NIHRDataInsights/HRCSData huggingface dataset:
Title: Rare and low frequency variants and predisposition to complex disease.
Funder: Wellcome Trust

Abstract: The proposed research investigates the impact of rare and low frequency variants that are present in the human genome on the prevalence of complex disease. In the first of two lines of research, this project plans to improve statistical methods to analyse genetic variation using independent and publicly available sequence datasets, so as to increase the chance to detect and include rare variants in disease-association studies. The second line of research integrates population genetic theory with aspects relevant for complex disease research. Because functional genetic variation is likely to carry detectable signatures of the population-specific evolutionary history and gene-specific drivers of selection, it is desirable to reconstruct the local genealogy around rare variants, in order to estimate the age of individual alleles and parameters of selection. For this purpose, theory will be developed and implemented in a statistical and computational framework. Forapplication of this methodology, this project focuses on type 2 diabetes (T2D)as a complex disease, for which larger datasets are available. Furthermore, these methods can be applied to similar disease datasets, so as to gain more knowledge about differences in the genetic architecture underlying complex disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: METABOLIC AND ENDOCRINE
Title: Redox-based circadian oscillation in human cells and mouse tissues.
Funder: Wellcome Trust

Abstract: Circadian clocks are a fundamental characteristic of almost all living cells and are essential for coordinated physiology. Traditionally, the mechanism of the circadian clock has centered on the transcriptional oscillations of a set of core clock genes; however, in recent years this transcriptional dogma has been challenged by the discovery that circadian cycles in peroxiredoxin oxidation persist even in the absence of transcription. The proposed research project will focus on investigating the origins of circadian redox oscillations in mammalian systems to test the hypothesis that redox-based oscillations serve the role of non-transcriptional cellular timekeeper. This will be achieved by using novel mass spectrometry-based redox proteomics to profile the dynamics of redox-sensitive proteins across circadian time in human cells and mouse tissues. The second aim of this project is to examine the relationship between the transcriptional and metabolic oscillators and to identify the key nodes in the integrated network that couples them. This will involve targeting of key components of both the transcriptional and metabolic oscillator by utilizing a combination of mutant animals and drug-based inhibition. The result of this project will therefore fill in a gap in our knowledge of the fundamental principles of circadian timekeeping and could provide the basis of novel therapeutic strategies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: Hormone release from the gastrointestinal tract: mechanisms underlying bile acid-induced GLP-1 release and characterisation of somatostatin signalling.
Funder: Wellcome Trust

Abstract: Gut hormones are key to the regulation of nutrient homeostasis and therefore particularly relevant to type-2 diabetes. This proposal involves determining the mechanisms underlying secretion of two gut hormones, glucagon-like peptide1 (GLP-1) and somatostatin (SST). GLP-1 is an incretin hormone released in response to components in the intestinal lumen and acts to support nutrient disposal throughout the body. A preliminary project recently identified a G-protein coupled bile acid receptor(GPBA)-independent signalling pathway of bile acid-induced GLP-1 secretion in the distal small intestine. This study proposes to characterise this pathway and determine the roles of apical sodium-dependent bile acid transporter (ASBT) and farsenoid X receptor (FXR) in vitro and in vivo using appropriate inhibitors/agonists and knockout mice. An investigation into the relatively poorly understood inhibitory gut hormone SST is also proposed. SST negatively regulates the secretion of many hormones including GLP-1 but the stimuli and signalling pathways by which SST release occurs are poorly characterised. This proposal involves in vitro assessment ofSST secretion in response to various nutrients and pharmacological tools as well as the relationship between SST and other gut hormones. These data, together with transcriptomics of SST-producing cells, will be used to identifycell-specific signalling pathways.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: The genetic basis of congenital hypothyroidism
Funder: Wellcome Trust

Abstract: Congenital hypothyroidism (CH, thyroid underactivity from birth) is common, and causes developmental delay if untreated. A screening programme enables rapid treatment in babies, however, health outcomes may be inferior to unaffected individuals. Defects in CH-associated genes are found in <20% cases with evidence for existence of, as yet undiscovered genetic causes. I have identified two new causes (SLC26A7 and IGSF1 gene defects) using whole exome sequencing, a technology enabling virtually al l genes to be analysed. I will continue this approach to identify further genetic causes of CH and will assess the role of putative causative genes experimentally. Defects in SLC26A7 cause CH due to failure of thyroid hormone production by a structurally normal gland. The human biological role of SLC26A7 is not known, but it may transport iodine in the thyroid. I will perform functional studies to characterize the transport properties of SLC26A7 and investigate the role of specific regions of t he SLC26A7 protein by testing the properties of naturally-occurring/engineered defective forms of SLC26A7. SLC26A7-associated CH is a new genetic disease, which I will also clinically characterize in detail.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Understanding regulatory variation in human diabetes.
Funder: Wellcome Trust

Abstract: The ENCODE project has identified a vast number of transcriptional regulatory genomic regions and noncoding RNAs. Several examples have demonstrated that sequence variation in noncoding genomic elements can cause Mendelian disorders, and it is widely thought that they are critically important for thesusceptibility of common complex diseases. In practice, however, our understanding of how noncoding sequence variation impacts human disease is still very limited. The advent of whole genome sequen cing along with functional genomic regulatory maps in different tissues provides an opportunity to identify all candidate disease-causing regulatory variants. However, we still lack robust experimental tools to distinguish pathogenic from non-pathogenic noncoding variants. In this project, I will address this problem in the context of human diabetes. I will use whole genome data from ongoing studies of Mendelian forms of diabetes and Type 2 diabetes. I will also exploit rich regulatory maps of pancreatic progenitors and adult islet-cells generated in my laboratory. These datasets will be integrated to identify candidate noncoding regulatory variants, which will then be tested inrelevant chromosomal and cellular contexts. The key goals of the project are: (a) To develop novel experimental paradigms that can reveal which noncoding variants disrupt a genomic regulatory function that is relevant to Mendelian forms of diabetes, or to Type 2 diabetes. (b) In doing so, to asses s the contribution of regulatory variation in general, and of discrete regulatory variants in particular, to Mendelian and Type 2 diabetes. (c) To exploit natural sequence variation to gain novel insight into genome regulation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Investigation of Mechanisms Linking PIK3R1 Mutations to Metabolic Diseases.
Funder: Wellcome Trust

Abstract: Phosphoinositide 3-kinase (PI3K) is involved in metabolic and mitogenic signalling pathways. Heterozygous autosomal dominant mutations of Class IA PI3K regulatory subunits (PIK3R1), p85alpha, p50alpha and p55alpha, have been identified in patients with SHORT syndrome. This is a rare monogenic disease characterised by a variety of abnormalities including insulin resistance (IR) and hyperglycaemia. Research within the Semple group has focussed on in vitro and in vivo studies of the SHORT mutation Y657X (Y, tyrosine; X, stop codon) of p85alpha. Previous work has not succeeded in deciphering the mechanisms causing the disease phenotype, and this project aims to develop our understanding of how PIK3R1 mutations lead to IR exhibited by patients with SHORT syndrome. It is hypothesised that insulin signalling defects may be facilitated by the shorter splice variants, p50alpha or p55alpha, and that these mutations alter regulation of p110beta-mediated pathways. Additionally, it is proposed that IR occurs in a cell-specific manner from either hepatocytes or adipocytes. Furthermore, PIK3R1 mutations are associated with


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Assessing the role of corticotrophin releasing hormone neurons in Hypoglycemia-Associated Autonomic Failure.
Funder: Wellcome Trust

Abstract: Control of blood sugar levels in the body is essential to life; too much or too little can cause illness and even death. Treatment in diabetes can cause accidental very low sugar levels (hypoglycaemia) and recurrent hypoglycaemic episodes lead to failure of the natural protective responses (termed hypoglycaemia associated autonomic failure HAAF). The brain is involved in the development of HAAF: specialised brain cells (neurons) sense and respond to changing glucose levels; this fails in HAAF , although the mechanism is unclear. Proteins known as transcription factors turn on/off groups of genes, thereby altering neuronal function. A transcription factor, deltaFosB, accumulates in parts of the brain in recurrent hypoglycaemia. We hypothesise that deltaFosB accumulation alters gene expression, thereby changing neuronal function, ultimately leading to HAAF. To investigate this, we propose to examine which specific genes deltaFosB alters and whether this affects neuronal function in specific brain areas in a mouse model of HAAF. We will also investigate whether preventing deltaFosB accumulation can prevent HAAF. This project would therefore improve our understanding of the mechanisms underlying the failure of protective mechanisms to hypoglycemia and, may identify novel therapeutic targets for diabetic patients with HAAF.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: A Phase I Safety Study of Intramuscular CTX0E03 in Lower Limb Ischaemic Patients
Funder: Innovate UK

Abstract: This project is led by ReNeuron, a leading UK-based biotechnology business developing stem cell therapies. Critical limb ischaemia, a significant unmet medical need, is the end-stage of peripheral artery disease, resulting in poor blood flow (usually in the lower limb). The leading risk factor for this disease is Type II diabetes which has become an increasing health burden around the world.with rising rates on a global scale. Patients have limited mobility, suffer pain and have non-healing ulcers that eventually progress to gangrene leading to amputations of the limb . Stem cells offer the unique ability to change the course of the underlying disease by promoting the growth of new blood vessels in the affected limb, increasing blood flow. This project aims to take the cell therapy product, CTX-DP, currently in clinical development as a potential treatment for stroke disability, and evaluate its safety in early stage critical limb ischaemia patients in a Phase I UK clinical trial .


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: METABOLIC AND ENDOCRINE;CARDIOVASCULAR
Title: Hypoxia inducible factor (HIF) activation by sirtuins and hypoxia mimetics in the diabetic heart
Funder: Diabetes UK

Abstract: Ischemic damage is increased in the diabetic heart owing to changes in substrate metabolism, that decrease glycolysis and increase fatty acid oxidation. The opposite metabolic effects are induced by activation of hypoxia-inducible factor (HIF). This project will determine whether HIF signalling is suppressed in the diabetic heart, thereby increasing ischemic damage, and whether HIF can be activated pharmacologically to rectify the metabolic and contractile abnormalities. The high-fat fed/low dose streptozotocin treated rat will be studied as a model of type 2 diabetes. In vivo cardiac function/morphology and metabolism will be measured using magnetic resonance imaging and dynamic nuclear polarisation, respectively. In summary, HIF activation may provide a novel mechanism to improve metabolism and ischemic recovery in the diabetic heart.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE;CARDIOVASCULAR
Title: AMPK-mediated suppression of endothelial inflammation associated with Type 2 diabetes
Funder: Diabetes UK

Abstract: As well as reducing life expectancy by approximately 6 years, obesity and Type 2 diabetes place an ever increasing financial burden on the NHS due to the ensuing complications, such as diseases of conduit vessels (e.g. heart disease, stroke) and microcirc


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE;CARDIOVASCULAR
Title: Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT) - Extension
Funder: Diabetes UK

Abstract: The aim of this proposal is to complete the recruitment and follow-up phase of the Adolescent Diabetes cardio-renal Intervention Trial, the first randomised placebo-controlled trial (RCT) of ACE inhibitors (ACEI) and Statin therapy in adolescents with type 1 diabetes at high-risk for renal and cardiovascular complications. From a screened population of 4,500 subjects, 500 deemed to be at high risk on the basis of higher than expected albumin excretion, will be recruited into a RCT, contrasting the effects of ACEI, statin, or combination therapy with placebo over a 3-4 year intervention period. Allowing for a 20% drop-out rate, 400 subjects would give 93% power to detect a 23% reduction in albumin excretion (repeated measures, area under curve), related to either drug. The trial also has sufficient power to detect longitudinal changes, in serial measurements of blood pressure, blood lipids, cardiovascular risk markers and between baseline and end of study measurement of carotid artery intima-media thickness, endothelial function and arterial stiffness. The impact of intervention on quality of life is also assessed and a health economic assessment is undertaken. The study will provide clear advice on the likely efficacy, safety and compliance of early intervention and inform future treatment guidelines.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE;CARDIOVASCULAR
Title: Mechanisms underlying the regulation of endothelial nitric oxide synthesis by glucose and insulin
Funder: Diabetes UK

Abstract: Cardiovascular complications are the leading cause of morbidity and mortality in people with diabetes, yet the molecular mechanisms underlying this association remain poorly characterised. Endothelial dysfunction, characterised by impaired NO synthesis, is a key early step in the progression of cardiovascular disease observed in people with type 1 and type 2 diabetes. Characterisation of the signalling pathways regulating NO synthesis by endothelial NO synthase (eNOS) and their modulation by factors altered in diabetes may, therefore, identify novel therapeutic targets to limit or prevent the vascular complications of diabetes. We have previously demonstrated that prolonged culture of human aortic endothelial cells (HAECs) in conditions that mimic hyperglycaemia or hyperinsulinaemia impairs NO synthesis. Furthermore, we provide evidence that in either case impaired NO synthesis is independent of eNOS phosphorylation status or superoxide synthesis. This proposal seeks to identify the mechanism(s) by which NO synthesis is impaired by high glucose/insulin. Specifically, we will assess whether the subcellular localisation of eNOS, association of eNOS with regulatory proteins or allosteric regulation of eNOS is altered by high glucose/insulin. Furthermore we will determine whether impaired NO synthesis can be reversed by anti-diabetic drugs.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE;CARDIOVASCULAR
Title: Reducing saturated fatty acids in the food chain through alteration of milk fat composition
Funder: Biotechnology and Biological Sciences Research Council

Abstract: UK exceeds its dietary target for saturated fatty acids (SFA) and milk/milk products are the single largest source i.e. about 30-40% of total SFA. Recent data show that there are likely to be benefits in terms of reduced vascular disease increased milk consumption although the evidence for cheese, butter and cream is lacking. Simply reducing consumption of milk to reduce intake of SFA may be counterproductive. Using simple markers like as plasma cholesterol, there is intervention evidence that replacing a proportion of the SFA in milk/milk products does improve their health value to humans. Recent studies also show the potential of animal nutrition to enable dairy cows to produce milk with reduced SFA and increased cis-monounsaturated fatty acids (MUFA) although a consequence is often an small increase in trans fatty acids (TFA), mainly trans-11 18:1. The project will be comprised of four workpackages (WP) and will examine: WP1 will study the milk fatty acid response (SFA, MUFA, TFA and polyunsaturated fatty acids - PUFA in particular) when cows on a selection of commercial dairy farms are fed oilseed-based diets scientifically proven to reduce SFA. WP2 will examine new approaches to the production of milk with increased SFA/ MUFA/PUFA changes whilst minimising TFA in milk and methane produced by the cow. WP3 will undertake a detailed human intervention study to assess the effect of including reduced SFA/enhanced MUFA/PUFA dairy products in the diet on markers of cardiovascular disease/metabolic syndrome. There are very few studies investigating the impact of modified dairy products on cardio-metabolic risk and those published have only investigated lipid outcomes. However vascular reactivity and novel biomarker of vascular function (such as endothelial progenitor cell and microparticle number are novel, emerging, important additional CVD risk factors and will be studied. WP4 will integrate all data from the other WPs and prepare a dissemination plan.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: METABOLIC AND ENDOCRINE;CARDIOVASCULAR
Title: Sedentary behaviour as an independent risk factor for chronic disease: associations with cardio-metabolic risk factors and determinants and corrrelates across adult life.
Funder: Department of Health (England)

Abstract: Recent research suggests that too much sedentary behaviour (as characterised by activities involving sitting, such as TV watching, transportation by car, working using a computer) may be harmful, even when people do the recommended amounts of physical activity. However, we have little information on specifically how excessive sitting affects health, who indulges in excessive sitting and what are their circumstances. Such information is important because it will improve the lifestyle advice health professionals give to patients and will help design better programmes to reduce sitting-related behaviours. The aims of this research will be: a) to look at whether too much sedentary behaviour (sitting) is a risk factor for cardiovascular and metabolic disease on its own right, and b) to study what are the circumstances and characteristics that determine adults’ sitting behaviour.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE;CARDIOVASCULAR
Title: Validating existing and developing new measures of comorbidity to predict mortality using Scottish routine datasets
Funder: Chief Scientist Office (Scotland)

Abstract: There is increasing recognition of the importance of multi-morbidity (the presence of more than one medical condition) and comorbidity (the presence of one or more additional conditions to an index condition of specific interest) in management of individual patients, in planning and evaluating the outcomes of health services and in research on risk prediction. Several comorbidity indices have been developed and validated using regional and national health care databases for example the Charlson Comorbidity Index and the Multipurpose Australian Comorbidity Scoring System. These use different measures of comorbidity from each other and neither has been validated for use in Scotland. The aims of the project are to assess the validity of selected existing indices and to develop a new index to predict mortality in Scottish populations of people with diabetes or colon cancer.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: METABOLIC AND ENDOCRINE;CARDIOVASCULAR
Title: Quantitative cardiac magnetic resonance for the evaluation of sub-clinical fibrosis and microvascular dysfunction in diabetic cardiomyopathy
Funder: Department of Health (England)

Abstract: "People with diabetes mellitus have a heightened risk of developing heart disease. In part this is due to diabetes and heart disease sharing risk factors. However, diabetes also causes heart wall fibrosis, contributing to the development of heart failure. This project aims to develop and test quantitative magnetic resonance imaging methods for measuring the degree of heart muscle fibrosis. The methods will be tested in healthy volunteers and patients with type 2 diabetes. They are expected to improve assessment of heart wall damage in its early, potentially reversible phase, allowing more timely treatment to help prevent or delay heart failure."


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE;CARDIOVASCULAR