NIHRDataInsights/HRCSData huggingface dataset:
Title: Physiological Genomics and Medicine
Funder: Medical Research Council

Abstract: The research of the Physiological Genomics and Medicine Group has combined the use of classical genetics with genome technologies for gene discovery and understanding of gene function in common human disorders including the metabolic syndrome, systemic lupus and autoimmune glomerulonephritis. Several years ago we pioneered a new approach for identification of complex trait genes, combining the classical genome-screen technique with new DNA microarray technology for global measurement of gene expression. The approach led us to identify a defective gene, Cd36, that causes insulin resistance and hypertriglyceridaemia in spontaneously hypertensive rats (Aitman et al 1999, Nature Genet 21:76-83). Cd36 is one of the first genes for a complex mammalian trait to be identified in a genetic linkage study. Following these results, we defined an evolutionary role for the Cd36 gene in African and Asian populations (Aitman et al 2000, Nature 405:1015-1016) and used mutation screening to identify the first family in whom type 2 diabetes is caused by Cd36 deficiency. More recently we have used gene expression profiling, linkage analysis and bioinformatics to identify control points and gene networks in the Metabolic Syndrome (Hubner et al 2005, Nature Genet 37:243-53).In the last year, we have carried out genetics studies of autoimmune glomerulonephritis and have shown that a new type of genomic sequence variation, gene copy number variation, is a cause of autoimmune glomerulonephritis in rats and in the common human disease systemic lupus erythematosus (Aitman et al 2006, Nature 439:951-5). This is the first description of structural variation in the genome as a cause of autoimmune disease and has led many laboratories across the world to test for structural variation in other autoimmune disorders.||The outcome of these studies has considerable potential impact on clinical practice. The positional cloning of genes for common human diseases such as metabolic syndrome and autoimmune glomerulonephritis, and the finding of new types of genomic sequence variation as a cause of autoimmune diseases has led to the search for new diagnostic tests based on the genes and allelic variants identified. We are now using new genomic techniques including high throughput genotyping, sequence detection and microarray-based measures of gene expression and gene copy number. In addition, the systems approaches we have taken to defining disease states such as hypertension and dyslipidaemia are an example of new strategies for drug development that focus on regulatory pathways as well as individual genes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: A pragmatic and scalable strategy using mobile technology to promote sustained lifestyle changes to prevent Type 2 diabetes in India and the UK
Funder: Medical Research Council

Abstract: Diabetes is a major healthcare problem in the developed and developing world. Clinical trials have shown diabetes prevention by lifestyle intervention focused on diet and physical activity. Translating these benefits to the population has been hampered by the intensive nature and expense of the lifestyle modification programmes and by the difficulties and expense involved in ascertaining high risk subjects. We propose a randomised controlled trial comparing intervention using mobile phone technology versus conventional management to induce lifestyle modification in people with impaired glucose regulation in both India and the UK. In India people at risk will be ascertained using the Indian Diabetes Risk Score followed by measurement of HbA1c in those with high risk scores. In the UK, subjects will be ascertained from the NHS Health Check Scheme and from routine screening in primary care. The NHS Health Check scheme in England is offered to people aged 40-74 years. UK recruitment will also be based on HbA1c measurements. The mobile phone intervention will use text messaging to deliver education, treatment targets, advice, support and motivation. Subjects will be invited to participate and, once recruited, will be randomised to usual care or the SMS intervention group. Usual care will consist of a 30 minute interview, delivering personalised diet and exercise advice. This will be supplemented by standardised written material and will be delivered once at the beginning of the study. The intervention group will undergo the same initial interview and will receive 3 times weekly text messaging with education, advice, support and motivation. These messages will be personalised to individual targets set at the initial interview. Lifestyle modification will be achieved by physical activity and diet. The primary outcome is progression to diabetes. Secondary outcomes will be improvements in measured physical activity, body weight and other cardiovascular risk factors.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: METABOLIC AND ENDOCRINE
Title: Developmental Clinical Studies- Combined Immunotherapy and Trophic Adrenocortical Stimulation in New Onset Autoimmune Addison's Disease
Funder: Medical Research Council

Abstract: The adrenal cortex is one of the most plastic tissues in the body. However, in autoimmune Addison's disease (AAD) it is destroyed, leading to lifelong dependency on daily steroid medication for survival. Importantly, at presentation most AAD patients have subnormal, but detectable circulating concentrations of the major adrenal steroid, cortisol. This demonstrates that there is residual adrenal function in new onset AAD that could be 'rescued' by appropriate therapy. We have been exploring this potential therapeutic window with two early-phase human studies. In the first study, we have demonstrated that B lymphocyte depletion appears to have disease-modifying properties in AAD. In the second study, we have shown proof of the principle that hormonal stimulation with adrenocorticotrophic hormone (ACTH) can improve steroidogenesis even in patients with primary adrenal failure. This information suggests a new treatment strategy. In this current study, we will use a novel combination of an immunotherapy, to ameliorate the autoimmune attack, together with specific trophic stimulation of residual adrenocortical cell function using synthetic ACTH1-24. We propose a 3-stage, adaptive, open-label trial design with the choice of immunotherapeutic agent as the adaptive component, along with a constant regimen of adrenal trophic stimulation with regular subcutaneous ACTH1-24. The three different immunotherapy stages will be 1). B lymphocyte depletion (rituximab); 2). T lymphocyte co-stimulatory blockade (abatacept) and 3). Conventional immunosuppression with high dose glucocorticoid and mycophenolate mofetil. We believe that this therapeutic approach, combining both immunomodulation and trophic hormonal stimulation of adrenal cortical regeneration, holds genuine promise for cure of this chronic condition.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Elucidation of the final stages in coupling of insulin signalling to GLUT4 translocation
Funder: Medical Research Council

Abstract: We plan to study mechanisms involved in regulating the fusion of GLUT4 vesicles with the plasma membrane of insulin target cells. We have identified Rab3 as a target of insulin signalling and using a novel photolabelling procedure have found that the loading of this G-protein is increased by insulin action. This labelling approach has also led to the identification of Rap1 as another regulated G-protein target of insulin action. In the beta cell of the pancreas Rap1 is downstream of trimeric G-proteins that augment glucose-dependent insulin release. Furthermore, it is associated with Rab3 control of vesicle traffic. In addition Munc18 is known to be a critical component of the vesicle fusion in both systems These similarities have led us to propose that there is a unifying mechanism underlying the membrane fusion roles of these components. We plan to examine whether known Rab3 effectors that link with Munc18 in the pancreas have similar counterparts involved in insulin regulation of GLUT4 vesicle fusion. Therefore, we plan to identify Rab3 effectors in insulin-target tissues and validate their involvement in the fusion reaction. We will then study the interaction of Rab3 and the Rab effectors with Munc18. We will also examine the extent to which Munc18 availability for fusion and interaction with SNARE proteins is dependent of its tyrosine phosphorylation. We will determine whether insulin receptor tyrosine kinase is responsible for this phosphorylation using intact receptor and intact plasma membrane as components in our cell-free fusion system. In addition, we will examine the extent to which Rab3 and its effectors are regulated downstream of trimeric G-proteins and through the intermediate Rap1, as occurs in pancreatic beta cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: Messenger RNA analysis of genes implicated in susceptibility to type 2 diabetes.
Funder: Medical Research Council

Abstract: Type 2 diabetes (T2D) is a growing public health issue, which places an increasing burden on scarce healthcare resources. In the past decade, we have seen enormous advances in our understanding of the genetics of T2D, with over 40 DNA genetic variants showing an association with susceptiblility to this disorder according to genome wide association studies (GWAS). A major challenge now lies in identifying the causal locus in each case, and determining their mechanisms of action. The vast majority of the observed genetic variation associated with T2D lies in non coding regions of the genome. Although these non-translated regions of the genome produce no proteins, there is a growing body of evidence to suggest that they are far from non-functional. In this study, I aim to determine whether variants identified in the GWAS can influence mRNA processing, mRNA stability or post-transcriptional regulation of the genes in question. I will first carry out a detailed bioinformatic analysis to identify genetic variants within candidate genes which have the potential to differentially affect features of RNA processing or RNA stability. Once promising targets have been identified, I will assess the potential of GWAS variants to affect aspects of mRNA processing or stability in a series of human pancreatic islet and peripheral blood lymphocyte samples. The proposed project is likely to provide mechanistic links between genetic variation and increased risk of T2D. This will aid our understanding of this common disorder and may highlight new pathways for therapeutic intervention.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: KLF14, adipose dysfunction, insulin resistance and type 2 diabetes: from genetic discovery to biological mechanisms and translation.
Funder: Medical Research Council

Abstract: This major objective of this proposal is to define the molecular, cellular and physiological mechanisms responsible for the association between variants upstream of KLF14 and type 2 diabetes. Our recent work has demonstrated that KLF14 is a master regulator of expression in adipose tissue, and implicate this KLF14-regulated transcriptional network in the genesis of insulin resistance in remote tissues such as muscle and liver. The research will seek to understand the causes and consequences of altered KLF14 expression using a variety of complementary approaches that include: (a) human genetics: resequencing, fine-mapping and epigenomic analyses; (b) integrative physiology: detailed metabolic analyses and genomic studies and their relationship to genotype; and (c) cellular studies: cellular phenotyping and genomic studies in adipocytes following knockdown and overexpression of KLF14 and selected trans-genes. The work has four main aims: (a) To characterise the molecular, cellular and physiological consequences of altered KLF14 expression; (b) To identify the trans-genes mediating the effect of KLF14 on insulin resistance and type 2 diabetes; (c) To define the cellular and physiological mechanisms whereby altered KLF14 expression in adipose tissue leads to generalised insulin resistance and T2D; (d) To characterise the mechanisms whereby common variants upstream of KLF14 influence KLF14 expression. Our research will, by elucidating the mechanisms linking KLF14 sequence variation to diabetes predisposition, provide valuable, generic, insights into the consequences of adipocyte dysfunction on whole-body physiology. The research can be expected to define novel, causally-validated, targets that are substrates for therapeutic and biomarker development, and the application sets out some of the strategies that we plan to deploy to support those translational goals.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Developmental Clinical Studies - Curing Obesity with the 'Medical Bypass'
Funder: Medical Research Council

Abstract: This project is divided into three Milestones. Note that the Y242 analogue is presently being developed in a separate DCS Project. Milestone 1: Statutory pre-clinical studies prior to starting Phase 1 studies on G3215 - Peptide synthesis to support clinical trial material (CTM) formulation and toxicokinetic studies. - GLP-standard bioanalysis method for G3215 for the human, rodent and dog plasma matrices. - Good Laboratory Practice (GLP)-standard toxicokinetic programme in two animal species, four weeks. - Synthesis of G3215 to Good Medical Practice (GMP) standard. - Formulation, manufacturing and stability studies on G3215 CTM. - Application to MHRA and a REC to allow Phase 1 studies to start. Milestone 2: Phase 1 trials on G3215 This will utilize a combined single ascending dose (SAD) and multiple ascending dose (MAD) protocol. The SAD trial is a single-blind, placebo-controlled, randomised study to establish the safety, tolerability, PK and dose proportionality of single doses of G3215 in healthy males. This is followed by a double-blind, placebo-controlled, randomised MAD study to establish the safety, tolerability and PK of multiple doses of G3215. The MAD trial will also collect preliminary efficacy data in terms of food intake, body weight, and glucose tolerance. Milestone 2: Statutory pre-clinical studies for combination of Y242/G3215 to enable Phase 1 studies - A toxicokinetic study in one animal species of Y242/G3215. - A study to ensure that both analogues are stable when mixed in a syringe. - Application to the MHRA and a REC to allow the combination Phase 1 studies to start. Milestone 3: Phase 1 trials on the Y242/G3215 fixed-ratio combination A similar SAD/MAD Phase 1 protocol for the Y242/G3215 combination will be used to establish the safety, tolerability, PK and dose proportionality of single and multiple ascending doses of the fixed-ratio Y242/G3215 combination, as well as efficacy data.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Costs and complications of diabetes - investigation of a comprehensive national diabetes register
Funder: Medical Research Council

Abstract: Aim This fellowship will extend my existing prevalence-based models in diabetes and develop more complex incidence-based models. I plan to take advantage of the unique data source available and develop new incidence-based models to estimate lifetime costs of people with diabetes and investigate the impact of novel treatments for diabetes. Objectives 1. Review existing incidence-based diabetes models in order to create my own model. This will involve 3 stages: a. Develop risk equations to predict first complications requiring inpatient care b. Develop equations to predict the time trends for modifiable risk factors c. Develop cost equations for predicting cost of complications 2. Combine all the equations created in 1) to develop a comprehensive predictive model 3. Use the model created in 2) to evaluate the impact of novel treatments on risk and cost of complications Methods Analysis of diabetes population and outcomes are based on the comprehensive national register of people with diabetes in Scotland based around the Scottish Care Information-Diabetes registry with linked outcomes from centralised Scottish Morbidity Records on hospital admissions and mortality records held by the General Register Office for Scotland. A major component of incidence-based models involves the timing of events in a survival analysis framework. I will apply more complex survival methods to create the equations that will be used to develop a comprehensive predictive model. This model will be used to assess the impact of novel treatments on risk of complications and admission and form a policy model to help plan future health care for patients with diabetes. Opportunities The maturing linked dataset offers an unrivalled opportunity to examine the health impact of diabetes. This project offers an excellent training opportunity because of the importance of the questions addressed and potential for interaction with several institutions working on different aspects of the data.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES);8.2 HEALTH AND WELFARE ECONOMICS
Health categories: METABOLIC AND ENDOCRINE
Title: The pituitary corticotroph: an organizing centre for oscillatory activity of the HPA axis?
Funder: Medical Research Council

Abstract: The hypothalamic-pituitary-adrenal (HPA) axis, which regulates the secretion of vital glucocorticoid hormones, is the major neuroendocrine system that provides a rapid response and defence against stress. The HPA axis is characterized by an ultradian rhythm of glucocorticoid secretion that changes in different physiological and pathological states. If we can understand the precise biological mechanisms that regulate this rhythm, then we will be in a better position to understand how and why this rhythm becomes disrupted in conditions such as ageing and chronic stress. There has been considerable dispute as to whether ultradian glucocorticoid oscillations originate from a neural pulse generator within the hypothalamus. I have used a combination of experimental and mathematical modelling to show that the ultradian rhythm of glucocorticoid secretion can originate from a pituitary-adrenal peripheral network, thus independently from any pulsatile hypothalamic activity. This in turn implies that corticotroph cells within the anterior pituitary play a crucial role by acting as an organizing centre that regulates the oscillatory activity of the HPA axis. To investigate this, I will use both theoretical and experimental approaches to understand how the balance at the pituitary between positive inputs from the hypothalamus, and negative inhibition from circulating glucocorticoids, determines the oscillatory activity of the pituitary-adrenal system. There is now clear evidence that oscillating levels of glucocorticoids are essential for optimal gene transcription in target tissues, including the liver and the brain. Identifying where this rhythm originates from is particularly exciting because, for the first time, it provides a platform from which we can now begin to systematically investigate the mechanisms underlying the ultradian rhythm, and how these may change or malfunction leading to disrupted rhythms that we see in various physiological and pathological states.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: Reprogramming of Redundant Human Exocrine Tissue to Endocrine Tissue for Transplantation in the Treatment of Type 1 Diabetes
Funder: Medical Research Council

Abstract: Transplantation of isolated islets of Langerhans is viewed as the only effective treatment for type 1 diabetes that will normalise blood glucose levels without the attendant risk of hypoglycaemic. However, a major problem with current transplantation protocols is that up to three donor pancreases are required for each recipient, and in many cases the function of the graft deteriorates over time. During the isolation procedure, the bulk of the pancreatic material, i.e. the exocrine tissue is discarded. In our preliminary studies we have shown that the exocrine enriched tissue can be reprogrammed using 4 transcription factors (Pdx1, MafA, Ngn3 and Pax4) in combination with 3 growth factors (Betacellulin, Exendin-4 and nicotinamide) and that the efficiency (and direction) of reprogramming is enhanced by inducing the cultured exocrine cells to undergo a mesenchymal to epithelial transition (MET). Our preliminary studies provide proof of concept that we can efficiently reprogramme the exocrine enriched cells of the pancreas. We now propose to take the next step towards developing a novel cell therapy by characterising the cells in detail with a view to generating cells with properties as close as possible to that of an adult human islet cell. The overall aim is to enhance the production of functional islet tissue. In aim 1 we will optimise the use of growth factors and small molecules. This will be done by ICC and ELISA using insulin and glucagon expression as an end-point. In aim 2 we will optimise further the transcription factor cocktail used in reprogramming. In aim 3 we will characterise in detail the fully reprogrammed cells, using standard in vitro insulin secretion protocols, and in aim 4 we will test the ability of the reprogrammed to reverse the symptoms of diabetes in an animal model.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: METABOLIC AND ENDOCRINE
Title: Roles of GWA genes in controlling pancreatic beta cell function and mass.
Funder: Medical Research Council

Abstract: Type 2 diabetes (T2D) represents an epidemic of the 21 st century and consumes almost 10 % of the health care budgets in westernised societies. Progressive pancreatic beta cell failure is a sine qua non for the development of the disease. Whilst diabetes risk is markedly increased by factors including obesity, T2D shows a strong element of heritability. Correspondingly, recent genome wide association studies have identified loci affecting disease risk, the majority of which alter insulin production rather than action. Our laboratories have been in the vanguard of those seeking to dissect the underlying molecular mechanisms Under Aim 1, we will explore the roles in the beta cell of five genes found at two novel risk loci, selected for study using defined criteria. The first locus, close to a single nucleotide polymorphism (SNP) on chromosome 11, includes two genes: CENTD2, encoding the GTPase activating protein Arap1, and STARD10 encoding a phospholipid transfer protein of presently unknown function. The second locus, on chromosome 9, encodes a cluster of genes implicated in cell cycle control: CDKN2A, CDKN2B and p14Arf, and a non-coding RNA termed ANRIL predicted to regulate the expression of the three former genes. In each case we shall use newly-available human beta cell lines, primary mouse and human islets, and a novel transgenic mouse (INS-Tva) which allows targeted delivery of shRNAs/miRNAs or cDNAs to the beta cell in vivo. In Aim 2 we shall dissect the mechanisms of action of the tumour suppressor LKB1, whose deletion in the beta cell causes a considerable increase in beta cell mass and enhances insulin release. We shall focus on the downstream roles of two well-established GWA genes: TCF7L2, a target of Wnt signalling, and SLC30A8, encoding the secretory granule zinc transporter ZnT8. The Programme will thus provide important insights into the mechanisms controlling beta cell mass and function, and potentially new avenues for therapy.


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