NIHRDataInsights/HRCSData huggingface dataset:
Title: Insulin signalling to the podocyte; pathological importance and therapeutic potential.
Funder: Medical Research Council

Abstract: The loss of albumin into the urine is called albuminuria and this, if prolonged, results in kidney failure and cardiovascular disease. A key cell in the filtration barrier of the kidney that prevents albuminuria is called the podocyte. We have recently shown that the podocyte is an insulin responsive cell type and that when insulin sensitivity of this cell is lost it results in widespread renal damage. In the pathogenesis of diabetic nephropathy, and indeed all forms of chronic kidney disease (CKD), there is associated cellular insulin resistance which starts early in the process. Diabetic nephropathy is the leading cause of kidney failure in the world. The aims of this project are to: (1) Focus on the proximal insulin signalling apparatus in the podocyte to understand the biological roles of the two major receptors through which insulin can signal, the insulin and the IGF-1 receptor, and map the signalling pathways they elicit. The importance of these receptors will be assessed in development and maturity. We will then go on to map the molecular pathways in the glomerulus which these receptors are modulating to understand the mechanisms underlying renal damage that occur when their signalling capabilities are diminished. (2) Examine if enhancing insulin sensitivity specifically in the podocyte protects against the development of renal failure associated with diabetes mellitus. If true, this has great therapeutic potential.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE;RENAL AND UROGENITAL
Title: Development of urinary microRNAs as biomarkers for diabetic kidney disease
Funder: Division for Social Care and Health Research (Wales)

Abstract: In the UK, 4.45% of the population suffer from diabetes mellitus. Approximately 40% of these individuals will go on to develop diabetesrelated chronic kidney disease, referred to in this application as diabetic kidney disease (DKD). Furthermore, the prevalence of diabetes mellitus and DKD is increasing steadily. DKD is a major cause of disability and premature death. Effective interventions for DKD exist, but targeting these to at-risk individuals, and monitoring response to treatment, is at present hampered by a lack of good biomarkers. Better tests for DKD patients are therefore a major focus for industry and academia, with efforts to date directed largely at urinary proteomic approaches. An alternative approach is the urinary quantification of microRNAs (miRs). miRs are a recently described class of molecular regulator found in all human tissues and body fluids, and are highly stable. Blood and tissue miRs are already established cancer biomarkers, and cardiovascular, metabolic and immune disease miR biomarkers are under development. We have identified renal miR signatures associated with progressive kidney dysfunction in DKD patients. In our recent studies, we have perfected a laboratory workflow for the analysis of miRs in urine. We have used these novel approaches to compare urinary miR profiles in unaffected individuals and DKD patients. By these means, we have identified six differentiallyexpressed miRs with significant potential as disease biomarkers in people with DKD. In this project, we will refine our understanding of the use of urinary miR quantification in DKD, and will optimise and streamline sample preparation and miR detection protocols. This work comprises the early stage development of a new test to guide therapy in DKD based upon urinary miR quantification.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE;RENAL AND UROGENITAL
Title: Pregnancy Interventions In Mothers Relating to Diabetes In Asian India and Low-income countries (The PRIMORDIAL Study)
Funder: Department for International Development

Abstract: Given the robust evidence that dietary modification and improved physical activity (PA) reduces T2D risk, such interventions during pregnancy should also reduce the risk of GDM similarly. Studies have shown that dietary changes and PA positively impacts gestational weight gain, maternal metabolic profile and also neonatal outcomes. However, most of the evidence arise from Western populations. The proposed study will be the first investigation to evaluate the effect of fermented yoghurt and PA initiated in early pregnancy and continued to late pregnancy on incidence of GDM in LMICs. We hope to confirm that such realistic and feasible interventions are effective in preventing GDM. We will also examine the effect of such interventions on other pregnancy-related and new born outcomes. This project will build capacity for improved antenatal services in LMICs specifically. The intervention may offer an efficient platform for future research into understanding diet and PA impact on alteration of the gut microbiota of the mother and its effects on child health. If we show that improving a mother's lifestyle during pregnancy using fermented yoghurt and PA reduces the incidence of GDM and improves metabolic health in both mother and the child, with a potential lifelong benefit, our findings will offer a scalable pathway for wide implementation.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: METABOLIC AND ENDOCRINE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Gestational diabetes in Uganda and India: Design and Evaluation of Educational Films for improving Screening and Self-management (GUIDES)
Funder: Department for International Development

Abstract: The prevalence of gestational diabetes mellitus (GDM) is rising rapidly in many low-middle income countries (LMICs). It is associated with adverse short-term and longer-term consequences for the mother and child. Most women with GDM in LMICs are undiagnosed and/or inadequately managed due to a lack of knowledge and skills about GDM on the part of both providers and patients. Therefore, we propose to develop and evaluate a package of three interconnected educational/behavioural interventions aimed at: a) improving knowledge and skills of GDM guidelines and skills of health providers; b) raising awareness of importance of GDM screening among pregnant women and their families; and c) improving confidence and skills in self-management among those diagnosed with GDM. We plan to deliver the intervention through the medium of film as they are low-cost and scalable, and can transcend barriers of literacy, making them ideal for LMICs. Evidence on effectiveness of films in changing behaviours is currently limited to high-income countries. The research will be carried out in Uganda (Entebbe) and India (Bengaluru). A careful contextual analysis will precede the development of a culturally-tailored film-based intervention for each setting, which will be iteratively refined using qualitative research methods till it is fit for purpose. Then the effectiveness of the intervention will be evaluated in independent cluster randomised trials, involving ~10,000 pregnant women across 30 maternity units at each site. Our principal research question is whether a low-cost educational/behavioural intervention delivered through a package of culturally-tailored films can provide scalable improvements in timely detection and management of GDM. The ultimate aim of the project is to contribute to scientific evidence underpinning the use of films in cost-effectively scaling up behavioural interventions in low-literacy settings.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: METABOLIC AND ENDOCRINE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Iron Regulation at the Fetomaternal Interface
Funder: Medical Research Council

Abstract: Limited iron supply in utero causes lifelong cognitive deficits that are not reversed by later iron supplementation. It is therefore critical that fetal iron stores are sufficient to support its development. Approximately 300mg of iron are deposited in the human fetus, all of which are acquired from the mother, through placental flow. This, together with the high prevalence of iron deficiency in women of reproductive age, has lead to the WHO's recommendation for universal iron supplementation. In the UK however, this was not advocated in the most recent NICE guidelines because of potential drawbacks for the mother and fetus. In addition, iron supplementation increases mortality rates in malaria-endemic regions. Therefore, to avoid unnecessary supplementaion, there is a need for it to be tailored to fetal iron demand, necessitating better mechanistic understanding of iron regulation at the fetomaternal interface. Ferroportin releases iron into the circulation from the sites of absorption (duodenum), recycling (splenic macrophages) and storage (hepatocytes). It is inhibited by the liver-derived hormone HAMP. Interestingly, FPN is also expressed in the basolateral side of the placenta. Animal studies have hinted at a role for FPN in delivery of fetal iron, its regulation by fetal HAMP, and the influence of fetal iron status on maternal iron homeostasis. However, due to the lack of appropriate tissue-specific models, it has not been possible to examine formally these hypotheses. We have generated novel conditional mouse models to enable deletion of placental FPN and HAMP and fetal liver HAMP, and expression of placental HAMP-resistant FPN. We will use these models to obtain a mechanistic understanding of iron regulation at the fetomaternal interface. Such undesrtanding will form part of the evidence necessary to help clinicians devise a targeted iron supplementation that is tailored to fetal needs and to avoid the harmful effects of unnecessary supplementaion.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Paternal obesity-associated DNA methylation: an investigation into its reproducibility, reversibility and association with fetal growth restriction
Funder: Medical Research Council

Abstract: Acquired parental obesity can be transmitted across generations via epigenetic mechanisms in animals. We propose a series of human studies to establish if validated DNA methylation profiles (DMPs) are associated with paternal obesity, insulin resistance and offspring birth weight. Study 1: In collaboration with a Norwegian mother and child cohort (MOBA), DNA from 1000 lean fathers and 1000 obese fathers will establish a validated set of obesity-associated DNA methylation marks. We will profile ~300 regions identified from a comprehensive review of published epigenome-wide association studies of obesity. Throughout, methylation will be measured using a targeted sequencing approach (Bis-PCR-seq). To identify potentially reversible, genetically-independent, DNA methylation profiles, we will investigate those SNPs previously identified as being associated with obesity and related traits. Custom multiplex PCR will be used to profile validated obesity associated SNPs. Study 2: We will prospectively recruit a cohort of pregnant women who have conceived with either an obese (n=250) or lean (n=250) partner. We will investigate whether obesity-associated DMPs are evident in blood and sperm of fathers and in cord blood of their offspring. We will determine relative parental contributions and validate our results using mother-offspring pairs from the MOBA cohort. In study 3 we will investigate whether paternal weight loss is associated with reversal of obesity-associated DMPs or small RNAs in blood and sperm of 15 morbidly obese men before and after bariatric surgery, using methods described above. In study 4 we will assess placental function, structure and metabolism of offspring of our obese fathers. Histology and quantitative PCR will characterise nutrient expression and Western blotting - metabolic signaling pathways. Analyses will establish whether small babies of obese fathers are a consequence of poor placental function, through obesity-epigenetic marks in sperm


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: METABOLIC AND ENDOCRINE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Gestational hyperglycaemia in Malaysia: early screening and intervention to improve outcomes of pregnancy
Funder: Medical Research Council

Abstract: Gestational diabetes mellitus (GDM) is one of the commonest maternal medical conditions, which if untreated, can cause maternal and fetal complications. Diagnosis is made between 24-28 weeks of pregnancy using the oral glucose tolerance test (OGTT). Thus, some harm may have already occurred prior to detection. Universal screening is backed by many guidelines but is not uniformly followed worldwide partly because of doubts about cost-effectiveness. Selective screening may be used based on presence of at least one of the high risk factors (age, BMI, etc.) but can miss up to 50% of women with GDM. In lower middle income countries, the major limitations are difficulty in conducting OGTT, which requires prompt access to laboratory facilities. An alternative to OGTT is screening with HbA1c at first antenatal clinic visit. The HbA1c is a one-step test, can be done at point of care and patients do not need to fast. However, the relationship of HbA1c levels in early pregnancy and outcomes of pregnancy (including the development of GDM) is yet to be determined in Malaysian populations. The aims of this study are to determine whether HbA1c testing at first antenatal clinic visit can predict the development of GDM and outcomes, whether a baseline HbA1c level can rule out later GDM and whether universal or selective screening is more cost-effective. Cost effectiveness analysis will also be performed to identify what levels of HbA1c should treatments be recommended in Malaysia. Finally, the study will evaluate whether metformin, a drug that is safe in pregnancy, can prevent the development of GDM. The project will recruit Malaysian women at <= 20 weeks gestation (n=5230). Recruits with HbA1c 5.4-6.4% will be randomised (online) to metformin treatment (50%), or to standard care (50%); both will have OGTT at 28 weeks (being treated if GDM develops). Detailed health economic analyses will enable policy makers to make informed decisions based on local data.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;8.2 HEALTH AND WELFARE ECONOMICS
Health categories: METABOLIC AND ENDOCRINE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Role of HbA1c and 50g GCT in early detection and prediction of gestational diabetes and associated maternal and fetal complications in Thailand
Funder: Medical Research Council

Abstract: Gestational diabetes mellitus (GDM) is one of the commonest maternal medical conditions, and if untreated, can cause maternal and fetal complications. Diagnosis is made between 24-28 weeks of pregnancy using the oral glucose tolerance test (OGTT). However, by then some harm may have occurred. Universal screening is backed by many guidelines but is not uniformly followed. Selective screening based on risk factors (age, BMI, etc.) can miss up to 50% of women with GDM. In lower middle income countries, it may be difficult to do OGTTs, which require access to laboratory facilities. In Thailand, women at high risk for GDM are supposed to be screened at the first antenatal visit with the 50g Glucose Challenge Test (GCT) but the rate of screening for GDM in Thailand varies from none at all in rural areas to 78% in urban areas. An alternative is to screen with HbA1c at first antenatal clinic visit. The HbA1c is a one-step test, can be done at point of care and patients do not need to fast. However, the relationship of HbA1c levels in early pregnancy and outcomes of pregnancy (including the development of GDM) is not known in Thai women. The study aims to determine whether HbA1c and 50g GCT testing at first antenatal clinic visit can predict the development of GDM and outcomes, whether baseline HbA1c and 50g GCT levels can rule out later GDM and whether universal or selective screening is more cost-effective. Cost effectiveness analyses will also be performed to identify what levels of HbA1c and 50g GCT should require treatment in Thailand. Finally, the study will evaluate whether diet/lifestyle interventions, can prevent GDM. The project will recruit women at <= 20 weeks gestation (n=4264). Those with HbA1c 5.7-6.4% and/or 50g GCT 140-199mg/dL will be randomised to interventions (50%), or to standard care (50%); both will have OGTT at 28 weeks (being treated if GDM develops). Economic analyses will enable policy makers to make informed decisions based on local data.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Circulating microRNAs as novel regulators of placental and fetal growth in pregnancies complicated by maternal diabetes
Funder: Medical Research Council

Abstract: Macrosomia affects 50% of pregnancies complicated by maternal diabetes. It can cause problems at birth and is associated with an increased risk of developing metabolic complications in adulthood; there are no treatments as the cause is unclear, although it is associated with enhanced placental growth. microRNAs (miRNAs) regulate placental growth. They are produced within cells but can be released into the circulation to act like hormones. We have shown that levels of a pancreas-derived miR, miR-375, are elevated in pregnant women with diabetes and that miR-375 can enter placenta and cross to the fetus. We now propose that maternal circulating miR-375 contributes to the development of macrosomia by influencing placental growth and/or impacting the future health of the offspring by directly influencing pancreatic development. In this study we will utilise a combination of ex-vivo human placental tissue and in-vivo rodent models to examine the role of miR-375 in regulating placental development and establish the impact of elevating circulating maternal miR-375 levels on the pre-natal growth and long-term health of the offspring. The incidence of pregnancy complicated by diabetes is increasing. Identification of new targets for therapeutic intervention may halt the transmission of the disease to the next generation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Establishing a new UK electronic health data tool for pregnancy research to study the management and consequences of thyroid disease in pregnancy.
Funder: Medical Research Council

Abstract: Electronic health record (EHR) datasets include a wealth of pregnancy data and their large size enables the assessment of rare outcomes and the safety and effectiveness of treatments given to pregnant women in real-world settings. However, identifying the timing and outcomes of pregnancies in EHR data presents challenges. A major advance in this area was recently achieved through a research collaboration between the London School of Hygiene and Tropical Medicine and the Clinical Practice Research Datalink (CPRD). We developed a new Pregnancy Register, identifying and characterising more than five million pregnancies recorded in anonymised primary care records. This innovative data resource offers unprecedented research opportunities. However, further work is needed to establish the robustness of the Pregnancy Register as a research tool and to identify optimal approaches for its use. This fellowship will address this need by using high quality linked EHR data to refine and validate the Pregnancy Register. I will then apply the enhanced Register, linked EHR data and state of the art methods to study a key under-researched area of maternal health: the management and consequences of thyroid disease in pregnancy. Building on an initial CPRD study, in which my clinical collaborators and I identified deficiencies in the UK management of hypothyroidism, I will address three critical areas of uncertainty: 1) prevalence of thyroid disease in pregnancy in the UK, 2) optimal management of hyperthyroidism in pregnancy, and 3) effects of thyroid disease and its treatment on pregnancy and neonatal outcomes. This work will establish the CPRD Pregnancy Register and deliver guidance to researchers on the optimal use of this new data resource in conjunction with linked EHR data to maximise its usefulness. It will also contribute substantially to the evidence base to guide improved clinical management of thyroid disease in pregnancy.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;6.1 PHARMACEUTICALS;7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: METABOLIC AND ENDOCRINE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Treatments for women with gestational diabetes mellitus: an overview of Cochrane systematic reviews
Funder: Department of Health and Social Care

Abstract: Gestational diabetes mellitus (GDM) affects a significant and increasing number of women (3-18% of UK pregnancies), and is associated with adverse perinatal and longer-term outcomes which repeat across generations. Treating GDM can reduce serious complications, leading to benefits and savings (e.g. NHS average daily unit cost of neonatal intensive care admission: £1,118; pre-eclampsia management cost: £4,300). There is great interest in tackling uncertainties surrounding the most effective treatments for GDM, with a recent ‘explosion’ of new research, as noted in the NICE ‘Diabetes in pregnancy’ guidelines. This overview will serve as the ‘friendly front end’ to the evidence, informing researchers, funding bodies, policy makers, clinicians and consumers (including NHS decision-makers and NICE guideline developers). There are eight Cochrane protocols/reviews focused on treating GDM. In a scoping search, an additional 248 Cochrane protocols/reviews were identified to assess for inclusion (evaluating interventions with other primary intents, but discussing GDM). GDM treatment reviews are currently being conducted or updated (some supported by an NIHR Programme Grant); it is imperative to conduct this overview now to summarise this ‘up-to-date’ evidence. The CRG has an excellent track record in delivering reviews within timeframes; no financial support is available for this overview.


Research activity codes: 6.1 PHARMACEUTICALS;6.7 PHYSICAL
Health categories: METABOLIC AND ENDOCRINE;REPRODUCTIVE HEALTH AND CHILDBIRTH