NIHRDataInsights/HRCSData huggingface dataset:
Title: How does SOX9 regulate the pancreatic niche of beta cell differentiation?.
Funder: Wellcome Trust

Abstract: Beta cell regeneration is an ambitious option for the treatment and potential cure of type 1 diabetes. Evidence to date indicates that understanding how beta cells develop is the best approach for how beta cells might be regenerated in adulthood. My research programme will investigate a regulatory protein called SOX9, which controls how beta cells form during development. I propose that this role depends on SOX9 regulating the production of proteins, which provide the scaffold around the cell. I n conjunction with factors that allow cells to communicate with each other, I propose that collectively, this forms a 'niche', a specialised local environment, which allows cells to perform specific functions, in this case turning into a beta cell. By characterising and investigating this niche during development, I anticipate gaining insights into the potential of duct cells from the adult pancreas to undergo beta cell regeneration. Experiments will be conducted using mouse models alongside nor mal human tissue to attempt to translate data as rapidly as possible into the cell-types of most relevance to patients with type 1 diabetes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Genes and Pathways in Type 1 Diabetes.
Funder: Wellcome Trust

Abstract: Type 1 (insulin dependent) diabetes is an autoimmune disease that is strongly inherited in families. We now understand this heritability to be a combination of several HLA genes and non-HLA genes in over 40 regions across the human genome. The next steps are to pinpoint as accurately as possible the particular genes and variants within them that predispose to type 1 diabetes, in order to identify the pathways in human physiology, probably operating mainly in the immune system, that cont ribute to its development. To achieve these aims substantial statistical analyses and careful statistical design of projects is required. We will need to process increasingly huge volumes of data to identify positions at which the genetic sequence varies between individuals ( variants ), and determine which of these are most predictive of disease state. Further, we want to understand how the most associated genetic variants alter the expression (the signals which tell a cell to make p rotein) and function of genes. We will examine how measures of gene expression and function relate to the disease predictive genetic variants we identify above.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: METABOLIC AND ENDOCRINE
Title: Diabetes and Inflammation Laboratory.
Funder: Wellcome Trust

Abstract: The DIL has helped identify over 40 regions of the genome that influence risk of type 1 diabetes. In each of these chromosome regions are DNA variants that alter the expression and function of genes and increase or decrease predisposition to the autoimmunity and pancreatic beta-cell destruction that causes the disease in most cases. By more detailed genetic mapping and by correlating polymorphism with alterations gene expression, splicing, protein product activity and perturbation of non-protei n coding RNAs, causal genes and their phenotypes will be identified. The effects of the major causal pathways will be modelled in vivo.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Characterisation of the role of perilipin in the molecular regulation of triglyceride hydrolysis
Funder: Wellcome Trust

Abstract: Obesity is a major reason for the prevalence of type 2 diabetes (T2DM) and the metabolic syndrome, both of which cause significant suffering. Obese people are prone to the metabolic syndrome/T2DM because obesity causes insulin resistance. Understanding this relationship is essential if we are to improve treatment options. Scientists have adopted several approaches to this problem including work in cells and animal models. I have chosen instead to focus on rare patients with inherited forms o f lipodystrophy, a disease in which people lack all or some body fat. Paradoxically these patients manifest the same metabolic problems as obese people. As well as providing a genetic diagnosis for patients my work enables us to learn about the metabolic role of the particular gene/protein responsible for lipodystrophy and provides novel therapeutic targets. In one or two cases it has meant that we can offer specific therapies. Patients with these rare diseases can also inform our understanding of common types of the metabolic syndrome/T2DM. It is now possible to derive stem cells from human skin so we can use cells from lipodystrophic patients to explore disease pathways, test new therapies and potentially correct genetic defects prior to transplanting the cells back into patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Temporal regulation of endocrine gene expression - timing in living cells and tissues.
Funder: Wellcome Trust

Abstract: We aim to understand the dynamic regulation of pituitary hormone gene expression in living cells and tissues using valuable transgenic rat models generated over our previous period of funding. Using luciferase or destabilised fluorescent proteins to report promoter activity in real time, we will use pituitary cells and tissue slice preparations to understand the spatio-temporal patterns of gene expression, with 4-dimensional non-linear mathematical modelling approaches to test in what ways cells are transcriptionally coordinated in different circumstances, including fetal and neonatal development, responses to oestrogen, and lactotroph hyperplasia. The transgenic rat models we have generated have shown dramatic induction of human prolactin gene expression in extra-pituitary tissues after inflammatory stress. In addition to detailed assessment of endogenous prolactin gene expression in human tissues, we will use this to identify the pathways involved in prolactin's role in different types of inflammatory response.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: The role of MRAP in extra-adrenal tissues.
Funder: Wellcome Trust

Abstract: The adrenal glands are small organs which produce a number of hormones, including steroid hormones, which are essential for life. MRAP is a gene present in the adrenal gland and works by helping a receptor (MC2R) move from inside the cell to the cell surface, where it can respond to a signal which results in the production of steroid hormones. Defects in MRAP and the MC2 receptor result in an inability to produce steroids, which causes a rare disease called Familial Glucocorticoid Deficiency. Previous research has shown that MRAP is not only present in the adrenal gland, but is also present in other tissues including white blood cells, the ovary and testis. The role of MRAP in these tissues is unknown. It is possible that MRAP is helping other receptors reach the cell surface in these tissues and allowing them to function. The aim of this project is to investigate the function of MRAP in these tissues and will be carried out using cells derived from these tissues. Understa nding how MRAP works may lead to further understanding of the role of steroid hormones, including their role in inflammation. This knowledge could lead to therapeutic applications.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: Use of proteomics and systems biology to dissect the molecular adaptability of metabolism in muscle and fat cells
Funder: Wellcome Trust

Abstract: Metabolic diseases, such as cardiovascular disease and type 2 diabetes, are world-wide health problems These diseases are thought to be caused, in part, by inactivity and overeating and are defined by a blunted response to the hormone insulin, or insulin-resistance, resulting in aberrant metabolism of nutrients. Mammalian metabolism is a complex and highly adaptive system that exists in precise equilibrium with the environment. Any changes in the environment (e.g. diet, exercise) will lead to major rearrangements in this equilibrium. Since this system comprises an intricate network of components, rather than focussing on individual molecules, I will adopt methods that are able to interrogate the entire metabolic system. I will perform these experiments in appropriate biological models, including mice and humans, which undergo a continuum from a healthy to a metabolically compromised state. These data will be analysed using engineering and mathematical principals; an interdisci plinary field known as Systems Biology. By examining healthy cells as they transition to an insulin-resistant state I aim to identify components of the metabolic system that are either protective or deleterious to the organism. This will lead to the discovery of unexpected features of these pathways thus facilitating novel approaches for both diagnosis and drug discovery.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Heritability and Pharmacogenetics in patients with Type 2 diabetes
Funder: Wellcome Trust

Abstract: There is considerable variability in how a drug works. Some people do not respond to a drug, whilst other might have life threatening side effects. A number of recent studies have found that differences in a person s DNA can be responsible for some of this variation. Finding more of these genetic variants will potentially allow individually tailored treatment. In Tayside, comprehensive clinical information including all previous prescribing is available for all patients with diabetes. In a Wellcome Trust funded study, over half of people with Type 2 diabetes in Tayside provided DNA. This resource is powerful for genetic studies of drug response, and work by the applicant, Sponsor and Research sponsor in Dundee have used this to identify a number of genetic variants that alter response to common drugs such as metformin and statins. It is apparent that the highly complex data requires new methods to be developed to deliver its full potential. In this fellowship the applicant w ill work with some of the world s leading geneticists to address some fundamental concepts in the study of drug response. This will allow greater insight into the genetics of drug response and will increase our progress towards personalized medicine.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: A structural and biochemical approach to understand the molecular mechanism of glycogen synthesis.
Funder: Wellcome Trust

Abstract: Glycogen is a large molecule composed of glucose units that are stored in long chains, tightly packed together. The process of storing glucose into glycogen in muscle cells, (e.g. after a meal), involves the enzyme glycogenin that initiates the process, and glycogen synthase a key enzyme that is under the control of the hormone insulin. The mechanism by which insulin activates glycogen synthase is complex, involving binding of a form of glucose (G6P), as well as removal of previous modificat ions from multiple positions on the protein. Impairment of this process can cause type 2 diabetes. My main aim is to precisely understand how the enzyme glycogen synthase is controlled by the action of insulin at the very detailed molecular/atomic level. Recently, I have overcome inherent technical problems and been successful in producing large amounts of glycogenin and glycogen synthase in the form of a tight complex-the first step in achieving the goal of visualising their molecular structure s. In particular, I am interested in how the small molecule G6P binds and alters the atomic structure of glycogen synthase. Understanding this process could pave the way for designing small molecules that stimulate glycogen synthase in diabetic patients that are unresponsive to insulin.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: METABOLIC AND ENDOCRINE
Title: Identifying low frequency and rare genetic variation involved in type 2 diabetes using next generation sequencing data.
Funder: Wellcome Trust

Abstract: To answer my research question, I will utilize the following datasets: Dataset 1: Whole genome sequence from 1500 Type 2 diabetes patients and 1500 characterised controls at 4 fold coverage. Dataset 2: Targeted sequencing of 50-200 selected genes from 480 young onset diabetes patients and 480 normo-glycaemic controls, at 50 fold coverage. Dataset 3: Variant data from the publicly available 1000 genomes project My project will then proceed in four stages. In Stage 1 I will use NGS data fr om datasets 1-3 to identify low frequency and rare variants in the coding regions of selected candidate genes. In Stage 2 I will annotate these variants including their likely functional effect and genomic context. In Stage 3 I will prioritise variants for follow up using a combination of criteria including nominal association (p<0.05). In Stage 4 I will follow up prioritised rare variants by genotyping in additional samples of up to 50,000 cases and equivalent numbers of controls. I will also t est the impact these variants have on beta-cell function and insulin resistance in well phenotyped non-diabetic cohorts. My fellowship will improve understanding of biological mechanisms involved in diabetes and may lead to stratification of individuals for treatment or preventative measures.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Age-dependent beneficial effects of PI3-Kinase pathway inactivation on glucose and lipid homeostasis: Mechanisms and therapeutic potential in metabolic disease.
Funder: Wellcome Trust

Abstract: Modern lifestyle and an increasing life expectancy have made the burden of age-related diseases, such as obesity and type-2 diabetes, a very significant problem of public health. There is an urgent need for development of medicines that prevent or treat these conditions. Using mice as model organisms, we have found that an enzyme, named PI 3-kinase p110alpha, is part of the mechanism by which the hormone insulin controls the metabolism. Remarkably, genetically engineered mice in which the p110a lpha gene has been inactivated do not accumulate as much fat as normal mice as they age and have lower blood sugar levels. Inactivation of p110alpha by drugs is therefore a promising treatment for metabolic diseases. Our research seeks to uncover the molecular pathway by which inactivation of p110alpha results in such improvements in metabolism. We will compare young and old mice, fed either a normal or a special diet containing an excess of fat. These studies will show whether inactivation of p110alpha protects the organism from the harmful effects of excessive fat intake. We anticipate that this knowledge will greatly facilitate efforts to develop therapeutic agents to treat obesity and type-2 diabetes and to extend the healthy lifespan of humans.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Functional analysis of the fat mass and obesity-associated gene FTO.
Funder: Wellcome Trust

Abstract: Obesity is a major problem in the Western world and increasingly also in the developing world. It increases the risk of numerous health problems, including diabetes, hypertension, heart disease and even cancer: and the costs of treating diseases caused by obesity places a severe burden on governments. It is easy to see that obesity can be caused by eating too much, exercising too little or having a high metabolic rate. But what causes these behaviours is far from clear. Recently, common vari ants in a gene called FTO were found to be associated with obesity: across the population, individuals with two copies of the at-risk gene variant have, on average, 3 kilograms more fat than those with the low-risk variant. How FTO regulates fat mass is not understood. Thus the aim of this project is to discover the role of FTO in regulating fat mass and body weight. We shall do this using a range of mouse models, which allow us to explore questions that cannot be addressed in human studies. The results of our research will increase our understanding of how body weight is controlled and may lead to the design of new drugs to help combat morbid obesity.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Regulation of growth and TORC1 signalling by the novel evolutionarily conserved amino acid transporter, SLC38A10: a new player in amino acid sensing?.
Funder: Wellcome Trust

Abstract: Surprisingly, insulin molecules that are released in response to increased food uptake can hasten ageing and are involved in several major human diseases linked to ageing, including cancer, diabetes and neurodegenerative disorders like Alzheimer s. If we are to understand how this works, we must discover how the cellular response to insulin is controlled. Surprisingly many recent advances in this area have been pioneered by studying genes in flies. One key discovery is that the response to in sulin is altered by cellular levels of amino acids, the building blocks of proteins. We recently used flies to identify a molecule that transports amino acids across membranes and showed it acts as an amino acid sensor in humans that is critical for insulin-dependent cancer cell growth. This transporter is currently being explored as a drug target for cancer. However, we believe other transporters are involved in normal cell growth. We have identified a new transporter in flies that is very simi lar to an uncharacterised mammalian transporter. The fly transporter affects growth and responses to insulin in normal cells. Here we will test whether it does this by sensing amino acids and whether it might be targeted by drugs to alter insulin responses.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: Understanding the molecular basis of the adaptive increase in fat oxidation seen in patients with lipodystrophy in response to excess fat intake.
Funder: Wellcome Trust

Abstract: 1. To confirm our initial (preliminary) results suggesting that fat overfeeding in AZIP mice leads to an adaptive increase in energy expenditure and fat oxidation. 2. To determine which tissue/sis/are responsible for the adaptive increase in fat oxidation and energy expenditure. 3. To determine the molecular mechanisms responsible for this remarkable adaptive response.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Genome-wide analysis of the interactions that mediate communication between central carbon metabolism and the cellular regulome.
Funder: Wellcome Trust

Abstract: Metabolism has been regarded as a series of chemical reactions that provide energy and bio-molecules by converting e.g. a sugar to an end product. However, since new strategies facilitated tracking of entire metabolic pathways, it became evident that metabolism is very flexible, and is an integral part of the cell s regulatory system. This is of medical relevance, since metabolic pathways are frequently affected in human disease, including cancer, diabetis and neurodegeneration. We focus on a shift in carbon metabolism which protects the cell from exposure to oxidants. Upon contact with such stressors, metabolism shifts rapidly, and there is evidence that this process is inducing further anti-stress mechanisms We will decipher genetic interactions of this transition by quantifying metabolites and enzymes in a large collection of yeast mutants by mass spectrometry, and identify all genes that are regulatorily associated with this pathway. Because both, the response to oxidants and pr imary carbon metabolism are of primary importance for aging and cancer, we expect important new insights for their molecular cause. In addition, we will study the influence of the identified genes on yeast aging phenotypes and by this shed light on the mechanisms that make aging a function of metabolic activity.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: FTO and appetite regulation.
Funder: Wellcome Trust

Abstract: Obesity is a major public health problem and a leading cause of illness and death. Unfortunately there are currently few effective long-term therapies for this condition and therefore there is a pressing need to develop new ways to prevent or treat obesity. Hereditary factors contribute to the development of obesity. Variation within a gene called the fat mass- and obesity-associated gene (FTO) confers the single greatest genetic risk yet identified. However, the mechanisms by which FTO varia nts cause obesity are unknown. Hormones released from the gut play an important role in regulating body weight by acting upon the brain to control appetite. I have found that subjects with an obesity at-risk FTO variant have higher circulating levels of the hunger hormone ghrelin after a meal. My work suggests that FTO regulates ghrelin levels. I now plan to undertake a series of studies in order to: i) understand how FTO variation affects the brain's response to food cues ii) investigat e how FTO regulates ghrelin levels and iii) test whether obese patients with the at-risk FTO variant have abnormal circulating ghrelin levels. Understanding how FTO predisposes to obesity could lead to the development of new obesity therapies tailored to their genetic make-up.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Wellcome Trust Clinical PhD Programme, University of Liverpool; 'Determinants of diabetic retinopathy severity and progression in Malawi'
Funder: Wellcome Trust

Abstract: The prevalence of diabetes mellitus, particularly type 2, is increasing rapidly in Sub-Saharan Africa. Recent data from Malawi indicates a prevalence of proliferative diabetic retinopathy approximately ten times that seen in diabetic populations in developed countries. The determinants of severity and progression of diabetic retinopathy (DR) in this population are poorly understood. This project focuses on the examination of a cohort of diabetic patients in Southern Malawi and address three key goals: 1. To investigate the prevalence, incidence and progression of diabetic retinopathy in Southern Malawi 2. To investigate the determinants of DR severity and progression in this population 3. To characterise endothelial function in diabetic Malawian subjects and investigate relationships with severity of retinopathy The first 2 goals will be achieved through a non-interventional prospective cohort study of patients attending a hospital diabetes clinic over 24 months (n=340). Severity, progression rates and patterns of DR will be correlated with clinical and laboratory biomarkers. Additionally, 281 patients attending a diabetes clinic who were previously examined by our group will be reassessed at 5 years. A case-control study (n=160) will address goal 3; assessments will include serum markers of endothelial dysfunction, clinical testing of endothelial function and characterisation of endothelial progenitor cell populations.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE