NIHRDataInsights/HRCSData huggingface dataset:
Title: T1D UK Clinical Trials Consortium – Mechanistic Core
Funder: Diabetes UK

Abstract: Mechanistic studies of immunotherapeutic interventions have provided important insights into why (or in whom) treatments succeed or fail and have begun to identify key biomarkers of safety and efficacy. However, all too frequently the focus is on a limited range of immune parameters, and/or the mechanistic analyses are conducted post hoc, resulting in an incomplete understanding of the relationship of therapy to outcome. We propose that UK-based studies should provide a rich resource of mechanistic insight to inform the design of future studies in the field. The T1D UK Clinical Trials Consortium Mechanistic Core will establish a tightly coordinated group of specialist laboratories to perform world-class, state-of-the-art, mechanistic assays. These span the breadth of immunobiology known to be linked to T1D pathogenesis and offer the opportunity for multi-dimensional and multi-pathway exploration. The Core will serve the rapidly expanding UK-T1D clinical research network and afford maximal data acquisition per subject recruited into trials, whether conducted within the Consortium or in linked efforts. We anticipate that using this contemporaneously acquired know-how will facilitate a more rapid evolution of informed study design, including stratification and rational selection of agents for combinations, which are the ultimate clinical goals of our Consortium.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: METABOLIC AND ENDOCRINE
Title: Development of a 3D human in vitro model of pancreatic beta cell health
Funder: Engineering and Physical Sciences Research Council

Abstract: Diabetes mellitus is a major health issue with ~390 million people affected worldwide (IDF Diabetes Atlas 6th edition, 2014). Most diabetics are type 2 (T2D), typically characterised by the loss of pancreatic beta cell function and beta cell mass and peripheral insulin resistance. Whilst current therapies do provide some level of glycaemic control, they do not prevent the debilitating long-term consequences of the disease. In the on-going search for better treatments, there is now a real focus on strategies that aim to preserve the function of remaining beta cells or replenish beta cell mass. To support this new focus of diabetes research, this project aims to develop a human 3D in vitro model of pancreatic beta cell health / beta cell proliferation. No such commercial model currently exists. The model will be developed using native human islets and Asterand Bioscience's (Asterand's) proprietary 3D cell culture platform. The consortium will then explore whether a more sustainable cell source can be utilised (eg., iPSC-derived beta cells) and ultimately whether the established model can be miniaturised using 3D printing. The 3D printing work is to achieve highly accurate spatial dispensing of beta cells onto membranes in well plates that the currently commercial platform is based on. The effects of dispensing conditions on cell viability and functions will be investigated to identify an optimal processing condition for dispensing beta cells. In addition, how cell population influences cell function will be studied by dispensing cell samples with different sizes. The proposed cell printing solution combined with technologies developed by two industrial partners will create a unique manufacturing advantage allowing the production of off-the-shelf products for drug discovery.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: METABOLIC AND ENDOCRINE
Title: Pre-clinical development of a novel oral therapy for hyperinsulinemic hypoglycaemia
Funder: Innovate UK

Abstract: Congenital Hyperinsulinism is a rare neonatal disease presenting severe hypoglycaemia associated with poor clinical outcomes and long-term neurodisability. The support of the Technology Strategy Board will enable Heptares, in collaboration with the University of Manchester and Great Ormond Street Hospital, to carry out the pre-clinical development of a novel safe, effective and orally available treatment for Congenital Hyperinsulinsm. A succesful outcome will provide a clinically ready molecule with anticipated additional benefits in other areas associated with intractable hypoglycaemia; including neonatal hypoglycaemia, hypoglycaemia occurring as a consequence of gastric bypass surgery and insulinoma-associated hypoglycaemia. .


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: DiaPOC - Assessing the feasibility of a rapid, accurate, pocket sized HbA1c POC
Funder: Innovate UK

Abstract: Type 2 diabetes is a chronic condition that affects 3.5m people in the UK and costs the NHS £13bn annually. Through improved monitoring and condition managment a patient’s risk of death can be dropped by 50, however current products on the market are insufficient. Only three meet clinically accepted performance criteria, and these are large, costly and relatively slow solutions. At AniPOC, we propose a pocket-sized, truly portable, accurate and precise device that delivers results ‘while you wait’ for the most advanced management of Type 2 diabetes available. This project aims to determine the commerical pull and market opportunity for such a technology.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: METABOLIC AND ENDOCRINE
Title: Cellular Identity and Metabolism
Funder: Medical Research Council

Abstract: Pancreatic beta-cells are essential endocrine cellular units regulating peripheral glucose uptake via the biosynthesis and secretion of insulin. The progressive decline in pancreatic Beta-cell mass associated with obesity and insulin resistance underlies the rising prevalence of type-2 diabetes (T2D) worldwide. Recently, beta-cell dedifferentiation was revealed as a novel mechanism of insulin insufficiency in T2D. Dedifferentiated beta-cells do not undergo apoptosis, but loose the expression of insulin and other markers maintaining their function. The genomic reprogramming is such that dedifferentiated beta-cells regress to a primitive multipotent state and present reactivation of several progenitors markers (e.g. NGN3, c-MYC, OCT4, NANOG, SOX2, SOX9) and can transdifferentiate into other islet endocrine cells. This indicates that the differentiation state of Beta-cells is not set in stone and suggest that genetic manipulation could be use to reprogram dedifferentiated cells into functional insulin-secreting cells in humans. Our previous work revealed that overexpression of miR-7 triggers dedifferentiation of beta-cells in T2D and represent a crucial pathological determinant in the etiology of T2D. The objectives of my research programme are the following: 1. To define the biological role of miRNAs in the differentiation of pancreatic Beta-cells during development. 2. To define the role of miRNAs in the dedifferentiation of pancreatic beta-cells in diabetes This research program will provide a basis for potential development of novel miRNA targeting therapeutic strategies aimed at reprogramming endocrine cells into functional beta-cells.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Metabolism and Gene Regulation
Funder: Medical Research Council

Abstract: The liver has a pivotal role controlling the metabolism of carbohydrates and lipids and the secretion of bioactive molecules, including pro- and anti-inflammatory hepatokines that are involved in multi-organ crosstalk. Characterisation of small molecules and hepatokines involved in this communication is critical to understand the molecular mechanisms leading to insulin resistance, the decline in -cell function, inflammation and cardiovascular complications associated with Type 2 diabetes (T2D) and obesity. However, the complexity of these metabolic diseases, that involve interactions between tissues such as the liver, adipose tissue, immune system and brain, the action of hormones and the network of signalling pathways linked to insulin, such as mTORC or the stress-activated cJUN N-terminal Kinase (JNK), has been difficult to decipher. JNK pathway is activated by consuming a high fat diet, and preventing this activation by tissue-specific ablation of JNK in mouse models inhibits the development of obesity, inflammation and insulin resistance. Therefore, JNK is critical in the crosstalk between metabolic organs and the immune response in the course of metabolic disorders, although its downstream effectors are largely unknown. We use mice with genetic and pharmacological inactivation of JNK in hepatocytes, Tandem Mass Tag (TMT-MS) proteomics and Next Generation Sequencing (RNAseq) as a viable strategy to identify new hepatokines involved in metabolic regulation. Using a TMT-MS screening we identified a group of JNK-regulated hepatokines, including proteins involved in immune response such as complement proteins or previously characterised metabolic regulators (such as RBP4), confirming the potential of this approach to identify metabolic regulators. In addition, we identified other secreted proteins without a known role in metabolic regulation. We aim to characterise interesting candidates identified in this approach. We will use adeno-associated viral vectors, CRISPR/CAS9-based systems and mouse models of obesity and insulin resistance to study the role of these hepatokines in the multi-organ crosstalk and metabolic regulation. The short-term goal of this proposal is to identify and characterise JNK-regulated hepatokines that may be involved in diet-induced inflammation and insulin resistance. The long-term goal of this proposal is to characterise novel mediators of the communication between organ systems that may be involved in diet-induced metabolic dysfunction, to uncover new diagnostic and therapeutic targets in metabolic pathologies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Gut Signalling and Metabolism
Funder: Medical Research Council

Abstract: We are investigating how the intestine controls energy homeostasis and nutritional decisions. The digestive system is emerging as a key regulator of appetite and metabolism. It is now recognised that signals emanating from the gastrointestinal tract and its neurons can contribute to increasingly prevalent conditions such as diabetes and metabolic syndrome. In addition to signalling, the digestive tract can also undergo dramatic functional remodelling in response to environmental or internal change – for example, during reproduction. Our lab has been exploring the mechanisms underlying intestinal plasticity and their functional significance. We recently identify a sex hormone required for intestinal remodelling during reproduction and, using targeted genetic experiments, demonstrated that such remodelling was required to sustain reproductive output (Reiff et al (2015) eLife). We also described extensive differences between the intestine of males and females, and showed that the intrinsic sexual identity of intestinal somatic stem cells played key roles during reproduction, but also increased gut tumour susceptibility in females (Hudry et al (2016) Nature). Finally, we described a new mechanism, key during malnutrition, by which enteric neurons sense lack of lack of specific nutrients (Linneweber et al (2014) Cell). Most of our work has taken advantage of the genetic amenability of Drosophila. Over 60% of our genes have equivalent counterparts in Drosophila. Fruit flies also offer two key advantages to investigate the genetic control of physiology and metabolic adaptations: 1) they allow rapid mutation or misexpression of large numbers if genes (allowing for rapid identification of metabolically significant genes) and 2) they allow temporal and spatial control of gene expression (key to establishing directionality of signalling when investigating organ crosstalk). While flies continue to be our primary discovery tool, we are also investigating whether the mechanisms of intestinal plasticity that the fly has revealed are evolutionarily conserved; are our organs sexually dimorphic and capable of similar remodelling? We are using mouse models and human cells to explore these questions. Conservation of these mechanisms and sex differences may have important implications for our ability to reproduce, handle nutrient overload/scarcity, resist certain diseases and respond to their treatment. Genetic or pharmacological interventions aimed at modulating similar pathways in humans may be advantageous in the contexts of fertility, weight gain/loss and preventing tumour formation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Non Communicable Diseases Phenotyping
Funder: Medical Research Council

Abstract: Disease epidemiology has changed rapidly in Africa. About a decade or so ago, African health services were dealing principally with infectious diseases. While these continue to have a high burden, chronic non-communicable diseases (NCDs) are increasingly becoming major contributors to morbidity and mortality in the region. There is however indication that NCDs in Africa may not manifest in a different way compared to the classical presentations in high-income countries. For example, the limited data available, including from our recent studies, suggest that type 2 diabetes and hypertension occur in relatively young and lean people in Africa. The biological mechanisms for this apparent heightened susceptibility are unknown, but may relate to environmental exposures (eg malnutrition), particularly early in life, which can influence long term risk of disease (perhaps by affecting organ size or via epigenetics). Our research will combine epidemiological studies and deep clinical and laboratory phenotyping to accurately document the burden and risk factors diabetes. In one study, we will address gestational diabetes (GDM) which, when not properly managed, is associated with significant morbidity to the mother and child. The true burden of GDM in Uganda (and most African countries) is not known, because of a lack of high quality studies. The objectives here are to 1) accurately document the burden, determinants and outcomes (fetal and maternal) of GDM; 2) using a combination of demographic, clinical and biochemical markers, develop as risk scoring tool that might be used to identify women at high risk of GDM who should be targeted for screening; 3) undertake formative research to gain a detailed understanding and document barriers and facilitators to GDM care, to inform a future intervention study to improve GDM care. Our second study will involve phenotyping of “type 2” diabetes. The primary objective is to describe, in detail, the metabolic and immunologic profile of newly diagnosed adult diabetic patients in Uganda in order to fully understand the unique phenotype of black African diabetic patients. Specifically, using dynamic testing, we will assess the contribution of defects in insulin secretion and/or insulin resistance, the role of inflammation and immunity and the frequency and determinants of co-morbidity with components of the metabolic syndrome (eg hypertension and dyslipidaemia). This work will not only help us to better understanding of the pathophysiology (including the contributions of beta cell dysfunction and insulin resistance), might lead to identification of novel biomarkers (and therapeutic targets) for the risk of developing diabetes and its progression, as well as a more rational use of the existing drugs.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: ADIPOSE TISSUE DYSFUNCTION AND LIPOTOXICITY
Funder: Medical Research Council

Abstract: This programme aims to identify the molecular mechanisms that link obesity with its metabolic complications. Our approach is adipocentric, focusing on adipose tissue expandability and function as main determinants of the pathophysiological link, and the contribution of quantitative and qualitative lipotoxic-related mechanisms. We aim to: a) establish the molecular mechanisms controlling adipose tissue plasticity as a strategy to prevent the development of obesity-associated metabolic complications b) define the anti-lipotoxic effects of oxidative pathways through strategies that promote mitochondrial oxidation in brown adipose tissue thermogenesis as well as to identify futile, energy costly, cellular and molecular strategies to increase energy expenditure (e.g muscle thermogenesis) c) identify biomarkers of prognostic, diagnostic and therapeutic value based on 1) specific lipid species or group of lipids associated with lipotoxicity and 2) targeted genes, pathways and molecules that promote energy dissipation. These objectives will be addressed through a multidisciplinary approach involving genetically engineered murine, fish and fly models, state-of-the-art in vivo and in vitro phenotyping, and systems-biology approaches such as RNAseq, lipidomics and metabolomics technologies, integrated bioinformatics platforms. Finally, we intend to work with our collaborators to validate those findings/candidate targets in human translational studies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE
Title: Entero-endocrinology including the effects of bariatric surgery
Funder: Medical Research Council

Abstract: The enteroendocrine system is a key player in the control of postprandial nutrient homeostasis, modulating the transit and digestion of nutrients within the intestine, the disposal of nutrients in peripheral organs and affecting future feeding behaviour/appetite. Some peptide hormones, notably glucagon-like peptide-1, are already exploited to treat diabetes and obesity, whilst changes in enteroendcrine responses are thought to contribute to the beneficial metabolic outcomes of bariatric surgery. This programme uses genetically modified mouse models to address the mechanisms underlying enteroendocrine changes in response to bariatric surgery with the aim to modulate the enteroendocrine system for the treatment of metabolic disease. We compare in vivo results in mice after vertical sleeve gastrectomy with observations in human volunteers, which have undergone gastrectomy with Roux-en-Y type reconstruction of the upper small intestine and in vitro studies with primary mixed epithelial cultures and intestinal organoids of both human and murine origin. Transcriptomic, mass-spec-based peptidomic, optical single cell second messenger dynamic and electrophysiological investigations are combined with pharmacological and/or genetic manipulations to identify and characterise signalling mechanisms underlying enteroendocrine hormone release and action.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.4 SURGERY
Health categories: METABOLIC AND ENDOCRINE
Title: Epigenetic programming of metabolic health across the life-course
Funder: Medical Research Council

Abstract: We aim to define the epigenetic mechanisms mediating the relationship between suboptimal nutrition in utero and metabolic disease in later life. It is well established that altered patterns of early growth, as a consequence of both in utero under-nutrition and over-nutrition are associated with increased risk of metabolic diseases such as type 2 diabetes and obesity in later life. These conditions are major health care issues of the 21stcentury in both the developed and developing world. Therefore, understanding mechanisms by which these conditions arise and which could therefore be targeted within intervention and prevention strategies could have a major impact. Although there is strong evidence, from human and animal studies that early diet, plays an important role in mediating these relationships, the precise molecular mechanisms by which diet during critical periods of development programmes metabolism and consequently influences long-term health remain poorly defined. Permanent changes in epigenetic regulation of gene expression have emerged as an important contributing mechanism. Our previous studies demonstrated that promotor-enhancer interactions and small non-coding RNAs such as miRNAs represent key nodes of epigenetic regulation leading to modulation of expression of complex gene networks. In the current proposal, using adipose tissue from well-established mouse models of developmental programming in combination with human biopsy material, we will apply state of the art epigenetic technology including promoter-capture Hi-C with complex bioinformatic analysis, to identify changes in 4D chromatin structure that mediate programming effects. Furthermore, we will establish if non-coding RNAs represent particular “hot spots” within the genome for such regulation. We will define the function of these non-coding RNAs and promotor-enhancer interactions in vitro using a combination of primary cell cultures and adipocyte cell lines and applying CRISPR-Cas9 genome editing technology. Our studies will therefore define novel programming mechanisms that are conserved between rodents and humans. Any programmed epigenetic changes that we identify could, in the future, be used prognostically, diagnostically and therapeutically to target individuals at risk of metabolic disease resulting from suboptimal early life programming. The findings could therefore help combat the growing burden of complex diseases such as type 2 diabetes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Enabling technologies
Funder: Medical Research Council

Abstract: This programme provides the core facilities and technologies that act as vital supporting infrastructure, not only for MDU Programmes 1-4 but also for the other investigators across the MRL. At the heart of this programme are the Disease Model Core (DMC), the Genomics and Transcriptomics Core (GTC) and the Biochemistry Assay Lab (CBAL). The DMC integrates two major platforms, physiology and histology, and provides a full range of support services to maximise scientific output from in vivo model systems. These include Home Office licensing support, cutting-edge in vivo phenotyping techniques, ex vivo tissue analysis, statistical analysis and data interpretation. The GTC provides access to high-throughput sequencing technologies, RNA quantification and ‘Sanger’ DNA sequencing as well as bioinformatics support. CBAL runs alongside the Clinical Biochemistry Lab of the Cambridge NIHR Cambridge Biomedical Research Centre and offers biochemical and immunoassay analyses (mainly rodent plasma and serum) to members of the MDU and IMS-MRL. While the DMC and GTC are the primary facilities within Programme 5, a number of other key technologies, which receive the majority of their funding from other sources (Wellcome Trust and NIHR BRC), also provide critical support to MDU scientists. These are Microscopy and Imaging, Metabolomics/Lipidomics, Proteomics and the Genome Engineering Core. We seek to build on the success of these cores facilities and strengthen key areas where there is pressing, multi-user need.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: METABOLIC AND ENDOCRINE