NIHRDataInsights/HRCSData huggingface dataset:
Title: Central and peripheral actions of FGF21 in promoting fat catabolism (invited resubmission)
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The overall aim of this project is to determine the sites and mechanisms of action by which FGF21 regulates body fat depots. This will be achieved by exploiting a natural animal model of body weight gain in long summer photoperiods, and weight loss in short winter photoperiods, where the body weight changes predominantly reflect changes in visceral adiposity: the Siberian hamster. Our pilot studies reveal that FGF21 and a monoclonal antibody (H7) which targets its likely receptor (FGFR1c) are more effective at reducing appetite and causing weight loss in seasonally fat hamsters as compared to those in the winter lean state, hence the importance of identifying where and how FGF21 exerts its effects. The first objective is to identify which tissues respond to FGF21. We will use 18F-2-deoxy-D-glucose and 16-18F-4-thia-palmitate tracers in a small animal quantitative positron emission tomography (PET)/nanoCT scanner to identify potential sites of action. Fat (long day) and lean (short day) hamsters will be tested, in the presence and absence of an insulin challenge. These in vivo studies will be complemented by ex vivo biochemical and molecular analysis of signal transduction pathways in tissues removed from the scanned animals, and by in vitro analyses of the effects of FGF21 on lipolysis and insulin secretion using isolated adipose tissue and beta cell islets, respectively. The second objective is to investigate the hypothesis that FGF21 also acts centrally to reduce food intake and to increase energy expenditure. We will determine whether administration of FGF21 directly into the brain (or a mimetic, LY2405319) changes appetite, metabolic rate, fat oxidation and body weight. We will also determine whether these central treatments alter gene expression and signalling in hypothalamic tanycytes, glial cell known to express FGFr1c which we have previously shown to mediate seasonal regulation of body weight via their regulation of the local thyroid hormone availability.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: Development of a brief evidence-based tool to assess dietary intake and promote healthy dietary change for people with Type 2 diabetes
Funder: Department of Health (England)

Abstract: People with diabetes often report that dietary advice is confusing and dietary change difficult to achieve. Currently there are no ways of rapidly assessing diet in patients with type 2 diabetes (T2D). We also know little about which dietary changes have the most benefits.Existing dietary, anthropometric and laboratory data, from a large lifestyle intervention study in patients with T2D, will be analysed to identify dietary patterns and changes in diet that have the most benefit for T2D. This will be used to develop a brief dietary assessment tool. Patients who have successfully made the key dietary changes will assist the student research in developing a tool guiding others towards these changes. Validity amongst an ethnically and socially diverse sample of adults with T2D will be assessed and the dietary assessment and change tool piloted in a group of randomly selected patients with T2D.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT)
Health categories: METABOLIC AND ENDOCRINE
Title: Development of orally administered sodium propionate to treat and prevent diabetes.
Funder: Department of Health (England)

Abstract: The NHS spends £1M per hour, 10% of its yearly budget, treating diabetes. In the UK cases of diabetes are expected to top 4 million by 2025. There is an urgent need for new therapies. The short chain fatty acid propionate is a natural substance produced in the colon by digestion of dietary fermentable carbohydrates. Preclinical and early human data demonstrate it improves pancreatic function and glucose control. I aim to conduct proof of principle studies to determine if oral delivery of propionate improves glucose control in patients at risk of developing diabetes.


Research activity codes: 5.1 PHARMACEUTICALS;3.3 NUTRITION AND CHEMOPREVENTION
Health categories: METABOLIC AND ENDOCRINE
Title: Managing thyroid disease to optimise vascular outcomes.
Funder: Department of Health (England)

Abstract: Managing thyroid disease to optimise vascular outcomes Mild hypothyroidism (SCH) affects up to 10% of the adult UK population and is associated with a 50% increased risk of heart disease. I have been working for several years to define the heart disease risk associated with SCH and to find out the optimal way to manage the risk of heart disease in SCH. I plan to study the effects of treatment of SCH in a high-risk post-heart attack situation and look at the long-term outcome and health resource utilisation of people with SCH. This research will provide key pieces of evidence to inform the treatment of nearly 2 million NHS patients.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: METABOLIC AND ENDOCRINE
Title: Urinary C-peptide creatinine ratio and glycaemic response to incretin based treatments in type 2 diabetes
Funder: Department of Health (England)

Abstract: Type 2 diabetes is a major and rapidly increasing health problem worldwide. Keeping the blood glucose (sugar) from going too high helps prevent complications. Recently a number of new treatments (collectively called ‘incretin based’ treatments) to lower blood glucose have become available but response is very variable and it is difficult to predict which will work for an individual. Insulin is the hormone which controls blood glucose levels and these new treatments act mainly by increasing someones own insulin secretion. We know that measuring thae amount of insulin someone makes is a strong predictor of response to older treatments (those with low levels have poor response to non insulin treatments) however until recently this has been difficult to measure in clinical practice. We have developed a simple test for measuring insulin secretion using a single urine sample (called urine C-peptide creatinine ratio). We want to see if we can identify whether the new treatments are likely to be effective for an individual patient. Identifying the right treatment would improve control and minimise the side-effects and costs from ineffective treatments. We will measure insulin secretion (and other information such as weight, average blood glucose level, age duration of diabetes) in people who are about to start these new ‘incretin based’ treatments and assess their response over the first 6 months of treatment. We will analyse this information to see if we can predict treatment response.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Chronic illness and online social networking: expectations, assumptions, and everyday realities
Funder: Economic and Social Research Council

Abstract: Although differences in Internet access still exist among demographic groups, the substantial growth in the use of social networking sites, such as Facebook, MySpace or Twitter, by individuals and organisations has recently revitalised policy and academic debates on the role of the Internet in health care. However, while marketing, clinical and practitioner literature on online networking and health is proliferating, social science has only just begun to address these issues. Given the recognised importance of social networks in health and wellbeing, the current rise in popularity of online networking affords a timely opportunity to learn more about their role in self-care associated with long-term conditions. Focusing on diabetes as one of the most pressing healthcare priorities, and Facebook as currently the most popular social networking site, this project will examine political and professional expectations surrounding the use of social networking sites in chronic illness management, and compare them with actual patterns of online experience. Bringing expertise from our previous research on public perceptions of health risks, and the use of new interactive media, we aim to provide access to the contextual factors that shape knowledge, attitudes and practices in relation to social networking sites and diabetes, and pinpoint potential 'gaps in understanding' which may lead to gaps in envisioning solutions in policy and practice. We adopt an interdisciplinary approach that combines linguistic and sociological frameworks, asking what online networking does and means for people with diabetes. The Facebook site allows its users to create textual and visual content, connections, organisational and individual pages, and groups, and in this way facilitates creation and maintenance of different network types (e.g. between relatives, partners, friends as well as wider circles). Our contextual study of Facebook use by people with diabetes will therefore help us understand the role of these different networks, and of the Internet, in shaping and supporting self-care practices outside formal healthcare organizations. Practitioners in both the diabetes education sector and broader health care sectors will be able to gain insights into how people with diabetes understand and use various networking and content-creating Facebook features in the everyday, how they evaluate their experiences, and what bearing it has on their lives and coping. The results will inform development of policy and practice initiatives aimed at provision of support for long-term conditions in the Web 2.0 age.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: METABOLIC AND ENDOCRINE
Title: Mesenchymal stromal cells for co-transplantation with pancreatic islets to improve graft function in type-1 Diabetes
Funder: Chief Scientist Office (Scotland)

Abstract: Pancreatic islet transplant for Type-1 diabetic patients can restore hypoglycaemic awareness, and in some cases reduce or eliminate insulin dependence, transforming the quality of life of these patients. Isolation of pancreatic islets is a highly complex process, and currently only 50% of isolates meet the stringent criteria for transplant. Mesenchymal Stromal cells (MSC) have potent tissue building and anti-inflammatory properties and are under intense investigation for their ability to improve solid organ grafts. MSC are strong candidates to improve transplanted islet function. We have developed techniques to isolate MSC from the same cadaveric donor pancreas material as transplanted islets, as a ready source of tissue-appropriate MSC. In this study we will generate and fully characterize pancreatic MSC to GMP grade; assess their immunomodulatory function and ability to protect islets from immune attack in vitro; assess the efficacy and safety of MSC for enhancing islet transplant in appropriate in vivo models


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: METABOLIC AND ENDOCRINE
Title: Type 2 diabetes in childhood: building a platform to support novel intervention strategies
Funder: Medical Research Council

Abstract: Obesity related Type 2 diabetes now occurs in children; we described the first UK cases in 2000 (Ehtisham S et al 2000) and shown that there are approximately 70 new cases a year under 17 completed years in the UK (Haines L et al 2007). There is a minimal evidence base for treatment of childhood type 2 diabetes, and children are not included in the NICE guidelines on the management of type 2 diabetes in the UK. We propose to establish a national cohort of children with type 2 diabetes. The purposes are to develop a tightly characterized cohort for intervention with clinical trials that will develop the evidence base for treatment; and to determine the natural history of type 2 diabetes in a UK population diagnosed in childhood.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: METABOLIC AND ENDOCRINE
Title: Epithelial stem and progenitor cells in the postnatal mouse lung
Funder: Medical Research Council

Abstract: Adult organs are maintained for the lifespan of an individual. There are two main models for how this is achieved. One, through the function of stem cells which both self-renew and produce differentiated daughters throughout the lifetime of the organ, such as in the intestine. Two, through the self-renewal of differentiated cells, such as in the liver. How is the long-term maintenance of the lung epithelium achieved? My hypothesis is that the lung uses a region-specific combination of both mechanisms Moreover, that the behaviour of the adult progenitor cells is controlled by similar mechanisms to lung embryonic progenitors. To address these questions, I have developed a panel of genetic tools that can be used either for lineage-labelling or manipulation of gene expression in different mouse lung epithelial cell types, including progenitor cells. These genetic tools will be used in combination with mouse models of lung injury to better characterize lung epithelial stem and progenitor cells and to define their contribution to lung disease. Specifically, I have two independent, but inter-related goals: 1. To employ single-cell lineage-analysis of known progenitor cell types in the lung epithelium to test the hypothesis that particular sub-sets of these cells are niche-localized stem cells. An analysis of patterns of progenitor cell division will also be performed. 2. To test the hypothesis that the same pathways which control the behaviour of mouse embryonic lung epithelial progenitors are re-used in the adult. The effects of manipulating Notch and FGF Receptor signalling in single stem or progenitor cells will be investigated. One in seven people in the UK live with some form of lung disease (British Lung Foundation). Many of these human conditions can be neither controlled nor cured, and their aetiology remains a mystery. The cellular composition of the human lung epithelium has been observed to change during the development of many conditions, including asthma, emphysema and pulmonary fibrosis. For example, there is evidence for changes in the epithelial repair process in both children and adults with asthma. It has been hypothesized that these changes contribute to the development or the severity of the disease. A greater understanding of the mechanisms that regulate how new cells are formed from progenitor or stem cells in the lung will help us to understand exactly how these, and other, lung conditions develop and will contribute significantly to the search for improved treatments.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Thymic and peripheral T cell tolerance in autoimmune diabetes
Funder: Medical Research Council

Abstract: T cell selection in the thymus is regulated to prevent high avidity self-reactive T cells from release to the periphery, and protects against autoimmunity. It is known that self antigens from peripheral tissues are expressed in the thymus and this contributes to negative selection by inducing deletion of cells recognising these antigens with high avidity. However, T cells that recognise peptides with low avidity may escape from negative selection and could then be released from the thymus. Peripheral T cell tolerance mechanisms that include deletion or alteration of activation threshold will then come into play to prevent potentially autoreactive cells from causing autoimmune disease. We will investigate central and peripheral tolerance controlling insulin-reactive CD8 T cells that recognise a peptide of insulin that binds with very low affinity to the MHC-Kd in the Non-obese diabetic (NOD) mouse model of spontaneous autoimmune diabetes. These cells infiltrate into the pancreatic islets at a very early stage of the disease process and can be activated to cause diabetes. We propose that because the cells have low functional avidity related to the poor binding of the peptide to the MHC, high levels of antigen expression are required to stimulate the cells. Thus, we will test whether they are subject to deletion in the thymus using models where expression of insulin in the thymus is altered. We will also study mechanisms of peripheral tolerance testing for peripheral deletion and alteration of activation threshold in the periphery, also utilizing models where proinsulin expression in lymph node stromal cells or dendritic cells is altered. Overall, this proposal will provide important information about selection, deletion and tolerance of low avidity, potentially highly autoreactive CD8 T cells that recognise a low affinity self peptide and could represent an important subset of cells that cause autoimmune disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: The role of NAADP and the two-pore channel proteins in mediating insulin secretion in pancreatic beta cells
Funder: Medical Research Council

Abstract: Changes in cytosolic calcium are a key signalling mechanism by which glucose triggers insulin secretion from the pancreatic beta-cell. Previous studies have emphasised the importance of KATP channels; however, our recent studies also implicate a central role for calcium mobilizing messenger NAADP. Recently we showed that the two-pore channel (TPC) proteins are integral components of the NAADP receptor. Here we will unravel the role of NAADP and TPCs in mediating insulin secretion by addressing a series of key questions: A. Does glucose increase NAADP levels in primary pancreatic beta-cells? We will measure NAADP concentration changes following glucose and GLP-1 stimulation in beta-cells to assess their effects upon NAADP production. B. How is NAADP synthesized in the beta-cell? We will investigate the role of ADP-ribosyl cyclase enzymes CD38 and CD157 as generators of NAADP in beta-cells using immuno-localisation and ARC knockout mice. C. Which store is targeted by NAADP in beta-cells? NAADP-targeted stores are acidic organelles but their precise identity in beta-cells remains unresolved. We will investigate this using targeted indicators and immuno-based approaches. D. Does NAADP-induced calcium mobilization generate glucose-induced calcium microdomains? Local calcium microdomains may be evoked beneath the plasma membrane of beta-cells in response to glucose but their origin is largely unknown. We will use TIRF and electrophysiology to study this issue in beta-cells from wild-type and TPC knockout mice. E. What is the exact nature of NAADP-induced inward currents? NAADP-induced depolarizing currents may combine with closure of KATP channels in setting the excitability threshold by which glucose activates VDCCs. We will use a variety of approaches to characterize these currents. F. What is the role of the NAADP receptor/TPCs in beta-cell physiology and insulin secretion? We will study how NAADP signals mediated by TPCs act with KATP channels to trigger activation of VDCCs using TPC and KATP knockout/mutant mice. G. What can TPC knockout mice tell us about beta-cell physiology and pathogenesis? TPC knockout animals can provide insights into the link between NAADP signalling and beta-cell physiology, but also highlight interactions with other signalling pathways. We will investigate this using DNA microarrays and proteomic approaches. H. What relevance do NAADP and TPCs have for human beta-cell physiology and diabetes? Our ultimate aim in this project will be to relate our findings to human beta-cell physiology and the understanding and treatment of diabetes. We will thus also investigate these questions in primary beta-cells obtained from donated human islets.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: Molecular mechanism of the recovery in infantile reversible cytochrome c oxidase (COX) deficiency myopathy
Funder: Medical Research Council

Abstract: We have recently identified the molecular genetic cause of a puzzling clinical syndrome, initially termed ?benign infantile mitochondrial myopathy due to reversible cytochrome c oxidase (COX) deficiency?. While childhood-onset mitochondrial encephalomyopathies are usually severe, relentlessly progressive conditions with fatal outcome, this syndrome stands out by showing complete (or almost complete) spontaneous recovery. We have detected the homoplasmic m.14674T C mutation in the mitochondrial mt-tRNAGlu gene in 17 affected individuals from 12 independent families of different ethnic origins. The m.14674T C mutation affects the discriminator base of mt-tRNAGlu, the last base at the 3‘-end of the molecule, where the amino acid via the terminal CCA is attached, therefore thought to impair mitochondrial translation, as reflected by the COX-negative fibres and the multiple respiratory chain defects in skeletal muscle. The identification of a homoplasmic mt-tRNA mutation in reversible COX deficiency myopathy raised a number of important issues. We will investigate, i) why patients with homoplasmic m.14674T C show an isolated muscle involvement, ii) why symptoms start uniformly in the first days or weeks of life, and iii) what is behind the molecular basis of the age-dependent, spontaneous recovery. The spontaneous recovery of the patients suggests the existence of so far unknown cellular compensatory mechanisms We will study mt-tRNA processing and function in human primary cells and muscle of patients with reversible COX deficiency myopathy, and based on the results we will extend the investigations on different types of mitochondrial disease. The identification of the pathomechanism of reversible COX deficiency myopathy may have implications in other mitochondrial conditions. The long-term goal of this approach would be to upregulate or boost compensatory factors in patients with different types of mitochondrial disease with the aim to open new avenues for therapy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: S Norris University of the Witwatersrand Health and wellbeing of female adolescents and young adults
Funder: Medical Research Council

Abstract: A major challenge in sub-Saharan Africa is the complex interrelationship between poor maternal nutrition and postnatal stunting on one hand and the increased risk of adolescent and adult obesity on the other leading to an increased risk of type-2 diabetes (T2D) and metabolic disease in future generations. Drawing upon two well-established longitudinal research platforms, the urban Birth to Twenty cohort (Bt20) and rural Agincourt Health and Socio-demographic Surveillance System (HDSS), studies of contemporary adolescent and young adults (generation 1) and their offspring (generation 2) ? including detailed examination of pre-pregnancy and pregnancy exposures ? provide a unique opportunity to evaluate outcomes relating to future T2D and metabolic disease risk. Primary hypotheses relate to the effects of adolescent weight gain, pregnancy risk for T2D, and subsequent offspring disease risk. The achievements of Bt20 and Agincourt HDSS in providing robust data, serum, DNA, and other samples for scientific study confirm their utility as platforms supporting advanced research and interventions-development in a sphere important to all transitioning societies


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE