of islet morphology and function. These studies will provide critical molecular insights into the control of GLP-1R trafficking by biased agonists and will potentially identify new targets for T2D treatment.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: IMPC: Is Lrg1 an autocrine/paracrine regulator of thermogenesis in brown and beige adipose tissue? Implications for cardiometabolic disease.
Funder: Medical Research Council

Abstract: Significance: An estimated 422 million people worldwide suffer from Type 2 Diabetes (T2D), making the discovery of novel therapeutics imperative. Context: Brown and beige adipose tissue are characterized by high levels of fatty acid oxidation, mitochondrial biogenesis and thermogenesis. Thermogenesis in beige and brown adipocytes alters systemic energy balance with anti-obesity and anti-diabetic effects. Brown and beige fat mass and thermogenic capacity decrease with age and obesity. Leucine-rich-alpha2-glycoprotein 1 (Lrg1) is a liver and adipose-associated secreted protein. Lrg1 plasma concentration is correlated with age, body mass index, and adiposity, suggesting a role in obesity. Our data indicate that Lrg1 inhibits thermogenic gene expression in beige and brown adipose tissue. Aim: To determine whether Lrg1 contributes to obesity related brown and beige adipose loss, and subsequent pathophysiology, using the Lrg1tm1(KOMP)Vlcg mouse. Objectives: 1) Establish an Lrg1tm1(KOMP)Vlcg mouse colony at the University of Leeds. 2) Investigate the effect of Lrg1 knockout on the brown and subcutaneous adipose tissue metabolic phenotype. 3) Assess the metabolic effect of Lrg1 knockout in a dietary-induced mouse model of T2D. Methodology: The effect of Lrg1 knockout on the phenotype of brown and subcutaneous adipose tissue will be investigated using molecular biology and metabolic approaches. The effect of Lrg1 knockout on metabolic parameters (weight, body composition, energy expenditure and glucose/insulin homeostasis) will be assessed in a dietary-induced T2D mouse model. Analysis of systemic metabolic phenotypes including indirect calorimetry, activity and food intake, body composition, and glucose/insulin homeostasis will be conducted using metabolic cages, MRI imaging and glucose and insulin tolerance tests. Applications: This research may identify whether Lrg1 contributes to the pathophysiology of obesity; and highlight Lrg1 as a therapeutic target for T2D.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Roles of the type 2 diabetes (T2D)-associated gene C2cd4a in regulating glucose homeostasis in the mouse
Funder: Medical Research Council

Abstract: C2CD4A lies in a genomic locus associated with increased risk of Type 2 diabetes (T2D) through genome-wide association studies (GWAS). Our own (see below) and others' expression quantitative trait locus (eQTL) analysis have revealed an association between genotype at one of the previously-identified single nucleotide polymorphisms (SNPs) at this locus (rs4502156), as well as with the likely causal SNP rs7163757 (r2=0.939, D'=0.979 with rs4502156) with C2CD4A mRNA (p=0.011, n=40) levels. Here, we will use functional genomics to explore the possibility that C2CD4A plays a role as a causal gene at this locus. Firstly, we will perform oral and intraperitoneal glucose tolerance tests in control and in mutant mice (8-20 weeks of age) deleted globally for C2cd4a using CRISPR/Cas9. Studies will subsequently be performed on mice fed (1) regular chow (2) high fat, or (3) high fat/high sucrose (60% calories) diets. Beta cell mass will be determined using optical projection tomography (OPT) alongside measurement of proliferation (ki67 staining) and apoptosis (TUNEL assay; transmission electron microscopy). Proinsulin processing will be examined in vivo (plasma proinsulin:insulin ratio) and in vitro from isolated islets. Advanced microscopy approaches will be deployed in isolated islets and beta cells to monitor glucose-stimulated energy metabolism (ATP/ADP measurements using the adenovirally-expressed recombinant probe, Perceval). Ca2+ dynamics will be examined using the entrapped fluorescent probe Fluo2, and hub-follower behaviour within the islet explored using rapid confocal analysis. The kinetics of the release of stored insulin by exocytosis will be explored using total internal reflection of fluorescence (TIRF). Depending on our findings, transcriptomic analysis (RNASeq) will also be deployed to explore changes in gene expression after C2cd4a deletion. These studies will thus help to assess the contribution of C2CD4A to T2D risk, and its mechanisms of action.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: IMPC - Understanding the role of 18kDa Translocator protein (TSPO) in the regulation of energy homeostasis in mice
Funder: Medical Research Council

Abstract: Currently available drug therapies for obesity are limited and there is a clear need for new approaches in this area. Obesity leads to chronic low-grade inflammation which is causative in the development of co-morbid conditions including type-2 diabetes. As such, targeting obesity-associated inflammation may represent an approach to improving morbidity. Systemic obesity-associated inflammation is mediated by a change in the immune milieu in white adipose tissue (WAT): macrophages change from a predominant "M2-like" homeostatic phenotype to an "M1-like" proinflammatory state. Emerging evidence suggests that metabolic reprogramming of macrophages influences their phenotype and function. This application focuses on understanding the potential role of a mitochondrial protein called translocator protein (TSPO) at the interface between inflammation and metabolism. Independent studies have demonstrated that 1) loss of TSPO signalling impacts cellular metabolism, and 2) pharmacological inhibition of TSPO is anti-inflammatory and protective in animal models of disease. Our published data demonstrates increased TSPO expression in WAT macrophages in obese mice. We hypothesize that absence of TSPO will confer relative protection from diet-induced obesity and insulin resistance in mice by impacting cellular metabolism and inflammation. Using TSPO-deficient mice obtained from the IMPC, we will test this hypothesis using the following aims: 1) To determine how global loss of TSPO signalling in mice impacts susceptibility to diet-induced obesity and insulin resistance; and 2) To determine how loss of TSPO signalling impacts macrophage function. It is hoped that this work will lead to a larger grant application interrogating the potential of TSPO as a therapeutic target for obesity and we have an established collaboration with a chemist who makes novel TSPO ligands that can be used to validate and extend the findings from this study.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: IMPC: Investigation into the function of pyrroline 5-carboxylate reductase 1 (PYCR1) in metabolic homeostasis
Funder: Medical Research Council

Abstract: Maintaining physiological redox homeostasis is essential for a long health span. Both acute and chronic perturbations in this homeostasis manifest as diseases such as cancer, diabetes and morbidities such as premature ageing. Although some mechanisms of maintaining cellular redox homeostasis are well-described, there are significant fundamental systems that are as yet unclear. Pyrroline 5-carboxylate reductase 1 (PYCR1) is a mitochondrial enzyme that synthesises proline with the concomitant oxidation of NADH. Preliminary data leading to this application suggest that through its contribution to maintenance of the mitochondrial NAD+:NADH ratio, PYCR1 forms part of the cellular response to redox stress. There are also initial data to suggest that loss of Pycr1 may alter glucose and lipid homeostasis in normal conditions. However, there are currently insufficient data currently to support a strong hypothesis-driven project to define the function of Pycr1 in health and disease. The investigations in this project will define the overall physiology of the Pycr1 knock-out mouse, physiological metabolic parameters (e.g. food/water intake, oxygen consumption), the cardiorespiratory response to changes in oxygen tension, and the biochemistry of the blood. Additionally, we will perform initial studies to determine whether loss of Pycr1 alters the physiology of major metabolic tissues, including muscle, liver and adipose tissue. Through these studies, this pump priming award will provide fundamental metabolic information to support a future grant application to the BBSRC to investigate the function of PYCR1 in maintaining 'healthy' redox homeostasis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: Steroid Metabolomics for Diagnosis and Monitoring of Inborn Steroidogenesis Disorders
Funder: Medical Research Council

Abstract: Aims: Improve the life-long health of patients with inborn steroidogenic disorders, including congenital adrenal hyperplasia (CAH) and disordered sex development (DSD), through improved tools for diagnosis and monitoring. Objectives: 1. Machine learning analysis of urinary steroid metabolite data. 2. Statistical comparison this metabolomics approach to the conventional biochemical approach. 3. Incorporation of neonatal-specific steroid metabolites to enhance the diagnostic performance in young children. 4. Development of a high-throughput urinary steroid profiling method. 5. Investigating the use of a machine learning-based "adrenal age" to monitor treatment quality in CAH. Methodology: We have developed a machine learning method, Angle Learning Vector Quantization (ALVQ), to discriminate healthy controls and patients with CAH and DSD. Further work will be done to extend this approach to very rare enzyme defects. Examining untargeted GC-MS spectra of urine from healthy babies under 6 months, I will identify important neonatal metabolites, inclusion of which will enhance diagnostic performance in newborns. I will develop a rapid high-throughput method for steroid profiling and use it to measure samples from CAH patients on two different glucocorticoid preparations. Using machine learning, I can determine an age-specific steroid metabolome prototype, an "adrenal age", and will examine whether the two treatments result in different distances from the adrenal age prototype and whether those relate to currently used biochemical and clinical markers of treatment quality. Scientific/Medical Opportunity: An interpretable machine learning method, utilising the entire steroid metabolomics fingerprint, informed by steroid biology, on a sensitive high-throughput platform represents an excellent novel test for diagnosis and treatment monitoring. This will enable clinicians to personalise treatment, and improve control and outcomes for these patients.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE
Title: A cluster randomised trial of an innovative, low-cost primary care programme for the detection and management of type 2 diabetes in rural Thailand
Funder: Medical Research Council

Abstract: The burden of diabetes and diabetic kidney disease is growing rapidly in Thailand but the healthcare systems, particularly in rural areas, are poorly equipped to address this problem. The aim of this project is to evaluate the impact of a bespoke diabetes management program designed for implementation within existing healthcare systems in rural regions of Thailand. The program, called SMART Health Diabetes and Kidney, uses trained non-physician health workers (NPHWs) to deliver evidence-based care to people with, or at risk of, diabetes assisted by an electronic, clinical decision support system. The study includes 2 phases: a development phase and an evaluation phase. In Phase 1, we will develop diabetes-specific screening and management algorithms based on national and international guidelines. These algorithms will be deployed using an existing java-based mobile platform which can be accessed directly on low-cost smartphone or tablet devices. Based on entered patient information through the application, output will be generated providing screening and treatment recommendations for frontline NPHWs or doctors. The algorithms will undergo iterative testing and refinement as part of Phase 1. In Phase 2, we will evaluate the effectiveness, cost-effectiveness and SMART Health Diabetes in a large cluster randomised controlled trial of 40 villages in Kamphang Pet province. The unit of randomisation will be the Sub-district (Tambon) health office catering to villages. The co-primary outcomes for the study are HbA1c and progression of albuminuria. We will use household surveys to sample individuals 30 years and older at baseline and at follow-up after 48 months. A parallel qualitative study will assess the scalability of SMART Health diabetes.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: METABOLIC AND ENDOCRINE
Title: A scalable solution for delivery of Diabetes Self-Management Education in Thailand
Funder: Medical Research Council

Abstract: Type 2 diabetes is amongst the foremost challenges facing policy makers in Thailand, accounting for considerable death, disability and healthcare expenditure. Under Thailand's strong primary health system, medical management of diabetes is widely available. However, control of blood glucose and other cardiovascular disease risk factors, and regular screening for early detection of complications remain low due to a lack of services for education and counselling to support behavioural changes necessary for good self-management of the condition. A substantial literature documents the effectiveness of Diabetes Self-Management Education (DSME) programs for improving diabetes outcomes, although little high quality data are available in Thailand, and traditional delivery models (health-professional led one-to-one or small-group sessions) are unlikely to be scalable in Thailand given current human resource and budgetary constraints. Thus we propose to develop a low-cost DSME program and scalable delivery model for roll-out within the Thai primary care system. The intervention will be based on behaviour-change and social support theories, delivered in monthly group meetings by lay health workers or nurses, and aided by a suite of short films to introduce key topics and stimulate discussion. We will randomise 15 community hospitals to offer to those newly diagnosed with diabetes DSME delivered by lay health workers, nurses (for comparative effectiveness), or usual care. After 12 months, we will compare glycaemic control and cardiovascular risk scores between the three arms. We will conduct cost-effectiveness, process and policy evaluations to produce best-buy recommendations for the Thai Ministry of Public Health.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: METABOLIC AND ENDOCRINE
Title: Genetic and nutritional control of pancreatic beta cell identity.
Funder: Medical Research Council

Abstract: Type 2 diabetes (T2D) is an epidemic of the 21 st century and consumes almost 10 % of the health care budgets in westernised societies. Progressive pancreatic beta cell failure, characterised by altered gene expression and cellular "identity", are central to disease development. GWAS for T2D have now identified more than 100 loci associated with disease risk, most of which affect insulin secretion rather than action. In an effort to provide new targets for disease treatment, our laboratories have taken a functional genomic approach to identity the causal gene(s) at selected loci, to dissect their mechanisms of action at the molecular level, and to understand how they interact with other genes and environmental risk factors including over-nutrition. STARD10, located at a T2D locus on chromosome 11q, encodes an intracellular lipid binding and transfer protein whose expression is decreased in the beta cell by possession of risk alleles. Under Aim 1, we will explore the molecular mechanisms through which STARD10 affects insulin processing and secretion in human beta cells and human embryonic cell stem-derived beta cell lines deleted for the gene or nearby regulatory elements using CRISPR/Cas9-medated gene editing. In Aim 2 we will explore the mechanisms through which the protein kinase LKB1, and its downstream substrate AMPK, a nutrient-sensitive protein kinase, control beta cell identity, focussing on epigenetic changes and chromatin remodelling. We will also explore the effects of small molecule AMPK activators on insulin secretion in vivo, and develop a photactivatable AMPK regulator to achieve local control of the enzyme in the pancreas. Aim 3 will determine whether the actions of STARD10 on beta cell function are altered by deletion of LKB1, using both conventional mouse genetics and in vivo imaging of islet function after engraftment into the mouse eye.


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