NIHRDataInsights/HRCSData huggingface dataset:
Title: Can microbiota modulate circadian oscillations to alter susceptibility to autoimmunity?
Funder: Medical Research Council

Abstract: Circadian Rhythms (CRs) reflect daily oscillations of gene activation/repression, influencing metabolic and immune responses. Recently, microbiota have been shown to modulate CRs but this has not been explored in autoimmunity. Most studies are conducted in the daytime, whereas animals are nocturnal and humans are diurnal, and thus studied in different CR phases. Thus, CR differences may be responsible for a lack of successful translation of therapies. This proposal will study the effect of CR on both the target pancreatic insulin-producing beta cells and the pathogenic islet-reactive CD8 T cells, in a mouse model of Type 1 diabetes (T1D). I hypothesise that microbiota modulate CR-induced beta cell functions, including metabolic perturbations and immunological changes in T cells, altering disease susceptibility to T1D. This will be studied in specific pathogen-free and germ-free (GF) mice by investigating: 1. Beta cell functions e.g. insulin secretion and mitochondrial respiration and the immunopeptidome at different CR times to identify changes in beta cell immunogenicity. Microbial translocation and bacteria-derived metabolites will be studied as a mechanism of microbially-induced beta cell changes. 2. Antigen-specific CD8 T cell metabolism and functions e.g. cytotoxicity, proliferation and cytokine responses at different CR times, to identify the best intervention times. Microbial mimic peptides of islet antigens will be studied in vitro and in vivo following colonisation of GF mice with molecular mimic-encoding bacteria to assess how different T cell receptor avidities alter CR responses. 3. Cell-specific CR-deficient beta cells and CD8 T cells to identify intrinsic CR-mediated effects as in 1 and 2. In summary I will identify the importance of CR-mediated effects and how microbiota can modulate them. This work is pivotal for developing future studies using modulators of CRs to improve translational success of current and new preventative treatments for T1D.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Control of pituitary stem cell activity in human and mouse through modulation of YAP/TAZ signalling
Funder: Medical Research Council

Abstract: Our recent work has demonstrated a central role for YAP/TAZ signalling in SOX2+ pituitary stem cells (PSCs), in promoting self-renewal and repressesing differentiation (Lodge et al. 2019). We have shown that levels of signalling are critical, and can lead to either homeostatic activation of SOX2+ PSCs resulting in normal differentiation of new hormone-producing cells, or paradoxically pituitary tumourigenesis. Our preliminary data support that a reduction in YAP/TAZ signalling can contribute to reduced PSC activity with age. Understanding the mechanisms by which YAP/TAZ regulate PSCs, their interaction with other pathways of known importance in this process and the validity of the findings in the human pituitary remain to be addressed. Here we will employ molecular and genetic approaches to dissect the mechanisms underlying SOX2+ PSC fate and how these are altered during ageing and in pituitary disease. Specifically, we will address the interplay between YAP/TAZ and WNT signalling, another critical pathway involved in PSC fate (Andoniadou et al. 2013, preliminary data) in their concerted regulation of PSCs. Moreover, we will extend these studies to the human pituitary to assess the degree of conservation and provide data of relevance for future development of novel regenerative approaches. Altogether, this research will reveal important insights into the function of YAP/TAZ signalling in PSC biology and regulation with potential translational implications in the field of pituitary disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: PEG-based hydrogels for iPSCs-derived regenerative therapies for diabetes
Funder: Medical Research Council

Abstract: We hypothesize that expansion of iPSC-derived pancreas progenitors using 3D cues provided by modifiable PEG-hydrogels will allow for the efficient and safe generation of insulin-producing beta cells. Using a multidisciplinary approach integrating molecular and cellular studies with advanced polymer and peptide chemistry approaches, transcriptomics, and imaging techniques we will leverage basic biology to improve beta cell generation. In Aim 1, we will design highly controlled PEG-hydrogels that allow for iPSC-derived pancreatic progenitor expansion. We will vary hydrogel stiffness (at least 3 stiffnesses, 100-1000Pa), ligand concentration (high vs low) and type (RGD, IKVAV, HAVDI), and degradability (high vs low) to identify conditions that best support pancreas progenitor cell expansion. The modular design of the hydrogel system will also allow us to combine ligands (RGD+HAVDI+degradable, e.g.) as we narrow down conditions to identify an optimum. In Aim 2, we will differentiate the iPSC-derived pancreas progenitors into beta cells. A comprehensive characterization of the generated cells will be performed to assess efficiency of differentiation. Specifically, we will test glucose challenge-induced insulin release, assess calcium dynamics, and carry out qPCR and immunofluorescence analyses of beta cell markers (glut2, pck1/3, insulin, gck). In Aim 3, we will assess the safety and in vivo functionality of the generated cells using a number of transplantation strategies in normoglycaemic or diabetes mice. We will test different routes (kidney, peritoneal) and encapsulation strategies (alginate, PEG-hydrogels) and assess transplanted cells' efficiency in insulin production. We will also carry out studies to assess the resultant immunological reaction to the transplanted cells using ELISA, immunostaining and qPCR analyses.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: METABOLIC AND ENDOCRINE
Title: Human experimental medicine studies of gut hormone LEAP2, an endogenous ghrelin antagonist and target for obesity, diabetes, cachexia and addiction
Funder: Medical Research Council

Abstract: In mice, the novel gut hormone LEAP2, an endogenous GHSR (ghrelin receptor) antagonist/inverse agonist, attenuates signaling by the biologically active stomach-derived hormone, acyl ghrelin (AG). This first study in humans, examines if LEAP2: (i) reduces appetite and food intake, (ii) lowers plasma glucose via stimulation of insulin secretion and decreasing GH secretion, and (iii) reduces brain cue reactivity and reward anticipatory responses to high-energy foods, money and alcohol, and negative emotional reactivity, while (iv) regulation of plasma LEAP2 is reciprocal to AG, possibly through direct interactions between the two hormones. This first-in-human experimental medicine study will address these hypotheses by first performing a dose finding pilot study, and a double-blind placebo-controlled cross-over study administering an acute intravenous infusion of LEAP2 (compared to placebo) to healthy, non-obese adults, and assessing the above outcome measures, through ratings of appetite and craving, ad libitum test meals, blood sampling for metabolites and hormones, and functional MRI brain scans during a food and alcohol evaluation task, an incentive delay task for money, food and alcohol, and a negative emotional reactivity task. Plasma LEAP2 and AG concentrations will also be assayed from studies involing weight loss through different dietary, surgical and endoscopic means, as well as after eating food and administration of other appetitive gut hormones including AG, desacyl ghrelin and GLP-1.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Precision medicine for diabetic Individuals: a joint Malaysia-UK Effort (PRIME) project
Funder: Medical Research Council

Abstract: The overarching ambition of the PRIME Partnership programme is to establish inter-disciplinary expertise, build partnerships and a research platform amongst physician scientists, genetic epidemiologists, big data analysts, machine learning scientists and policy makers to cohesively deliver multi-level strategies to augment precision medicine for diabetes in Malaysia. We propose to build upon the precision medicine expertise in Dundee where we have recently established the £7 million NIHR Global Health Research Unit on Global Diabetes Outcomes Research INdia-Scotland Partnership for Precision medicine in Diabetes (INSPIRED) that aims to combine clinical, retinal and molecular information to achieve personalised diabetes treatment in India. The PRIME project we are proposing will leverage the INSPIRED Global Development initiative for the benefit of the Malaysia population. PRIME will involve two large, well phenotyped cohorts individuals with diabetes - the Tayside Bio-resource including GoDARTS (Genetics of Diabetes Audit Research Tayside Scotland) which will have access to 30,000 individuals with genome-wide genotype data with linkage to comprehensive electronic health records and the PRIME cohort within large population based The Malaysian Cohort study that will comprise of 5000 individuals with diabetes in Malaysia. The PRIME project will establish the PRIME cohort that will have their DNA genotyped and their detailed demographic and biophysical data digitised to provide a level of high-quality phenotyping and updated detailed follow-up. The plan is to embed insights from the ongoing INSPIRED programme into the PRIME project to identify at-risk individuals by their phenotypic, genetic and retinal imaging profiles. This will inform tailored population-specific interventions to reduce the impact of diabetes in Malaysia.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: METABOLIC AND ENDOCRINE
Title: The Malaysian GestatiOnal Diabetes and prevention of DiabtES Study (MY GODDESS)
Funder: Medical Research Council

Abstract: Nearly 20% of women in Malaysia develop gestational diabetes mellitus (GDM). Recent international findings report that around half of women with GDM are likely to develop (T2D) or prediabetes within 10 years. Despite many randomised controlled trials (RCT) of diabetes prevention interventions (DPI) in GDM the effectiveness of DPIs remains unclear. There is no evidence base for the most effective DPI for GDM in Malaysia. We propose to use the MRC complex interventions framework to address this major deficit in evidence. The overall aim is to develop and test the feasibility of a novel interactive culturally appropriate digitalised DPI specific for GDM. In workstream 1 (development phase) we will conduct a literature review of the process evaluations of RCTs of digitalised DPIs in GDM to identify implementation, mechanisms of action and contextual factors important in optimising effectiveness (study 1a). In parallel we will conduct a focus group with women with GDM and health care professionals to understand the barriers and facilitators of uptake of DPI, and solutions to optimise the DPI (study 1b). We will integrate these findings to develop a logic model of our digitalised DPI and use participatory learning and action methods to finalise the intervention including the contents of the DPI app (studies 1c & 1d). The key components of the DPI proposed are: initial face-to-face group session; online educational diabetes prevention curriculum appropriate for Malaysian culture; biofeedback of physical activity, diet and emotions levels; motivational SMS messages; chat function for women to communicate with each other; facilitation by a dietician trained in behaviour change techniques and supportive counselling; a manual. In workstream 2, we will conduct an RCT comparing the DPI with usual care for 12 months for 50 women with current GDM to assess the feasibility of conducting a future full scale definitive effectiveness RCT (study 2).


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: METABOLIC AND ENDOCRINE
Title: Using big data to improve population health and resource allocation for people with diabetes in Malaysia
Funder: Medical Research Council

Abstract: The project aims to promote the economic development, health and welfare of Malaysia. In a close collaboration between researchers from Malaysia and the UK, this involves developing economic/epidemiological programmes aimed at improving policies to treat and prevent diabetes in Malaysia. The project will take advantage of large clinical datasets, which are currently held by the University of Oxford (and include long-term follow-up of people from Malaysia with diabetes). We will also analyse data collected by the Malaysian National Diabetes Register and the JADE study to understand patient characteristics, treatment patterns and access to care, as well as how these influence outcomes for people with diabetes, with a special focus on more deprived groups. A key component of the project is to use big data to develop a diabetes simulation model for making short-, mid- and long-term projections of health outcomes and associated costs for people in Malaysia with type 2 diabetes. This model will then be used to evaluate the cost-effectiveness of various interventions including different health service models, diabetes medications and lifestyle modifications. Using large nationally representative household survey data, we will also compare the size of out-of-pocket (OOP) medical payments that diabetic people make compared to those without diabetes, and their vulnerability to 'catastrophic' or impoverishing payments. These analyses will provide evidence to allocate resources for the prevention and treatment of diabetes efficiently and equitably, and inform national health policy and planning. As part of the project, we intend to build research capacity in Malaysia through running workshops and providing training on the use of simulation models. Finally, we will develop strong policy links with the Ministries of Education and Health to provide evidence to inform decisions on more efficient and equitable resource allocations in Malaysia.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: METABOLIC AND ENDOCRINE
Title: The Bangladesh D:CLARE Project (Diabetes: Community-Led Awareness, Response and Evaluation)
Funder: Medical Research Council

Abstract: Our DMagic trial of monthly group meetings led by lay facilitators who guided participants through a Participatory, Learning and Action (PLA) cycle focused on diabetes prevention and control in rural Bangladesh. Through a four-phase cycle, community members: 1) identified local behavioural, social and environmental threats to their health and prioritised areas for action; 2) planned strategies to address these threats; 3) implemented their chosen strategies, which typically included greater awareness-raising, local exercise groups, or lobbying markets for better access to healthy foods; and 4) evaluated the success of these strategies. Facilitators were locally recruited men and women who received one week's training in group facilitation and in the basics of diabetes prevention and control. Using robust measurements we compared population prevalence of intermediate hyperglycaemia and diabetes between intervention and control villages. After 18 months of intervention, the prevalence of diabetes and intermediate hyperglycaemia was 65% lower in intervention villages compared to control villages. Further, among individuals identified with intermediate hyperglycaemia before the intervention, the cumulative two-year incidence of diabetes was more than 60% lower in intervention villages. The robust evidence of impact of our low-cost, social intervention demands replication and scale-up in Bangladesh. This research will roll out the intervention across six Unions in Faridpur district, as well as all the control villages from our aforementioned trial. In total, the scaled-up intervention will cover a population of approximately 215,000 people. We will characterise PLA implementation and impact of the intervention at scale using qualitative, economic and quantitative methods, engage with national stakeholders to identify optimal intervention delivery mechanisms, and develop strategies to strengthen scale-up systems across Bangladesh and the region.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: METABOLIC AND ENDOCRINE
Title: Effects of the Artificial Pancreas on Glucose Control, Cardiac Arrhythmia Risk and Sleep in Older People with Type 1 Diabetes
Funder: Medical Research Council

Abstract: Background: The prevalence of hypoglycaemia unawareness and severe hypoglycaemia is higher in older compared to younger people with type 1 diabetes (T1D). Hypoglycaemia has been hypothesised to increase the risk of cardiac arrhythmia through exaggerated sympathoadrenal responses and abnormal cardiac repolarisation. Poor glycaemic control has been hypothesised to be an important and modifiable cause of sleep disturbance in T1D. This proposal integrates artificial pancreas (AP), cardiac and sleep monitoring technologies to evaluate glucose control, cardiac arrhythmia risk and sleep traits in older T1D patients. Objectives: To determine the impact of AP on 1) overall glycaemic control; 2) cardiac arrhythmia risk and relationship between hypoglycaemia, cardiac rate and rhythm; 3) sleep patterns and relationships between hypoglycaemia with measured sleep parameters. Methods: Randomised, cross-over design trial comparing AP vs. conventional sensor-augmented pump therapy in older T1D patients (>60 years old). Outcomes assessment: 1) Glycaemic control analysis will be between-group comparison of time spent within target sensor glucose range (3.9-10 mmol/l). 2) Holter data from both groups will be analysed for arrhythmic events, heart rate variability and sympathetic/parasympathetic balance. Within-individual values in periods before and after intervention will be compared. 3) Actiwatch data will be analysed for sleep duration and quality, and automatically scored using validated software. AP impacts on sleep traits will be assessed by comparing within-individual data in periods before and after intervention. Potential impact: My study is expected to establish: a) efficacy & safety of AP in older T1D patients; b)whether AP reduces cardiac arrhythmia risk; c) whether AP improves sleep traits. It is also expected to: i) define links between glycaemia, cardiac arrhythmia and sleep traits and ii) improve current treatment paradigm for older people with T1D.


Research activity codes: 6.3 MEDICAL DEVICES
Health categories: METABOLIC AND ENDOCRINE
Title: Deciphering mechanisms of disease associated with Sphingosine-1-phosphate lyase deficiency
Funder: Medical Research Council

Abstract: Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS), secondary to biallelic loss of function mutations in SGPL1, is associated with endocrinopathy (primary adrenal insufficiency, hypothyroidism, gonadal failure), steroid resistant nephrotic syndrome, ichthyosis, and neurodevelopmental deficit. SGPL1 is a key enzyme within the sphingolipid pathway and we aim to test the hypothesis that the disease manifests by perturbation of sphingolipid homeostasis, using patient studies and a CRISPR engineered SGPL1-knockout adrenal cell line. We will gather prospective clinical information using Research Electronic Data Capture on patients identified through genetic screening of cohorts with primary adrenal insufficiency and congenital nephrotic syndrome. For the first time we will interrogate the effect of harbouring rare variants/ copy number variants in SGPL1 in a cohort with developmental delay, with comparative analysis of phenotype and available MRI Brain. It is critical that we understand the sphingolipid signature of SGPL1 deficiency by plasma sphingolipid and sphingolipid pathway product profiling by LCMS. As a research tool, we will establish a fluorogenic lyase activity assay for use in patient white cells. In vitro, we will interrogate the sphingolipid and pathway product profile in a compartment specific manner following cellular fractionation. We will test whether steroidogenesis can be restored by chemically inhibiting de novo sphingolipid production and/or replacing the pathway product phosphatidylethanolamine, which has an established role in normal autophagy. Accordingly, we will assay expression of regulators of lysosomal biogenesis, the function of representative lysosomal enzymes and expression of autophagy markers. Finally, beyond the study of adrenal disease, we will establish a consortium of experts to develop future studies of the disease mechanisms in this multi-systemic disorder and identify therapeutic targets.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Diagnosis of Childhood Growth Hormone Deficiency and Prediction of Therapeutic Response Using Gene Expression Data
Funder: Medical Research Council

Abstract: Over 2,000 children are assessed for growth hormone deficiency (GHD) using pharmacological stimulation tests in the UK each year. These tests involve the child fasting, having multiple blood samples taken via an intravenous cannula and require administration of medications which cause side effects e.g. nausea and vomiting. Of the 2000 children evaluated around 500 of the children will be diagnosed with GHD and started on treatment. Unfortunately around 25% will show a poor response to GH treatment. Currently response can only be assessed after around 1 year of therapy which requires daily subcutaneous injections at an average cost of £7500 per year. We have shown in a preliminary study that it is possible to predict both the diagnosis of GHD and response to GH therapy using peripheral blood gene expression data measured using Affymetrix arrays. In 98 GHD children and 20 controls using rank regression we identified 347 genes whose expression correlated with peak GH concentrations on the stimulation test. A Random Forest Algorithm using these genes gave an AUC of 0.98 for predicting GHD status (GHD versus controls). Using the same gene expression data, this time correlating gene expression with height velocity over the first year of therapy we were able to predict a poor response (defined as lower quartile) with an AUC of 0.89. This study aims to recruit 120 patients (60 with GHD and 60 non-GHD short stature patients). Peripheral blood gene expression samples will be taken at the same time as the GH stimulation test will be assessed with RNASeq. The random forest algorithms for predicting GHD status and response to therapy will be developed using the technique above in a test set of 80 patients and validation set of 40 patients. The algoirhtms will be developed separate code and made available to diagnostic services. The net result of this study is to produce a test based on a single blood sample to both diagnose GHD and predict response to treatment.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE