NIHRDataInsights/HRCSData huggingface dataset:
Title: The genetics of sleep patterns and their relationship to obesity and Type 2 diabetes
Funder: Medical Research Council

Abstract: This study will provide new insights into sleep and circadian rhythm biology and help determine the causal direction of the association between metabolic disease and disrupted sleep. There are well-known associations between sleep patterns and metabolic disease. The observational nature of the associations in human studies means that convincing evidence of causality in humans is lacking. In this study, we will identify genetic variants associated with sleep patterns and use these in Mendelian Randomisation analyses to test the causal role of sleep on BMI and Type 2 diabetes. Identifying genetic variants associated with normal variation in sleep will also provide new insights in the biology of sleep patterns and provide new therapeutics targets for sleep disorders. We will perform GWAS on >20,000,000 genetic variants in 500,000 individuals from the UK Biobank on a range of sleep traits. We will use data from self-report on all individuals and in a subset of 100,000 individuals we will derive activity-monitor based estimates of sleep traits. We will perform GWAS on both the self-report and objective estimates and integrate and cross-validate the results. We will replicate the associations in >200,000 individuals from a range of studies including 23andMe, the CHARGE and Chronogen consortia and the Rotterdam and CoLaus studies. We use the Mendelian Randomisation techniques of instrumental variables analysis and Eggers regression on robustly associated variants to test whether any sleep patterns are causally associated with obesity and Type 2 diabetes. To avoid overfitting biases we will test the variants against the phenotypes in independent large-scale genome-wide consortia datasets such as the GIANT consortium. We will also use robustly associated signals and perform in silico fine-mapping analyses to identify likely causal variants at each loci and we will perform pathway-based analyses to look for biological connections between associated loci.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: National Innovation Centre for Ageing (NICA)
Funder: Medical Research Council

Abstract: The proposed National Centre for Ageing Science and Innovation (NASI) will use high quality research and innovation, from one of the leading ageing research centres in the world Newcastle University, to solve societal challenges and create new economic opportunities. NASI will bring together, in one centre, world-leading scientists from a range of key disciplines to work together with industry, the NHS, the public and public sector to create a critical mass of expertise in the ageing and innovation arena and to develop, evaluate and, with industry, bring to market products which optimise health and wellbeing as people age.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: METABOLIC AND ENDOCRINE
Title: Characterising the feedback control mechanisms of the glucocorticoid receptor within the adrenal steroidogenic regulatory network
Funder: Medical Research Council

Abstract: The Hypothalamic-Pituitary-Adrenal (HPA) axis modulates circulating levels of glucocorticoids (CORT), which are key hormone mediators of our body's response to stress. CORT is synthesised by the adrenal gland following stimulation by adrenocorticotropic hormone (ACTH) secreted by the pituitary, and both hormones normally exhibit tightly correlated fluctuations. However, under pathological conditions (e.g. inflammation, chronic stress, neurological dysfunction) or ageing, these pulsatile dynamics are altered and the tight synchrony between ACTH and CORT becomes significantly disrupted. Uncovering the mechanisms through which the HPA axis maintains a "dynamic equilibrium" is critical to understand stress-related disorders affecting a large portion of the population. In this sense, my current models suggest that certain factors involved in CORT synthesis may be responsible for the dissociation of these hormone signals. In this project, I will develop mathematical models of the regulatory mechanisms underlying CORT synthesis and predict how hormone dynamics is disrupted during disease. To test this, I will perform experiments to explore how ACTH and CORT modulate gene expression. This includes determining how transcription factors interact with gene promoters and synergise to modulate their expression. I will use these models to evaluate the plausible biophysical mechanisms through which these factors may regulate gene expression and disrupt hormone dynamics. Lastly, I will develop multiscale models of the adrenal gland and the HPA axis, and use them to analyse a number of experiments, drug treatments, and relevant physiological and pathological conditions. Importantly, this will include designing novel CORT replacement therapies and understanding the effects of synthetic versions of CORT, which are widely used in the clinic and constitute some of the most frequently prescribed drugs in the UK to treat inflammation and stress-related illnesses.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: METABOLIC AND ENDOCRINE
Title: Intercellular communication in pseudoislets: shaping the dynamics of insulin secretion
Funder: Medical Research Council

Abstract: Insulin, one of the key hormonal regulators of blood glucose levels, is secreted into the blood by beta cells in the islets of Langerhans. Intercellular communication is critical to the secretory response of the islets. In particular, efficient insulin secretion has been linked to the synchronisation of electrical activity of beta cells across an islet, which is achieved through communication, primarily via physical connections between adjacent cells. Disruptions to the network structure can result in a loss of normal functioning of the islet. This project will explore the mechanisms by which a network's size and structure impact its synchronisation properties using pseudoislets cultured from human beta (EndoC-BH1) cells. Pseudoislets are populations of beta cells that are grown in three dimensional structures that approximate real islets. Through the development of a detailed mathematical model of the pseudoislet, incorporating all relevant ion channels, I will examine in a systematic way how cellular communication affects synchronisation of the islets and ultimately, their secretory response. To calibrate the model, I will collect data from pseudoislets to characterise the electrically excitability of EndoC-BH1 cells using electrophysiology techniques and map out the connections between them using immunohistochemical staining procedures. After identifying the key network components, I will use the model to generate predictions about how manipulations to network size and structure will impact insulin secretion and perform experiments to test these and thus validate the model. I will then predict how the function of real islets becomes compromised as beta cells are lost during type 1 and 2 diabetes. Finally, I will identify the optimal size and configuration of an islet with respect to insulin secretion. This is particularly important as islet transplantation has been identified as a potential therapy for type 1 diabetes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: The Cambridge Initiative: Proposal to enhance linked research in human fat metabolism and pathophysiology between MRC HNR, MRC MDU and MRC Epi
Funder: Medical Research Council

Abstract: A central question in diabetes and nutrition research is why some individuals are predisposed to developing type 2 diabetes, while others are remarkably resistant to the disease despite similar levels of obesity and activity. While genetics plays a role, there is growing evidence that there are clear associations between insulin resistance and the handling of dietary lipids, in particular the uptake, synthesis and storage of lipids. This proposal is to develop a platform in human pathophysiology of fat metabolism using a combination of HNR's state-of-the-art high-resolution mass spectrometry for lipidomics and world-class facilities in stable isotope labelling to directly measure turnover of fats. This work will provide a collaborative bridge between MRC Human Nutrition Research, the proposed MRC Metabolic Disease Unit and MRC Epidemiology, by facilitating the translation of fundamental cellular and animal studies through into population and policy-relevant outcomes and clinical treatments. We will examine fat metabolism in small, well-defined patient groups which will inform the modelling of specific aspects of the Metabolic Syndrome including fatty liver disease, polycystic ovary syndrome, non-obese diabetic individuals and obese insulin sensitive individuals. We will use stable isotope labelled fats to probe lipid handling and metabolism, conducting stable isotope techniques alongside high resolution mass spectrometry used to detect intact lipids directly, including triglycerides, phospholipids, and cholesterol lipids, as well as lipids thought to be involved in lipotoxicity such as eicosanoids, long-chain carnitines and acyl-CoA derivatives, ceramides, monoacylglycerides and diacylglycerides. In particular, we will develop techniques to investigate (i) differences in de novo lipogenesis, (ii) uptake of fatty acids in different meals to model how lipid absorption changes across individuals, (iii) responses to glucose and insulin in the different patient groups.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Insulin therapy in pancreas and islet transplantation
Funder: Medical Research Council

Abstract: Pancreas and islet transplantation are highly-effective life-saving therapies in type 1 diabetes. The paucity of suitable organs for transplant and the high subsequent failure rate creates an urgent need to: a) optimise methods for selecting good-quality pancreata; and b) identify the ideal physiological environment for a transplanted pancreas to succeed. My preliminary data show that use of insulin in pancreas donors on intensive care is associated with higher rates of subsequent pancreas transplant failure. It is unclear whether donor insulin therapy can predict transplant failure independently of a risk score used to select donors - the Pancreas Donor Risk Index (PDRI), or if it is a marker of irreversible beta-cell death. In islet transplant recipients, peri-transplant insulin therapy is standard of care, but the relationship between peri-transplant glucose control and subsequent transplant function is unclear. My data show that peri-transplant hyperglycaemia occurs in one third of pancreas recipients but it is unknown if insulin therapy could improve outcomes. Objectives: 1) In a large scale registry of pancreas transplant recipients, to determine whether donor insulin use improves clinical prediction of transplant failure beyond the PDRI; 2) In a lab-based study of pancreas donors, to describe the relationship between donor insulin therapy, and beta-cell function and death; 3) In islet transplant recipients, to relate peri-transplant glycaemic control to beta-cell function at 3 months; 4) In pancreas transplant recipients, to determine whether a multi-centre randomised controlled trial (RCT) of peri-transplant insulin therapy can be justified and would be acceptable and feasible. My Fellowship is expected to lead to better pancreas donor selection and improved patient outcomes through incorporating donor insulin use in the PDRI. It will lead either to an RCT of peri-transplant insulin therapy in pancreas recipients or a national consensus statement.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: AMPK-mediated regulation and roles of miR-125b and miR-184 in pancreatic beta-cell function.
Funder: Medical Research Council

Abstract: MiRNAs are small RNAs essential for endocrine function and altered in T2D. AMPK is an important energy sensor essential to maintain beta-cell function and survival by mechanisms not-well understood. My preliminary data show that miR-184 and miR-125b expression is altered in islets from mice lacking AMPK in beta-cells (AMPKdKO) and that beta-cell levels of both miRNAs are regulated by glucose. MiR-184 is already known to impact beta-cell function, whereas the role of miR-125b, a strong regulator of signalling and apoptosis in tumours, hasn't been studied in beta-cells. I hypothesize that miR-125b impacts beta-cell function and survival, that AMPK mediates the effects of glucose on miR-184 and miR-125b expression in beta-cells and that miR-184/miR-125b in turn contribute to the effects of AMPK in beta-cell identity and function. I will: 1. Assess the effect of AMPK depletion in the regulation of miR-184 and miR-125b by glucose in vivo and in vitro. 2. Use ChIP and reporter experiments to identify the regulatory sequences and proteins in the miRNAs' promoters. 3. Determine miR-184/miR-125b contribution to AMPK action by restoring the function of these miRNAs in AMPKdKO islets. 4. Apply the innovative iCLIP technique in beta-cell lines to identify miR-125b gene targets in a high-throughput manner. 5. Generate mice with genetic beta-cell-specific miR-125b alteration. 6. Transplant human islets with altered miR-125b levels into the mouse eye, generating a humanized mouse model with optically accessible islets to study in vivo. 7. I will use conventional and state-of-the art technologies, such as high-resolution in vivo confocal microscopy, to assess beta-cell function and survival. This work will help to understand the mechanisms underlying AMPK and miRNA action in beta-cells while introducing the use of new cutting-edge technologies for the study of beta-cell function. This is vital for the development of better-targeted drugs to treat T2D.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Body size trajectories and cardio-metabolic resilience to obesity in three United Kingdom birth cohorts
Funder: Medical Research Council

Abstract: Overweight or obese individuals, who now form the majority of United Kingdom (UK) population, do not represent a single homogenous group in terms of cardio-metabolic health prospects. The concept of metabolically-healthy obesity (MHO) has been widely debated. Regardless of one's perceptions of MHO, however, there is heterogeneity in cardio-metabolic risk factors among obese adults and little is known about the biological, life course processes that explain that heterogeneity. The aim of this grant is to reveal the body size trajectories and pubertal development patterns that might attenuate the positive associations of adulthood obesity with cardio-metabolic disease risk factors, thereby providing cardio-metabolic resilience to obesity. This information will not only represent a gain in scientific knowledge, but may stimulate other research and be used to guide public health policies that aim to improve disease processes. This is a secondary data analysis project across three large, nationally representative UK birth cohorts, the first born in 1946, the second in 1958, and the third in 1970. A significant aspect of this work will be collating and harmonising life course data across the studies, which will require close liaison with the key stakeholders, and developing advanced and powerful statistical models. Select observational findings will be followed-up in genetic instrumental variable analyses in large bio-medical surveys, thereby helping assess causality. Working across multiple cohorts born at different points in time adds another important aspect to this grant; we will be able to quantify any secular trend in resilience to obesity (and in the roles of body size trajectories and pubertal timing). This knowledge will represent a significant advancement in our understanding of UK population level changes in health among obese individuals.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: METABOLIC AND ENDOCRINE
Title: Beta-defensins in the prevention of obesity
Funder: Medical Research Council

Abstract: Obesity (excess adiposity) has reached epidemic levels in the UK and globally: in both adults and (most worrying in the longer term) in children. Obesity and obesity-related disease (including type 2 diabetes, hypertension, dyslipidaemia, asthma and some forms of cancer) are major contributors to NHS and welfare costs and to reduced quality of life. Lifestyle and sociodemographic factors clearly play major roles, but so do genetic factors. Obesity is highly heritable, estimated to be between 50% and 70%. Understanding the phenotypes in genetically mutant rodents is a valuable path towards understanding both factors contributing to obesity and those that may help prevent it. We have deleted a cluster of antimicrobial and immunomodulatory (beta-defensin) genes from the mouse and find that homozygous mutant animals of both sexes are obese (25% heavier) in adulthood. Conversely, transgenic expression of a human beta-defensin leads to reduced weight. Together, these data strongly imply that beta-defensins have a role in bodyweight regulation and have therapeutic potential. We seek here to characterise the phenotypes we observe in the defensin deletion and transgenic mice to understand the mechanism by which deletion causes obesity and yet over expression leads to a lean phenotype. We wish to clarify whether the lean phenotype requires neuronal expression or whether systemic delivery will allow the lean phenotype to be evident. This proposal outlines work essential for considering rationally designed novel, defensin-based therapeutic approaches for obesity reduction in humans.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: EXTending availability of self-management structured EducatioN programmes for people with type 2 Diabetes in low-to-middle income countries (EXTEND)
Funder: Medical Research Council

Abstract: Globally, it is estimated that 415 million people have diabetes (90% type 2, T2D) and that three quarters of people live in Low-to-middle income countries (LMIC). Urbanisation and an ageing population are considered to be the main drivers for the increasing prevalence of chronic non-communicable diseases such as T2D. Indeed, LMICs health services are are increasingly under pressure with this "double jeopardy" of communicable disease (e.g. HIV) and chronic NCD. Significant development challenges in LMIC are lack of healthcare infrastructure and wide disparities in access to high-quality healthcare due to poverty, both of which impact on diabetes management. Subsequently, there is a demand for effective and cost-effective treatment options for people with T2D. Structured Education Programmes (SEPs) are a potential solution for this scenario. Leading international health organisations promote self-management as the cornerstone of diabetes care, and recommend SEPs for all people with T2D. There are no SEPs available is LMIC such as Malawi and Mozambique that have proven effectiveness and cost-effectiveness. We propose to take a SEP, developed in the UK, with proven effectiveness and cost-effectiveness and undertake a cultural and linguistic adaptation of the programme in Malawi and Mozambique. Through development of infrastructure and training, using a multi-disciplinary approach we will build the capability of these LMICs to deliver such programmes. We will conduct feasibility studies at each locality to explore accessibility and acceptability. We will build new methodological knowledge and develop a SEP adaptation toolkit and implementation model for SEPs in LMIC. These will be made freely available. The data and knowledge gained from the feasibility studies will inform the development of a protocol for the formal evaluation of each SEP in their localities. It will also form the basis for attracting future funding to secure the legacy of this work.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: METABOLIC AND ENDOCRINE
Title: Selective CYP11B1 inhibitors as a novel treatment option for endogenous cortisol excess
Funder: Medical Research Council

Abstract: Aims: Perform a systematic preclinical testing of the most promising selective CYP11B1 inhibitors to develop a superior drug treatment option for endogenous Cortisol excess. Objectives: 1: Use of a rodent model to provide proof-of-principle for in vivo efficacy of selective CYP11B1 inhibition for the treatment of endogenous cortisol excess. 1.1: In vitro identification of selective murine Cyp11b1 (mCyp11b1) inhibitors. 1.2: In vivo proof-of-principle in a murine model of endogenous cortisol excess 2: Translation to human: Identification of the most promising inhibitor compound for future in vivo studies in human. 2.1: Evaluation of selected inhibitor compounds in different in vitro models. 2.2: Initial assessment of biodistribution and bioavailability for the most promising inhibitor compound. Methodology: In preliminary work I have identified eight novel selective inhibitors of human CYP11B1. To demonstrate that selective inhibition of CYP11B1 successfully reverts the adverse metabolic consequences of endogenous glucocorticoid excess, I will select one compound that selectively inhibits the murine Cyp11b1 to be applied in a proof-of-principle mouse model of Cushing's. The selective human CYP11B1 inhibitors will then be evaluated in different in vitro models to assess their effect on residual steroidogenesis, steroidogenic enzyme expression and potential toxic effects. I will subsequently perform an initial assessment of bioavailability for the most promising compound in a commercially available assay to estimate metabolic stability and perform an in vivo assessment of biodistribution in rats. Scientific/Medical Opportunity: For endogenous cortisol excess, a highly effective drug treatment option that can be tailored to the individualised needs of every patient is strongly needed. My study will ultimately lead to a first-in-man testing of a novel CYP11B1 inhibitor as a new treatment option that can be tailored to the degree of cortisol excess.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE