NIHRDataInsights/HRCSData huggingface dataset:
Title: Nutrient sensing in the brain
Funder: Medical Research Council

Abstract: Growing evidence indicates that human obesity is a disease of brain pathways regulating appetite. The characterization of these pathways to eventually develop safe and efficient therapies mitigating hyperphagia is one of the top priorities in obesity research. Although protein is known to be the most potent appetite suppressant among all macronutrients, little is known about how the mammalian brain senses protein availability to create neural representations that guide behaviour and modulate metabolism. The goal of this programme is to characterise the central representation of protein abundance and determine whether brain protein sensing pathways can be targeted to produce satiety and improve energy balance. We hypothesise that the branched-chain amino acid leucine signals protein abundance to brain circuits controlling appetite and metabolism. During the past 5-yrs, we have characterised hypothalamic leucine-sensing neurons and are developing strategies to specifically target these neurons using molecular genetics. We are developing gain- and loss-of-function approaches to test the role of discrete leucine-sensing neuronal populations in the control of appetite and energy balance in mice. Using these models, we are testing the role of specific neuronal populations in leucine and protein sensing, in the regulation of energy balance and in the response to diets with varying protein contents. We are planning to characterise the neural circuits downstream from leucine sensing neurons , and determine how these circuits are intergrated with energy sensing neural circuits controlling appetite and weight.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: Mitochondrial Medicine
Funder: Medical Research Council

Abstract: This project is aimed at identifying new genes responsible for mitochondrial disorders, characterized by isolated or combined defects of the mitochondrial respiratory chain (MRC) complexes by exome sequencing of human DNA samples using Illumina technology. An inter-institutional agreement between the MRC-MBU in Cambridge, UK and the Fondazione Istituto Neurologico Carlo Besta, Milan, Italy, allow us to get access to genomic DNA samples from numerous patients with biochemically defined mitochondrial diseases. To the same aim, collaborations have been established with other Research Centres in the UK, such as the Mitochondrial Disease Centre at the University of Newcastle and the Institute of Neurology at Queen Square in London; and abroad, e.g. the Max Planck Institute for Aging in Cologne, and the Institute of Human Genetics in Munich, Germany. We expect that the project will lead to the genetic definition of all or most of our cohort of probands, an achievement that will contribute to define the molecular-genetic basis of this vast group of conditions. The identification of new mitochondrial disease proteins is essential to further elucidate the pathogenesis of mitochondrial disorders, is important to complete our knowledge on the composition of the human mitochondrial proteome, and will contribute to the molecular characterization of mitochondrial energy-related pathways. This goal will be implemented by creating recombinant cell models for new mutant genes, in vitro characterization by proteomics approaches, and investigating suitable animal models, including mouse and zebrafish. Examples of gene products that will be studied include TTC19, an assembly factor for complex III; Mpv17, a mitochondrial protein of unknown function whose mutations cause profound depletion of mtDNA in livers of knockout mice and patients; FBXL4 and Apopt1, two proteins of unknown function associated with mtFDNA depletion and deficiency of cytochrome c oxidase, respectively; and Pitrm1, a mitochondrial protease we recently found mutated in patients showing a neurodegenerative disease. The molecular and functional characterization of new disease genes/proteins and pathways will underpin the development of rational therapeutic strategies. Effective therapy for OXPHOS diseases is missing. We have collected a huge series of mutant cell (fibroblast) lines and created numerous mouse recombinant lines with specific defects in genes associated with human mitochondrial disease. The availability of these tools will be exploited to develop experimental therapy transferable to humans. The translational agenda that will be implemented at the MBU will include three main strategies for experimental therapy, based on (a) Activators of mitochondrial biogenesis acting on the PGC1-alpha axis; (b) Gene replacement using adeno-associated viral vectors; (c) Xenogene targeting using alternative oxidases expressed in recombinant mouse lines.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: METABOLIC AND ENDOCRINE
Title: Lipotoxicity and obesity-associated metabolic complications
Funder: Medical Research Council

Abstract: This programme focuses on the roles of adipose tissue expandability and function in mediating the link between obesity and associated metabolic complications through lipotoxic mechanisms. Specifically we aim to: a) establish mechanisms controlling adipose tissue plasticity and expansion as a strategy to prevent the development of obesity-associated metabolic complications; b) define the anti-lipotoxic effects of mitochondrial oxidation through strategies that promote the differentiation and activation of brown fat (BAT); and c) identify candidate diagnostic biomarkers and therapeutic approaches based on patterns of lipid species associated with lipotoxicity in mice, for subsequent validation in human translational studies. These objectives will be addressed through a multidisciplinary approach that will make extensive use of genetically modified murine models, state of the art in vivo and in vitro phenotyping, and systems approaches based on transcriptomic and lipidomic technologies integrated by multiple bioinformatics platforms.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: The Enteroendocrine System in Health and Disease
Funder: Medical Research Council

Abstract: This programme addresses enteroendocrine cell physiology, identifying strategies to enhance secretion of gut hormones that regulate appetite and insulin release. The gut endocrine system is increasingly recognised as a central player in the coordination of appetite, insulin release and post-prandial nutrient homeostasis. It likely underlies many of the beneficial physiological responses to gastric bypass surgery, and some of the secreted hormones have already been harnessed successfully for the treatment of diabetes and short bowel syndrome. Emerging therapies based on the secretion and action of gut peptides are predicted to be major players in the future treatment of metabolic disease. Understanding the physiology of the gut endocrine system is critical for identifying novel strategies to modulate hormone release in humans and interpreting post-ingestive and post-bypass physiology. This is an area of research that has advanced dramatically in the past decade, with the introduction of technologies to identify, isolate and interrogate enteroendocrine cells in murine models. As a result, some general principles of stimulus detection in incretin-secreting K- and L-cells have now been established, but there are many unanswered questions such as the relative importance of different enteroendocrine signalling pathways in vivo, the functional overlap between different enteroendocrine cell types, and the impact of genetics, diet and metabolic disease on the enteroendocrine system? These questions will be addressed here using a candidate gene approach. Genes for functional evaluation will be selected based on their predicted effects on whole body physiology, enteroendocrine cell development, nutrient sensing and/or secretion. State-of-the-art optical and electrophysiological recording techniques will be utilised to monitor dynamic physiological responses of single identified enteroendocrine cells in primary culture, and the intact gut-brain-pancreatic axis will be assessed in vivo using genetically modified mouse models. Promising enteroendocrine target receptors and pathways will be further evaluated for translational effects on appetite and glucose homeostasis in humans.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE
Title: Regulation of brown adipose tissue activity in humans by glucocorticoids
Funder: Medical Research Council

Abstract: To assess macronutrient metabolism by human BAT, PET/CT scanning is currently the only available in vivo technique, but PET does not allow repeated measurements due to radiation exposure and only measures glucose uptake. We aim to measure cold-induced BAT lipid and glucose metabolism in healthy humans using three alternative techniques during stable isotope tracer infusion: 1) intra-adipose microdialysis and 2) selective venous cannulation of BAT (for arterio-interstitial and arterio-venous differences, respectively, in glucose/lipid uptake and energy production); and 3) 13C-magnetic resonance spectroscopy to measure TCA cycle activity. These in vivo techniques will be used to investigate the regulation of human BAT activity by glucocorticoids, which are potent suppressors of BAT in rodents. In parallel, we will use a protocol that we have established for primary culture of human brown adipocytes (obtained from patients undergoing elective neck surgery) to investigate glucocorticoid-sensitive pathways mediating effects on macronutrient metabolism and the role of local glucocorticoid regeneration by 11beta-hydroxysteroid dehydrogenase type 1. If successful, these tools will be vital to dissect BAT metabolic activity in human obesity, its control by other putative regulators, and the key transcription factors controlling differentiation, and to prove the concept that inhibiting glucocorticoid action increases BAT activity in humans.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: The role of B cell regulation in type 1 diabetes in NOD mice
Funder: Medical Research Council

Abstract: In type 1 diabetes, pathogenic T cells destroy insulin-producing beta cells. Although autoantibodies are present in humans to a number of autoantigens, antibodies to insulin, indicating the presence of insulin-reactive B cells, are often present early and are more likely to be found in young children who develop the disease. The Non-obese diabetic (NOD) mouse develops spontaneous diabetes that has considerable similarities to the human disease and both T and B cells are important in pathogenesis of the diabetes. Although T cells are directly pathogenic to the islet beta cells, recently, anti-CD20 monoclonal antibody therapy has been shown to delay progression of disease in patients who are newly diagnosed with diabetes. This is one of the few immunotherapeutic strategies that has shown promise. In NOD mice, several strategies to deplete B cells, including the use of anti-CD20, have also delayed and prevented the onset of diabetes. Importantly normoglycemia was restored in a proportion of mice after the onset of diabetes. We have previously shown that B cells that repopulate after depletion treatment have an increased percentage of a "regulatory" phenotype. In this project, we will investigate whether regulatory B cell function is defective in the NOD mouse model, particularly as the mice age and develop diabetes. Although there are a number of targets of the autoimmune attack, insulin is considered to be a primary autoantigen. We will use transgenic models to specifically study the effect of B cell depletion on insulin-specific B cells. Our studies will test whether removal of insulin-specific cells leads to protection or if insulin-specific B cells repopulate with a regulatory phenotype and it is these regulatory B cells that are protective. Our studies will also focus on the interaction of insulin-specific B cells with pathogenic insulin-specific T cells and examine whether this interaction can be exploited to protect against diabetes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Do gut hormones mediate the beneficial effects of Roux-en-Y bypass surgery?
Funder: Medical Research Council

Abstract: Obesity and the consequential type 2 diabetes (T2D) is the biggest pandemic the world has ever seen, afflicting 300 million people and causing an estimated 3 million premature deaths a year (WHO 2008). This is a considerable problem for public health and for therapeutics. The modern Roux-en-Y gastric bypass surgical procedure (RYGB) is highly effective in treating obesity and T2D: typically there is ~33% loss of body weight, producing complete remission of diabetes in about half the patients. Long term health and life expectation is dramatically increased. RYGB, however, is expensive, somewhat dangerous and is variable in effect. It is not desired by the majority of patients, nor is it practicable to treat the very large numbers of patients who might require it. The challenge, therefore, is to demonstrate how RYGB works. This is the first step to identifying whether this could be translated into a practical, safe and titratable medical therapy for obesity and diabetes. The remission of T2D and weight loss after RYGB has been attributed to a number of possible mechanisms, for example restriction of the stomach, interference with postprandial neural signals, delayed absorption of bile salts, delayed absorption of nutriments causing a change in breakdown of nutriments in the colon and / or an alteration of the gut microbiome. The evidence for each of these being the main cause of remission of diabetes is relatively weak. Outstandingly the likeliest mechanism proposed has been the elevation of gut hormones and enhancement thereby of the entero-insular axis. Our previous work has shown gut hormones induce satiety, can enhance insulin release, and delay food absorption. They are elevated after RYGB. Evidence in animals suggests they might be the key mechanism producing the weight loss and improved carbohydrate tolerance in RYGB. We will establish in man whether this hypothesis is correct.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Defining the molecular and physiological mechanisms of pancreatic islet dysfunction which lead to type 2 diabetes
Funder: Medical Research Council

Abstract: Our research strategy has four components: (i) to identify risk variants causal for T2D and informative for islet function, we will leverage large-scale (>100,000 individuals) genome-wide association, next-generation sequencing and targeted genotyping studies; (ii) to prioritise amongst T2D-associated variants for those causing islet dysfunction we will (a) interrogate quantitative trait data ("epidemiological physiology"); and (b) exploit cellular and molecular studies in human islets and human beta-cell lines to confirm the islet phenotype and distinguish islet-autonomous transcript effects from those driven by external factors (e.g. incretins); (iii) we will then use large genotype-based recall samples (Oxford Biobank and EXTEND primarily) to perform intensive physiological phenotyping in human volunteers comparing those carrying variant alleles of interest with matched controls. We will perform tests that target specific components of islet response and function. Initial efforts will be targeted to variants at ARAP1 and G6PC2 with additional signals considered in subsequent years; (iv) finally, we will deepen understanding of the basis of T2D-associated islet dysfunction by further rounds of cellular, epidemiological and physiological analyses. The approaches to be taken will be transcript- and variant-specific but will involve further interrogation of human beta-cell lines, and patient-derived induced pluripotent stem cells (iPSCs); population scale targeted resequencing; and biomarker analyses. This proposal implements the vision that, by combining powerful approaches for the characterisation of human pancreatic islet function - sequence-based human genetics and genomics, the first authentic human beta-cell lines, the ability to perform detailed physiological analysis in cohorts consented for genotype-based recall - we have a singular opportunity to characterise processes key to the development of T2D.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Targeting etiologic molecular mechanisms to treat human diabetes
Funder: Medical Research Council

Abstract: One of the major goals of modern medicine is to develop more efficient personalized therapies to treat chronic diseases that impose a heavy burden on our society. Recent progress in our understanding of the genetic predisposition of Type 2 diabetes promises to facilitate personalized therapies that target the molecular mechanisms that underlie this disease. We have set out to discover novel therapies that target the molecular mechanism in patients who develop early-onset diabetes to heterozygous mutations in the gene encoding the transcription factor HNF1A. This genetic defect represents the most common known form of Mendelian diabetes. Although it is rare compared to classic late-onset Type 2 diabetes, sequence variants near HNF1A predispose to late-onset disease, suggesting that different variants in the same locus might lead to different forms of diabetes. HNF1A-deficient diabetes is of interest to us because it has a clearly recognizable molecular defect. In the current proposal we plan to develop novel therapies that target this molecular defect. We will use an integrative chemical and genomic approach that is designed to uncover the molecular mechanisms that mediate the beneficial effects of novel therapies. We will also create new genetic models of HNF1A-deficient diabetes for in vivo drug testing and development. In conclusion, this programme is expected to deliver candidate targeted therapeutics for patients with highly penetrant mutations in HNF1A, and possibly for individuals that harbor Type 2 diabetes risk variants in the HNF1A locus. Such therapies have the potential for rapid translation into the clinic, and unlike current drugs that simply modify glycemia, they can impact the underlying pathogenic defects and thereby modify the progression of disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE
Title: High resolution systems biology to determine the role of gut microbiota on type 2 diabetes
Funder: Medical Research Council

Abstract: Type 2 diabetes (T2D) has been increased in the UK over the last ten years, which can be partly explained by a combination of poor early diagnosis and inappropriate prophylactic strategies as well as low treatment compliance leading to an ineffective management of the disorder. It is known that T2D results from complex interactions between genetic and environmental factors. Thus, having a more individualised prophylactic and therapeutic strategy is the way forward towards efficient control of T2D. To date, an important effort is directed towards a more personalised medical approach by stratifying populations in subgroups that share common disease patterns. One emerging environmental component that contributes to stratify patients is the gut microbiota. Indeed, gut microbiota play an essential role in many functions, including energy metabolism. It has been shown that type 2 diabetic patients displayed a gut dysbiosis accompanied by strong perturbations of the microbial metabolic activity. Besides, it has recently arisen that the maternal microbial environment may have a programming influence on the future child's metabolic health. Hence, this project aims at addressing the complex interactions between genetics, development and microbial environment to improve understanding of the aetiology of T2D. For this purpose, we will dissociate the genetic from the microbial component by crossing diabetic and wild-type animals under controlled microbial conditions to generate discordant genotype/microbiota individuals such as wild-type animals raised in a diabetic microbial environment, in which we will be able to assess the influence of the microbiota on energy metabolism. The biological mechanisms underlying this interaction will be investigated by a high resolution systems biology approach combining metagenomics, metabolomics and transcriptomics analysis. This unique approach will provide new insights into the pathophysiological processes leading to T2D


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Role and regulation of GLP-1 receptor trafficking in pancreatic beta cells
Funder: Medical Research Council

Abstract: Glucagon-like peptide-1 (GLP-1) is an incretin hormone that induces insulin secretion from pancreatic beta cells via the glucose-regulated activation of the G protein-coupled receptor (GPCR) GLP-1 receptor (GLP-1R), resulting in adenylate cyclase activation, cAMP generation and downstream signalling. As well as promoting insulin release, GLP-1R increases beta cell mass, suppresses glucagon secretion, slows gastric emptying and induces satiety. Various GLP-1R agonists have been successfully developed as therapies for type 2 diabetes. Endocytic sorting and trafficking of GPCRs is a well-known mechanism for the modulation of receptor activities in a wide variety of cell types. GLP-1R trafficking is however a relatively understudied area whose deeper understanding may provide new ways to improve the efficacy of GLP-1R agonists. I will use confocal, super-resolution and electron microscopy, as well as biochemical approaches to analyse the trafficking pathways followed by GLP-1R in beta cell lines and in physiologically relevant primary beta cells. The molecular machinery regulating GLP-1R traffic will be identified by si/shRNA depletion of candidate proteins, an siRNA library screen of membrane trafficking factors and analysis of GLP-1R-interacting proteins by co-immunoprecipitation and mass spectrometry, with defects on GLP-1R traffic probed in murine models of diabetes. The effect of manipulating GLP-1R trafficking on downstream signalling will be assessed with FRET-based cAMP sensors and other biochemical readouts, as well as measures of beta cell insulin secretion, survival and proliferation. I will also characterise the trafficking patterns elicited by a panel of GLP-1R agonists with known differences in GLP-1R signalling. These studies will identify fundamental mechanisms regulating GLP-1R trafficking after exposure to GLP-1 and other agonists, and will reveal novel molecular links between agonist-induced GLP-1R trafficking, signalling and beta cell behaviour.


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