NIHRDataInsights/HRCSData huggingface dataset:
Title: Effects of LAT1 amino acid transporter (SLC7A5) gene deletion on mammalian growth, nutrient signalling and foetal development
Funder: Wellcome Trust

Abstract: Cells grow in response to the availability of nutrients including amino acids, which are required both as building-blocks for new protein and as metabolic fuel. Amino acids are also able to act as a green-light signal for cell growth when they accumulate within tissues, for example after absorption of a protein meal. The nutrient-signalling system includes a biological sensor linked to a master regulator protein named mTOR. Our research has identified LAT1, a protein in the surface membran e of many human cell-types, as a key component of the amino acid sensor which determines the strength of the nutrient signal (LAT1 is named because it transports Leucine, the most potent nutrient activator of mTOR). We have recently developed a genetically-modified mouse strain in which we can knockout the LAT1 gene, placing us in a unique position to investigate the importance of LAT1 in generation of nutrient signals and its impact on the relationship between amino acid signalling and cell gro wth in relation to protein intake. The results will help development of LAT1 as a drug target by which to promote cell growth (e.g. to counteract age-related muscle wasting) or, using inhibitors, to reduce cell growth (e.g. for cancer chemotherapy, immunosuppression).


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: Bridging the gap from type 2 diabetes genetics to functional mechanisms of disease.
Funder: Wellcome Trust

Abstract: Type 2 diabetes (T2D) is a disease of major global impact yet the treatment of diabetes and its complications remains far from ideal. As a consequence, the development of novel approaches for preventing and treating the disease represents a major objective of medical research. The improved understanding of the mechanisms involved in diabetes development that can flow from identification of genetic differences influencing disease risk is one of the most powerful ways of delivering this. Indeed, r esearch on rare, highly-genetic forms of diabetes has clearly demonstrated how appreciation of the molecular events that are responsible can lead to substantial improvements in clinical practice. The aim of my fellowship is to continue and extend my research in this area to tackle variants influencing common forms of diabetes. I will take existing and novel genetic discoveries in diabetes and use a range of approaches to tease out the ways in which these genetic differences result in an increase d risk of disease. My work will seek to understand the effects of these variants at the level of the molecule, the cell and the whole organism. The biological knowledge which results will drive clinical translation leading to improved treatment and prevention.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Investigation of the role of prokineticin 1, a newly identified gut hormone which potently inhibits food intake
Funder: Wellcome Trust

Abstract: Obesity is a major health problem; however, current treatments are largely ineffective. To establish a more effective approach we need to better understand the natural systems that regulate appetite. Circulating factors called gut hormones have been shown to inhibit appetite. I have found that a newly discovered hormone released from the gut called prokineticin-1 powerfully reduces appetite. In order to establish the importance of PK-1 in the regulation of food intake and investigate its mec hanisms of action I will now study this effect in greater detail. I will investigate the effect of single injections of PK-1 on food intake in mice. I will determine the brain pathways by which PK-1 reduces hunger. Because PK-1 is difficult to synthesise, gene therapy will be used to produce a mouse with high levels of circulating PK-1 for longer periods of time. These mice will be used to study the long term effects of high levels of PK-1 on food intake and body weight. I will also study the ch anges in the levels of PK-1 in hungry and fed mice. Together these experiments will establish PK-1 as a powerful inhibitor of food intake and assess whether it is a useful way to treat obesity.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Insulin Resistance: Lessons from Extreme Phenotypes.
Funder: Wellcome Trust

Abstract: I study a condition called insulin resistance, in which the body is unable to respond properly to the hormone insulin. Insulin resistance often develops as a consequence of obesity. Left untreated it can develop into Type 2 diabetes (T2D), which has serious health consequences. Although T2D is common, current treatments are limited and not ideal - thus, developing new approaches for prevention and treatment is a major goal of medical research. In these studies we will 1. Use the latest gen etic techniques to investigate a rare condition called severe insulin resistance (SIR). Unlike T2D, SIR is not associated with obesity and results from a defect in a single gene (different genes are involved in different patients). 2. Identify genes that protect some people from developing insulin resistance, even though they are at high risk. For example not all obese individuals develop insulin resistance, endurance athletes also appear to be protected, even when they are no longer actively training. 3. Study how the genes we identify act within individual cells and model organisms to control insulin sensitivity. Our aim is to use this knowledge to develop improved strategies for the prevention and treatment of insulin resistance, T2D and SIR.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Investigation of the molecular basis by which mutations in SH2B1 lead to human obesity and insulin resistance.
Funder: Wellcome Trust

Abstract: Obesity is a major problem across the world and changes in our diet and levels of exercise contribute to this. However, to some extent our body weight is also inherited from our parents. Small changes (mutations) in genes lead to variation between individuals and by studying these it is possible to determine why people have different physical characteristics. Recently, mutations have been found in a gene called SH2B1. SH2B1 mediates the effects of the hormones insulin and leptin which allow the brain to control blood sugar levels and how much we eat and when. The aim of this project will be to determine how these mutations affect the function of SH2B1 in response to leptin, insulin and other hormones. In addition, SH2B1 plays an important role in the brain. We will also study the areas of the brain in which SH2B1 is particularly important. This work will allow us to gain further understanding of the pathways involved in controlling weight and find better treatments for people in the fu ture.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Scottish Consortium Translational Medicine and Therapeutics Programme: 'Corticosterone versus cortisol: distinct roles for endogenous glucocorticoids in human health and disease'.
Funder: Wellcome Trust

Abstract: The role of the glucocorticoid hormone cortisol in cardiovascular disease has been extensively studied, and key findings from our group have helped lead to the development of novel pharmacological agents targeted against metabolic syndrome. Very little attention has been paid to the glucocorticoid corticosterone in humans, as it circulates in lower concentrations. However, it has recently been shown that movement of corticosterone and cortisol across the cell membrane is controlled by transporter proteins (mdr1 and mrp), which handle the two hormones very differently and in a tissue-specific manner. We intend to test the hypothesis that corticosterone is the principal negative feedback signal in control of the hypothalamic-pituitary-adrenal axis, and is associated with metabolic syndrome through its control of cortisol. We will perform a series of studies in vivo and in vitro studying the effects of corticosterone in the CNS and adipose tissue. We will assess the effect of manipulating glucocorticoid transport using inhibitors of mdr1 and mrp. Finally, using a large cohort, we will evaluate the relationship between corticosterone and the metabolic syndrome. Confirming a distinct physiological role for corticosterone may be of clinical relevance for patients with adrenal insufficiency, and also provide a novel target for therapies aimed against metabolic syndrome.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Dissecting the mechanisms of metaboregulatory thermogenesis
Funder: Wellcome Trust

Abstract: The recent discovery of brown adipose tissue (BAT) in adult humans makes possible a new therapeutic approach to treat obesity, by activating endogenous BAT or making white adipose tissue more like BAT. To understand how to achieve these aims, physiological activation of BAT must be understood. Whiles much is known about thermoregulatory thermogenesis, the neuronal networks regulating metabregulatory thermogenesis (thermogenesis to counteract increased calorie intake) are not well understood. The central and peripheral mechanisms of metaboregulatory thermogenesis will be examined unsing three approaches in mice. Firstly, to determine whether the neuronal pathways regulating thermoregulatory and metaboregulatory thermogenesis are distinct, candidate hypothalamic nuclei that respond to a HFD will be identified by measuring c-Fos activation. Secondly, control of sympathetic tone to BAT by orexin neurons will be evaluated by ablating orexin neurons in adult mice and determining the effect on thermoregulatory and metaboregulatory thermogenesis. Finally, the molecular mechanisms by which Bmp8b increases sensitivity to adrenergic stimulation and thermogenesis in BAT will be investigated. Candidates signalling pathways and molecules will be identified by transcriptomic and proteomic approaches, and characterised in vitro. These experiments will help to eradicate the mechanisms of metaboregulatory thermogenesis, from central to peripheral regulation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: Wellcome Trust Clinical PhD Programme at the University of Oxford: 'The role of the G-protein subunit Galpha11, in the regulation of calcium homeostasis.
Funder: Wellcome Trust

Abstract: G-protein coupled receptors (GPCRs) play a central role in facilitating cellular responses to diverse extracellular stimuli such as ions, metabolites and hormones. Moreover, GPCR mutations result in diseases that include tumour development and endocrine dysregulation. One such GPCR is the calcium-sensing receptor (CaSR), mutations of which cause familial benign hypocalciuric hypercalcaemia (FBHH) and parathyroid tumours. However, only approximately 65%of FBHH patients harbour CaSR mutations. GPCRs signal through association withheterotrimeric G-proteins that consist of alpha, beta and gamma subunits, and the CaSR specifically signals via Galphaq/11, Galphai and Galpha12/13. Professor Thakker's group therefore postulated that FBHH patients without CaSRmutations may have mutations in these downstream heterotrimeric G-proteins andidentified Galpha11 mutations in FBHH patients. My key goal is to determine the role of Galpha11 in the CaSR signalling pathway and in calcium homeostasisby: 1) Characterising the in vitro effects, by transient transfection assays, of the Galpha11 mutations in the CaSR signalling pathway. 2) Determining the in vivo role of Galpha11 and its mutants by investigating wild-type and established N-ethyl-N-nitrosurea (ENU) mutant Galpha11 mice. 3) Undertaking pharmacological studies using Galpha11 inhibitors and targeted peptides to determine their in vitro and in vivo modulatory effects.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Clinical PhD Programme at the University of Edinburgh "Changes in chromatin structure during the response of macrophages to glucocorticoids".
Funder: Wellcome Trust

Abstract: Glucocorticoids (GC) are important in the physiological response to stress and there is evidence of dysregulation in severe illness requiring intensive care, which is linked to increased mortality. Exogenous glucocorticoids may be effective therapeutically but uncertain benefit from clinical trials and the absence of newer more effective specific therapies demonstrates that our current understanding of their mechanism is inadequate. We hypothesise that, similar to other nuclear hormone receptors, ligand-bound glucocorticoid receptor (GR) alters chromatin structure in macrophages and that this is not limited to local changes in histone modifications at target gene promoters. As for the oestrogen receptor, many GR binding sites may be far (>10kb) from target genes and induce changes to the higher order structure of chromatin. We suggest that these changes will be important in controlling cell behaviour in the presence of GC. After characterising the transcriptome in response to GC in human and mouse macrophages we will then identify the binding sites of the GR in these cells. This will provide us with the target loci at which to analyse the changes in nuclear organisation and chromatin structure using nuclear imaging during the response to, and withdrawal of, GC. Where reorganisation is demonstrated we will probe mechanisms using knock down of e.g. known remodelling complexes. We will also compare this data to the regulatory sites known to be involved in the inflammatory response. Our goal is to elucidate novel pathways which may be targets for future, non-steroidal, therapy.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: Investigation of Metabolic and Growth-related Diseases Associated with Mutations in Phosphoinositide-3-kinase, Catalytic, Alpha Polypeptide (PIK3CA).
Funder: Wellcome Trust

Abstract: Phosphatidylinositol-3-kinases (PI3K) are a critical group of molecules that transmit signals regulating cell growth and metabolism. Disorders of these signals play a central role in devastating common diseases including cancers and type 2 diabetes. Critical scientific questions are how PI3K play so many different roles, how they go wrong in disease, and how this can be targeted therapeutically. Many experimental approaches in current use have limitations, either artificially disturbing the deli cate signalling balance being studied and thereby masking important effects, or concentrating solely on experimental organisms One way around this is to study patients with naturally occurring genetic defects in PI3K. The host laboratory has recently identified three patients who will be studied in this project; two with possible loss-of-function mutations in the PIK3CA gene and resistance to insulin and one with a gain-of-function mutation and massive lifelong leg overgrowth . Through examinat ion of growth and metabolism of the patients themselves, study of signalling pathways in cells from the patients using state-of-the-art techniques, and trials of possible therapies in these cells, it will be possible to gain unique insight into new genetic disorders in humans, and to learn lessons about the normal function of the critical PI3K pathway.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Biomarker validation and proof of efficacy in conjunction with clinical therapies for Niemann-Pick Type C disease
Funder: Wellcome Trust

Abstract: The laboratories of Prof. Platt and Dr. Porter have identified a series of potential human protein biomarkers in Niemann-Pick Type C (NPC1). I propose to validate these markers in the NPCNIH mouse model over the course of diseaseprogression to determine when these markers can be detected within the pathogenic cascade and to exclude species variation. Once validated in the mouse model I plan to test the two therapies currently in use, Miglustat and Cyclodextrin. This data will be critical in supporting what biomarkers shouldbe evaluated in a clinical trial, and can be easily adapted for new therapies.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Characterising causal alleles for common disease.
Funder: Wellcome Trust

Abstract: Type 2 diabetes represents a major challenge to global health. However, poor understanding of the mechanisms responsible for the development of disease continues to frustrate efforts to deliver improvements in prevention and treatment. Recent advances in human genetics have discovered many regions of DNA sequence that clearly influence individual risk of diabetes, but it has, for a variety of reasons, proved difficult to translate these findings into an appreciation of disease biology. The rese arch I propose to undertake, funded by the Wellcome Trust Senior Investigator award, brings together a range of complementary approaches designed to address current limitations in the transition from 'gene' to 'biology'. These include the use of human genetics to identify the specific points (rather than broad regions) in the DNA sequence involved in disease risk, and studies of cells to pinpoint the processes that are influenced by this variation in DNA sequence. This will be followed by effort s to use the results to advance improvements in clinical care, for example through an enhanced ability to identify different subtypes of diabetes which can benefit from more targeted preventative or therapeutic strategies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Genetic dissection of mechanisms linking cell dysfunction, insulin resistance & major human disease
Funder: Wellcome Trust

Abstract: Insulin resistance (IR) means reduced ability of insulin to lower blood glucose. IR is closely associated with obesity, and drives associated diseases including diabetes, heart attacks, liver cirrhosis, reduced fertility and some cancers. However how IR is linked to these major diseases is incompletely understood. This project will yield new insights into this question, and will help to clarify the nature of IR, by focussing on humans with severe IR or insulin hypersensitivity due to novel ge netic mutations affecting either the phosphatidylinositol-3-kinase(PI3K)/AKT pathway that transmits the insulin signal inside cells, or in the pathways allowing cells to respond to damaged DNA. Affected patients will be studied in detail, while laboratory analysis of their skin cells, stem cells and other derived cell types will be used to investigate cellular dysfunction caused by each mutation. Two lines of mice carrying the same mutation as patients studied will be generated, permitting mor e detailed study than possible in humans across the lifespan. Anticipated outcomes are 1. Description of up to 5 novel human genetic diseases 2. Therapeutically relevant insights into the role of PI3K/AKT in IR-related disease and 3. Insights into the role of abnormal DNA damage responses in IR.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Genetic and Physiological Studies in Obesity Associated Neuroendocrine Dysfunction.
Funder: Wellcome Trust

Abstract: People with weight problems frequently suffer from reduced fertility or thyroid hormone problems By looking at the genes of people with severe obesity, we have previously discovered a key pathway in the brain that links excess weight to these specific hormonal problems We have identified 230 patients who suffer from severe obesity who have problems with fertility or thyroid hormones that cannot be explained by faults in the genes we already know about. In this proposal, I aim to use state of t he art techniques to study a large number of genes in these patients. By comparing the genes of these patients to patients with severe obesity who dont have hormone problems and to normal weight volunteers, I aim to identify the genes that link a persons weight and hormone levels. After finding the genes, I will study the function and impact of these faulty genes in the laboratory and in more detail in these patients. I aim to learn from these patients how weight problems such as obesity affect hormone levels and fertility. This information may guide the development of better treatments for people with a range of hormonal and weight problems


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Translational Medicine and Therapeutics Programme at the University of Cambridge: 'Activating Akt mutations and metabolism: translational and therapeutic opportunities.'
Funder: Wellcome Trust

Abstract: AKT is a protein that relays important signals from hormones outside the cell to inside the cell and has been implicated in cancer and diabetes. Insulin, a hormone crucial for controlling blood glucose levels and cell growth, is dependent on AKT to function properly. However, the mechanisms by which AKT is able to selectively control the metabolic versus cellular growth effects of insulin remain unclear. To further complicate matters, three highly similar AKT proteins exist (AKT1, AKT2 and AKT3) and it is unknown whether these molecules have similar, unique or redundant functions. We have recently identified three children with a rare genetic mutation in AKT2 that causes the enzyme to be active in the absence of insulin. These patients are unable to maintain normal glucose levels and as a result have been burdened with a life of glucose infusions and artificial feeding to keep them alive. The research programme described in this fellowship seeks to understand how the mutant AKT2 causes the observed disease in these children and using this information I hope to undertake further studies with drugs that block AKT function to test whether they would be effective treatments in the fight against cancer and diabetes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: The role of novel genetic and epigenetic mechanisms in the pathogenesis of Type 2 diabetes.
Funder: Wellcome Trust

Abstract: Type 2 diabetes (T2D) is a metabolic disease characterised by insulin resistance and beta-cell failure and a leading cause of mortality and morbidity. Although a large number of susceptibility variants has been identified by Genome-wide Association Studies (GWAS), the genetic predisposition has not been fully explained, nor have biological mechanisms been clearly defined. Hence, the aims of this DPhil project are to investigatethe contribution to T2D of novel genetic mechanisms (focusing on rare copy number variants leading to loss of transcript function) and epigenetic processes (notably patterns of DNA methylation in pancreatic islets). To improve capture of loss of function variants, I will apply novel methods that I am developing to detect insertions and deletions in dense array data. Subsequently, I plan to test these variants for their association with T2D. Additionally, to improve understanding of beta-cell regulatory machinery, I will map pancreatic islet DNA methylation levels on a genome-wide scale. I will integrate these new sources of data with other public and proprietary genetic and genomic datasets to characterise molecular mechanisms operating atloci such as those discovered by GWAS or sequencing. Ultimately, I will undertake focused experimental studies to confirm these mechanistic inferencesat selected T2D-risk loci.


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