NIHRDataInsights/HRCSData huggingface dataset:
Title: Performance of EArly Retinal Laser (PEARL)
Funder: Medical Research Council

Abstract: The prevalence of diabetes in China has risen tenfold since 1981. Virtually all of China's 114 million diabetic persons will develop diabetic retinopathy (DR) eventually, and timely laser treatment reduces blindness by 50%. Still, only 10% of rural persons with DR in China receive treatment, partly because current care requires them to be followed for several years before reaching treatment criteria, during which many are lost. Our recent review suggests that earlier treatment, which could reduce the compliance burden, may be clinically efficacious and cost effective, but current evidence is insufficient. Our pilot work confirms rural patients find long-term adherence difficult, and earlier treatment is acceptable to patients and providers. We now propose a pilot randomised trial to determine whether earlier laser treatment improves outcomes and compliance among those with diabetic retinopathy in China. Patients will be recruited from one of China's largest hospitals, and treated after training provided by the top-ranked eye hospital in the country. Participants with severe non-proliferative diabetic retinopathy (NPDR) in both eyes will be randomized to receive: pan-retinal photocoagulation (PRP) applied immediately in one eye at random and PRP in the fellow eye only when proliferative diabetic retinopathy (PDR) develops (Early Intervention-n=100) or PRP at the PDR stage in both eyes (Standard Care group-n=100). The latter group is needed in particular, to test whether early laser treatment has an effect on adherence. At 1 year follow-up, the primary outcome will be progression to PDR, with secondary outcomes including loss of vision, complications, quality of life and cost effectiveness. In addition to informing a full trial, this study will address questions of importance to diabetic eye care in low resource settings by validating physician clinical diagnosis of DR compared to more expensive technologies and testing a simplified definition of severe NPDR.


Research activity codes: 6.4 SURGERY
Health categories: METABOLIC AND ENDOCRINE
Title: MICA: Tackling iatrogenic Cushing's syndrome through 11beta-HSD1 inhibition
Funder: Medical Research Council

Abstract: Currently, 2-3% of the population of the UK and US receive glucocorticoid therapy. Significant adverse effects are not confined to chronic use; recurrent short-course administration is associated with increased morbidity and mortality. The adverse metabolic features associated with glucocorticoid use include obesity, skeletal muscle myopathy, hypertension, insulin resistance and diabetes and are collectively termed 'iatrogenic Cushing's syndrome'. The efficacy of glucocorticoid therapy is not in doubt, but there are no interventions to reduce their metabolic consequences. Within metabolic tissues (liver, skeletal muscle, adipose), 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) regenerates active glucocorticoid and therefore is able to tightly control the availability of glucocorticoids to activate the glucocorticoid receptor. In preclinical studies, we have shown that 11beta-HSD1 is critical in regulating the development of the adverse features associated with circulating glucocorticoid excess, endorsing our observations in a patient with Cushing's disease, who was protected from a classical phenotype due to a functional deficit in 11beta-HSD1. We will perform a randomized, double-blind placebo controlled study to determine if co-administration of the selective 11beta-HSD1 inhibitor, AZD4017, limits the adverse effects of short-course exogenous glucocorticoid administration. 30 healthy male volunteers will have detailed metabolic investigations including 2-step hyperinsulinaemic euglycaemic clamps (with stable isotope measurements of lipid and carbohydrate metabolism), as well as assessment of skeletal muscle forearm glucose uptake. All volunteers will then be treated with Prednisolone (20mg daily) and randomized to the co-administration of placebo or AZD4017. After 1 week of therapy, all investigations will be repeated. Our hypothesis is that the adverse metabolic effects of Prednisolone will be reduced by co-administration of AZD4017.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: METABOLIC AND ENDOCRINE
Title: In vivo characterisation and manipulation of succinate-dependent free radical injury during ischaemia-reperfusion
Funder: Medical Research Council

Abstract: This research will investigate the essential role of succinate driven ROS production and injury during IR. To do so, complementary research aims will: (1) determine the in vivo mechanisms that control succinate-driven ROS production (2) elucidate the generality of the succinate-ROS mechanism in established cardioprotective interventions (3) develop targeted inhibitors for the manipulation of the succinate-ROS pathway in vivo, and (4) establish succinate as a novel diagnostic marker of IR. 1. Succinate driven ROS during IR occurs by a process of reverse electron transport (RET) at mitochondrial complex I, but the bioenergetic parameters required for this process to occur in vivo are unclear. We will use pharmacological tools to manipulate mitochondrial parameters and characterize the RET mechanism in vivo for the first time. 2. We will apply our recently developed tools for comparative metabolomics to examine the consequences on metabolic flux of established cardioprotective regimes that have uncharacterized modes of action. We hypothesise that manipulation of succinate-ROS mechanism provides a unifying explanation of various cardioprotective strategies. Testing this hypothesis will provide critical mechanistic insight and determine the extent to which manipulation of ischaemic succinate accumulation is a universal predictor of IR damage. 3. Having established that competitive inhibition of succinate dehydrogenase mediated succinate accumulation is a promising strategy to protect against the upstream damage of IR injury, we will now develop and test targeted inhibitors of the pathways that control succinate driven ROS production. 4. Using a combination of in vivo models of IR injury with established and variable levels of consequent pathophysiology, we will develop a mass spectrometry based screen of mitochondrial metabolites from circulating fluids as a predictive diagnostic for the extent or IR injury.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE
Title: REVing-down: targeting the circadian clock in metabolic disease
Funder: Medical Research Council

Abstract: In obesity, white adipose tissue (WAT) hypertrophy is associated with a shift in local immune cell populations, with displacement of beneficial cells by pro-inflammatory immune cells (eg M1 macrophages). From human and animal studies, we know that this inflammatory state drives WAT dysfunction, dyslipidaemia, and insulin resistance. What remain unclear are the events that signal the transition from efficient fat storage to WAT dysfunction and inflammation. REVERBa-/- mice are profoundly obese; yet do not exhibit loss of insulin sensitivity or exacerbation of WAT inflammation. A role for REVERBa in lipid metabolism and within the immune system is already well established. REVERB typically inhibits macrophage inflammatory response. This led us to hypothesise that loss of REVERBa in adipocytes circumvents inappropriate programs of lipolysis and adipocyte stress which normally accompany WAT hypertrophy, and signals a selective preservation of distinct immune cell populations in the tissue (M2 macrophages, iNKT and ILC2 cells) even amid pronounced obesity. To test these hypotheses, we will: - Selectively delete REVERBa, or its DNA-binding domain (thereby segregating REVERBa control over metabolic and inflammatory processes) in adipocytes, and define the consequences of obesity in the mice. - Identify, isolate and phenotype WAT immune populations during the development of obesity in normal (inflamed/insulin resistant) and transgenic (insulin sensitive) mice. We will similarly define immune populations in WAT of obese and normal weight patients, to reveal common cells and events that define the inflamed insulin-resistant WAT in humans and mice, and use pharmacological manipulation of REVERBa to validate candidate pathways in cultured WAT. These studies will bring new understanding of WAT function and identify new strategies in the fight against obesity-related diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: MICA: Exploring a new perspective on the mechanism of action of Glucokinase Activators in liver, a preclinical study
Funder: Medical Research Council

Abstract: Current information on the mechanism of action of GKAs is derived from: (i) blood glucose, insulin and other biomarkers during acute or chronic GKA therapy in animals or man; (ii) short-term effects of GKAs on primary cell models (hepatocytes or islets) from rodents not exposed to GKAs. The acute and short-term effects of GKAs on blood glucose in man concur with predictions, but the loss of efficacy on blood glucose lowering during chronic therapy remains unexplained. To identify the underlying mechanisms and test whether GKA therapy is protective to NAFLD development we will use mouse models (C57BL6, GKRP-deficient, GKRP:446L) treated chronically with AZD1656 in conjunction with a high-carbohydrate diet or a Western style diet (to induce NAFLD) to determine 3 sets of end-points: (a) basal blood glucose, insulin and lipids and glucose and insulin tolerance; (b) liver glucokinase and GKRP protein expression and cellular location, and liver histopathology (steatosis, inflammation, fibrosis); (c) detailed characterization of the hepatic metabolic adaptations in primary hepatocytes from the AZD1656 treated models. The latter will involve determination of metabolic flux (glucose phosphorylation, glycolysis, lipogenesis); metabolite excursion (cell content of phosphorylated intermediates); gene regulation and expression in response to a graded glucose challenge to determine affinity for glucose. To test the validity of the mouse GKRP-446L model for the human GCKR variant linked to liver disease we will use hepatocytes from GKRP null mice transfected with human or mouse GKRP (446Pro or 446Leu) for study of metabolic flux, metabolite excursion, gene regulation and chromatin binding of GKRP. To test for concordance between the mouse models and human NAFLD, we will perform immunohisto-chemistry for glucokinase and GKRP in human liver biopsies from NAFLD and NASH patients and compare this with the mouse data.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Role of Rab3 in peripheral tissue insulin resistance
Funder: Medical Research Council

Abstract: The aim of our study is to investigate the role of Rab3 isoforms and their interacting partners in the development of the peripheral tissue insulin resistance. Our previous work has identified that isoforms of the small GTPase Rab3 and their effector Noc2 (RPH3AL) are activated by insulin and that they play a role the final stages of insulin-stimulated GLUT4 translocation to the plasma membrane in adipocytes. Our preliminary data demonstrate that treatment of adipocytes with TNFa, a pro-inflammatory cytokine known to induce insulin resistance, decreases the levels of Rab3 and Noc2 in cells and this effect is reversed by treatment with the PPARg agonist rosiglitazone. In addition, analysis of human adipocytes from obese insulin resistant subjects showed that the levels of Rab3 isoforms are reduced compared to weight-matched insulin-sensitive subjects. These novel findings led us to hypothesise that alterations in the activation and abundance of Rab3 isoforms and their interacting partners, play a key role in mediating pro-inflammatory cytokine induced insulin resistance by disrupting the final stages of GLUT4 translocation in adipocytes. We propose to study how TNFa alters Rab3 isoforms expression at transcriptional and post-translational level. We will compare TNFa action on Rab3 with other treatments known to induce insulin resistance, such as chronic insulin treatment, or high palmitate treatment. We will study the molecular interactions between the Rab3 guanidine exchange factor DENN/MADD and Rab3 and their reported association with the TNFa receptor. Using proteomic, biochemical and cell biology approaches, we will determine how insulin regulates these interactions and how TNFa alters their function. To understand the role played by Rab3 in whole body insulin sensitivity, we will carry out a human intervention study to determine whether restoring glucose tolerance in overweight and insulin resistant subjects affects Rab3 isoforms' expression and regulation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Variation in Glycocalyx Structure in Diabetes
Funder: Medical Research Council

Abstract: My broad hypothesis is "Diabetic induced hyperglycaemia causes alterations to the glycocalyx marcostructure resulting in the observed increase in permeability" of the vasculature. To test this a system must be used that can determine the macrostucture, the structure that determines the permeability. Electron microscopy is a system is able to determine the glycocalyx fibre parameters of permeability (Depth, Diameter, spacing, lattice and overall coverage) in physiological cases. I propose to use glycocalyx generated by cultured endothelial cells (human choroid, human retinal, human glomerular and mouse bEND5) to observe the structure under a variety of electron microscopy stains (Alcian Blue, Ruthenium Red, Lathanum and Dysprosium) that target differing elements. The permeability will be inferred form an electrical cell impendence system. Moreover fenestrations, the primary hydraulic route if present, will be induced by VEGF-A or latrunculin A. These systems will be compared to cells grown in normal or hyperglycaemic conditions. A key component of the glycocalyx that has been implicated in hyperglycaemic loss of function is the glycosaminoglycan heparan sulphate (HS). The role of HS will be uncovered using shRNA for components of the HS biosynthetic pathway together with characterisation of the resulting shifts in sulphation patterning and HS distribution - linking these to function in the in vitro model. The positioning of elemental components will then be detected using altered staining and cryo-analytical electron microscopy. Following validation of the relationship between cryo-analytical EM/altered staining and HS composition in the in vitro setting, the protocols will move to physiological models of diabetic retinopathy and nephropathy where the permeability of the vasculature and the quantitative glycocalyx structure are compared to the structure with specific components missing to compare phenology via quantification of the permeability parameters.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Sex-specific disease aetiology from developmental steroid insults: mechanistic understanding and biomarker development towards disease prevention.
Funder: Medical Research Council

Abstract: Fetal development, including sex development, is modulated by steroids. Incorrect steroid exposure in utero predisposes to altered postnatal disease risk. If we understand the postnatal health legacies that are consequences of excess steroid exposure in utero, we can advise upon issues such as limiting exposure to exogenous compounds that alter steroid signalling, and develop amelioration strategies where exposure is due to underlying medical conditions. RESEARCH PLAN We will interrogate, using Next Generation Sequencing and shotgun proteomics, pre-existing sets of ovine tissues, where excess sex steroid signalling was experimentally driven during fetal life to model human PCOS. Due to its modulatory role in steroid exposure during development and postnatal life, the liver is our focus. We capitalise on previous investment in large animal modelling, and require no additional animal experimentation. We add translation to humans by interfacing this work with ongoing work examining the human fetal liver. DELIVERABLE 1 We will identify hepatic differences in postnatal life attributable to developmental androgenisation in sheep. We will examine the outcomes of steroidal excess during development on male and female postnatal hepatic function. This work will identify postnatal legacies, and fetal antecedents of, disrupted steroid signalling in utero, in a sex-specific context. DELIVERABLE 2 We will use health relevant indices collected in vivo, to delineate 'effect' from 'adverse effect'. We will utilise human data sets to provide translational confidence between interventional ovine models and observational human studies. DELIVERABLE 3 We will identify postnatal biomarkers of specific fetal steroid excesses (androgen or oestrogen) in offspring from birth to adulthood that are relevant to health, and deliver mechanistic insights to inform future therapeutic strategies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Macronutrients and Metabolic Health - Understanding how metabolic disease arises at the population level using metabolomics and lipidomics.
Funder: Medical Research Council

Abstract: Both obesity and type 2 diabetes (T2DM) are increasing in the UK impacting on the nation's health. We aim to address this major health issue by understanding the interactions between over nutrition, subsequent obesity, and the development of insulin resistance (IR), and how this ultimately leads to T2DM and cardiovascular disease. Our global aim is to understand the underlying mechanisms that determine why on an individual basis certain people are predisposed to developing IR and subsequently T2DM, while others stay metabolically healthy. To achieve this aim we have identified four themes to be developed in parallel. 1. White adipose tissue (WAT) function in health and disease: We will apply metabolomics in conjunction with molecular biology tools to investigate the balance between lipid storage and oxidation, and in particular continue our study of the browning of WAT. Furthermore, using measurements of lipid mediators we will investigate further how over nutrition produces adipose tissue dysfunction and inflammation. 2. Ectopic fat deposition: We will use comprehensive metabolomic and lipidomic mass spectrometry approaches to profile the impact of excessive fat storage in the liver, heart and skeletal muscle, and in particular focus on the transition of non-alcoholic fatty liver disease to non-alcoholic steatohepatitis and cirrhosis, the development of ER-stress in skeletal muscle, and how diet influences cell membrane composition and ultimately cellular function across the body. 3. Lipidomics at the epidemiology scale: To investigate IR and T2DM development in humans we have developed assays that can be performed on a global scale to allow us to address questions about T2DM and diet, ethnicity and age. These will be applied to large scale studies (n>5000) such as Fenland, PROMIS and INTERVAL. 4. Method development in mass spectrometry and bioinformatics: We are currently developing tools in mass spectrometry imaging and ion mobility for lipidomics.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Exploitation of metadherin as a regulator of hepatic energy metabolism
Funder: Medical Research Council

Abstract: In the metabolic syndrome, an early event is triglyceride accumulation in the liver, which then leads to inflammation, fibrosis, disordered organ function, cirrhosis, and finally liver failure, or hepatocellular carcinoma. Glucocorticoid signalling lies at the heart of many of these processes, but how the glucocorticoid receptor (GR) engages effector mechanisms remains unclear. We discovered metadherin is required for some, but not all actions of the GR, and that this interaction is pronounced within the liver, with a target gene ontology of lipid metabolism. To define metadherin action and modification of GR function we will: 1. Use mass spectrometry and fluorescence correlation spectroscopy to define post-translational state, trafficking dynamics of GR, and GR:metadherin interaction under normal conditions and following metadherin disruption. We will validate GR modification using CRISPR engineered cells, and ascribe function using target gene expression measurements. 2. Metadherin serves as a protein scaffold, and in addition to our discovery of its interaction with GR, other metadherin client proteins include kinases and LXR. To reveal mechanisms of MTDH-mediated GR modification, we will determine the metadherin interactome, including potential effector kinases in livers from control and obese animals. 3. As metadherin regulates GR recruitment to the genome in vitro, and enhancer activation in response to glucocorticoid in vivo, we will map the GR cistrome in the liver in response to energy excess, and determine how metadherin regulates this action. Emerging mechanisms will be tested in primary hepatocytes recovered from wild type and metadherin null livers. 4. The physiological consequences of metadherin disruption on liver energy metabolism will be measured using hepatocyte metadherin null mice. We will use chronic glucocorticoid or high fat challenges, and measure lipid synthesis, oxidation, and export.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Understanding the nutritional regulation of 'healthy' fetal and infant growth and development
Funder: Medical Research Council

Abstract: The overall aim of my research is to identify mechanisms through which maternal and infant nutrition may impact on maternal health and influence infant development and hence identify pathways by which nutritional interventions to mothers and/or infants can be effective. The specific focus is on the nutritional regulation of 'healthy' fetal and infant growth, and in gaining a detailed understanding of the mechanisms underpinning this. The research is concentrated on vulnerable populations, especially mothers and infants in settings of widespread undernutrition in resource poor settings, but with implications for nutritional inequalities globally. Within this overall aim, the specific objectives of this research are to: 1. Improve understanding of normal and abnormal fetal and infant development, utilising detailed phenotypic data from existing and ongoing birth cohort studies and focusing specifically on growth and brain development. 2. Identify mechanisms through which maternal nutrition impact on fetal and infant growth and brain development. 3. Identify mechanisms linking infant nutrition to growth and brain development, with a specific focus on maternal nutrition and breast milk quality. 4. Identify and test nutritional interventions for improvements in women's nutrition and infant health outcomes globally.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE