NIHRDataInsights/HRCSData huggingface dataset:
Title: Maternal Obesity During Pregnancy: Translatable Programmed Cardiovascular Dysfunction in Offspring
Funder: Medical Research Council

Abstract: Obesity has reached epidemic proportions, including in women of reproductive age. Over half of women in the UK are now obese or overweight during pregnancy. This is of significant concern as obesity during pregnancy not only has detrimental effects on the mother, but also on the children. Evidence derived from human studies and from animal models shows that maternal obesity can markedly increase the risk of heart disease in the offspring, even when young and when the progeny are fed a healthy diet and they themselves do not become obese. This highlights that it is something about exposure of the embryo or fetus to an obesity environment during gestation itself that either triggers a fetal origin of cardiovascular dysfunction and/or increases the risk of heart disease in the adult offspring. Therefore, this project will test the hypothesis that maternal obesity during pregnancy promotes a fetal origin of heart disease via adverse mechanisms triggered by mitochondria-derived oxidative stress. Causality will be addressed directly using mitochondria-targeted antioxidant intervention with MitoQ. The hypothesis will be tested using an established ovine model of maternal obesity during pregnancy. In contrast to rats and mice, which are born highly immature, the timing of cardiovascular developmental milestones in sheep and humans is much more similar. Therefore, using sheep markedly improves the human clinical translation of the biomedical research. The work will adopt an integrative approach, combining experiments of in vivo cardiovascular function with those at the isolated organ, cellular and molecular levels in the pregnant mother, as well as in the fetal and adult offspring.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Elucidating and modelling complex postnatal steroid hormone changes in preterm infants: insights into the developing immature neonatal adrenal cortex
Funder: Medical Research Council

Abstract: Over the past 20 years the rates of preterm birth have risen with increased survival of infants to term. Premature neonates frequently undergo endocrine testing as part of investigation of hypotension, hypoglycaemia, abnormal neuroimaging or genital appearance. Random serum cortisol concentrations, whilst often measured, are difficult to interpret with limited normative data for preterm neonates. Without such data, infants may receive inappropriate long-term steroid therapy, with associated morbidity and socioeconomic burden. This is therefore a priority area for research in the fields of neonatology and endocrinology. The human fetal adrenal is unique and undergoes significant postnatal remodelling and evolution of function. It remains unclear whether the timing of these events is related to birth or gestational age and understanding normal neonatal adrenal development and physiology, and its role in postnatal adaptation to extra-uterine life, are key objectives of this research. It is also critical that a comprehensive method of analysis is established for interpreting steroid hormone concentrations in this population. To date, studies have been limited by small sample size, single time point measurements, and cross-reactivity in immunoassays. This study aims to provide the first characterisation, utilising sophisticated mathematical modelling (using variants of the super-imposition by translation and rotation (SITAR) method) to produce age-specific growth curves, of serum cortisol measured by immunoassay and urinary steroid profiles measured by mass spectrometry in preterm neonates. This will allow for correct and timely interpretation of steroid hormone results for preterm neonates. A secondary objective of this study is the development of a bio-resource of neonatal samples. Any unused material deposited from this research would be made available to other projects with suitable research aims. The resource would also have the potential for retrospective analysis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Investigating hypothalamic kisspeptin neuronal dysfunction as a key mediator of the pathophysiology of PCOS and HA
Funder: Medical Research Council

Abstract: Background: Alteration in gonadotropin releasing hormone (GnRH) pulsatility is recognised as a key abnormality that underpins polycystic ovary syndrome (PCOS; characterised by increased GnRH pulsatility), and hypothalamic amenorrhea (HA; characterised by reduced GnRH pulsatility). Kisspeptin (KP) neurons in the arcuate (ARC) nucleus of the hypothalamus (infundibular nucleus in humans) are thought to be the 'GnRH pulse generator'. Data assessing whether manipulation of ARC kisspeptin neuronal activity can either, induce a PCOS-like phenotype or reverse the pathological features found in PCOS and HA animal models, is needed to provide direct evidence of the importance of these neurons in the pathophysiology of these common reproductive disorders. Aims: I will use 'designer receptor exclusively activated by designer drugs' (DREADDs) technology to regulate the activity of ARC kisspeptin-neurons and determine whether manipulation of these neurons mediates the features of PCOS and HA. - Firstly, using an in-house mouse model of HA, I will determine whether restoring ARC KP neuronal activation can rescue estrus cyclicity. - I will subsequently study whether reducing ARC KP neuronal activation in an established PCOS-like model (prenatal androgenised) can restore physiological estrus cyclicity. - I will also determine whether increasing ARC KP neuronal activation in healthy adult female mice induces a PCOS-like phenotype. - Finally, I will evaluate the use of KP as a diagnostic test to differentiate HA and PCOS in women presenting with oligo/amenorrhoea. Summary: This proposal will aim to provide direct evidence for changes in ARC kisspeptin neuronal activity mediating a PCOS-like or HA-like phenotype. I will also evaluate whether assessment of hypothalamic dysfunction using a KP test can objectively classify the two commonest causes of menstrual disturbance and thus would have potential as an objective diagnostic test for oligo/amenorrhoea.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Is Fat in the Liver a marker of post-Pregnancy Glycaemic Deterioration in women with Gestational Diabetes (FLiP GD2)?
Funder: Diabetes UK

Abstract: Is Fat in the Liver a marker of post-Pregnancy Glycaemic Deterioration in women with Gestational Diabetes (FLiP GD2)?


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Does following a vegetarian diet during pregnancy causally affect the health of offspring?
Funder: Wellcome Trust

Abstract: Vegetarian diets are defined as diets without the intake of meat, fish, or seafood. Vegetarianism is socially and culturally patterned, and nutrient intakes also differ between vegetarians and non-vegetarians. While previous studies have found that vegetarian diets are associated with a range of health outcomes in the general population, evidence on the relationship between maternal vegetarian diets during pregnancy and offspring health remains scarce. Using the data from several European birth cohorts, we will first profile and compare the nutrient intakes and nutritional profile between vegetarian and non-vegetarian pregnant women and then apply a series of causal inference methods (e.g. observational association analysis, Mendelian randomisation, paternal negative control, within-sibling comparisons, and cross-context comparisons) and multi-omic approaches (e.g. epigenomic and metabolomic analyses) to find out whether following a vegetarian diet during pregnancy causally affects the health of offspring and whether any of these effects are mediated by early-life epigenetic and metabolic alterations. Given the increasing popularity of vegetarianism and the importance of optimal nutrition during pregnancy for maternal and child health, our findings will help comprehensively evaluate the pros and cons of the increasingly popular vegetarianism and have implications for dietary counselling and guidelines for pregnant women.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Determining the role of placental endocrine function in the development of gestational diabetes mellitus and its maternal metabolic long-term health consequences
Funder: Wellcome Trust

Abstract: Gestational diabetes mellitus (GDM) is a serious and common pregnancy complication that can evolve in type-2 diabetes (T2DM) years after delivery. Placental hormones have wide-ranging effects on maternal physiology, including the regulation of glucose metabolism. However, we lack information on whether placental hormones could drive changes in maternal metabolism that leads to GDM and the subsequent progression to T2DM. This fellowship aims assess this by using a newly-developed genetic mouse model of placental endocrine malfunction. This is achieved by selectively disrupting the expression of the imprinted Igf2-H19 locus in the placental endocrine cells. Using this approach, I obtained data showing that mice with placental endocrine malfunction have metabolic disturbances, including high blood glucose concentrations during pregnancy. Also, these females show changes in their metabolism in the months after delivery. This project will further these findings in the model by using state-of-the-art in vivo metabolic tests and use transcriptomics, proteomics and methylome analyses to identify how placental hormones induce changes in maternal tissues that cause metabolic problems during and after pregnancy. My long-term aim is to identify biomarkers that could be explored as diagnostic tools or therapeutic targets to prevent the development of GDM and T2DM.

Lay abstract: In the UK, one in six women cannot control their blood sugar levels during pregnancy. This can lead to gestational diabetes (GDM) and predisposes mothers to type-2 diabetes (T2DM) years after delivery. Despite this, we lack information on what drives changes in maternal metabolism in pregnancy and how disruption to this process may lead to disease in later life. There is evidence that placental hormones can affect the metabolism of the mother. This project aims to examine, in a mouse model that has increased placental hormone production, if hormones from the placenta drive changes that lead to GDM and T2DM in the mother. It will use molecular methods to identify which hormones are involved and examine how they leave cellular memories in the mother that impacts her later risk of disease. This work will increase knowledge on the cause of GDM/T2DM and identify ways to prevent and treat metabolic diseases.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Prevention of progression to type 2 diabetes in women with gestational diabetes (OMAHA): A feasibility study for a randomised trial on metformin and Mediterranean diet
Funder: Barts Charity

Abstract: Four in 10 mothers with gestational diabetes (GDM), a condition with raised blood sugars detected for the first time in pregnancy, could develop type 2 diabetes in the five years after delivery. However, despite efforts, mothers engage poorly with health services for annual tests to detect type 2 diabetes, which may go undiagnosed. In addition to the increased risks in subsequent pregnancies, they may present in later life with diabetes related complications such as stroke, heart attacks, kidney failure and raised blood pressure. Intake of the drug metformin, and following a Mediterranean diet, are two promising methods to prevent the type 2 diabetes. Their benefits need to be confirmed through a large trial. Prior to investing in a large trial (£2 million), we plan to study the feasibility of delivering these interventions in the NHS setting, and their acceptability to mothers and healthcare professionals.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: METABOLIC AND ENDOCRINE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Disorders of human pubertal timing
Funder: Wellcome Trust

Abstract: My proposal is focused on understanding the genetic basis, and consequently the pathophysiology, underpinning disordered human puberty. Pubertal disorders are common, but associated with severe comorbidities. Delayed puberty presents a diagnostic challenge in adolescence, as conditions of gonadotropin deficiency and isolated delayed puberty display the same clinical and biochemical phenotype. However, correct management is vital because the former is associated with infertility and requires intensive reproductive therapy, whereas the latter is self-limiting but associated with a shortened reproductive lifespan. The biological mechanisms of precocious puberty, a condition associated with increased long-term cardiovascular and cancer risk and thus with significant impact on public health, remain similarly opaque. The identification of causal genetic defects in disordered puberty allows interrogation of the key regulators of human puberty. I will use whole genome sequencing, comparative transcriptomics and methylomics studies in my large human cohort with disordered puberty, to define shared exonic and regulatory mutations resulting in delayed and precocious puberty. I aim to characterise the biological mechanisms underlying pubertal disorders through functional characterisation of novel genomic defects using cellular assays and animal models. These findings will ultimately translate to improved diagnostics, tailored therapeutic management and improved long-term outcomes for patients with disorders of puberty.

Lay abstract: Puberty is the essential period of physical and psychological change from a child to an adult. Disturbances of pubertal timing are common, and are associated with increased risk of obesity, type 2 diabetes and in severe cases infertility. Moreover, both early and delayed puberty are associated with early menopause. While we know that these conditions often run in families, we still understand very little about how they occur and which gene changes are responsible. Currently, it can be difficult to distinguish which patients with early or late puberty need intensive treatment and follow up. I will use up-to-date genetic, cell and animal experiments to identify gene defects in our patient families with early and late puberty, and to understand how these inherited changes influence the timing and progress of puberty. This knowledge will enable us to improve diagnosis, allow tailored treatment and direct careful long-term follow up for our patients.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Prevention of foot ulcer recurrence in diabetes patients using novel biofeedback technology.
Funder: Diabetes UK

Abstract: Diabetic foot ulcers and their associated increased risk of lower-limb amputation present a significant problem for people with diabetes. The risk for recurrence of previously healed diabetic foot ulcers is extremely high and necessitates development of an effective intervention. High plantar pressures developed during walking are largely responsible for these high recurrence rates, but cannot be self-regulated by patients due to their loss of plantar sensitivity. We propose to use a novel biofeedback system aimed at preventing diabetic foot ulcer recurrence and subsequently improving quality of life. People with diabetes and a recently healed plantar ulcer will be randomly allocated to either biofeedback or control groups. The biofeedback group will use a novel system that measures and displays plantar pressures in real-time on a mobile phone. Patients will be trained to use this biofeedback system during their daily life to modify their plantar pressures to prevent the recurrence of foot ulcers. Patients in the control group will not receive any biofeedback but will wear insole sensors so that pressures can be measured during their daily activities. We will follow both groups over a period of 18 months and monitor the development of foot ulcers, quality of life and foot-self care.


Research activity codes: 6.3 MEDICAL DEVICES
Health categories: METABOLIC AND ENDOCRINE;SKIN
Title: Inhibition of macrophage protein tyrosine phosphatase 1B (PTP1B) as a novel therapy for improved wound healing in diabetes
Funder: Diabetes UK

Abstract: Diabetic foot ulceration is a serious complication of diabetes, resulting from peripheral neuropathy, macrovascular and microvascular disease, impaired angiogenesis and chronic inflammation. Both tissue resident and recruited macrophages make a substantial contribution to wound healing following injury and infection. In addition, it is known that protein tyrosine phosphatase (PTP)1B expression and activity are increased in diabetes, and diabetic foot ulcers. In this proposal, we aim to evaluate the mechanisms underlying the role of macrophage PTP1B in wound healing, by assessing the regulation of inflammation during the earlier phases of wound healing. The primary hypothesis of this project is that macrophages play an essential role in wound healing, and that inhibiting macrophage protein tyrosine phosphatase1B (PTP1B) will enhance wound repair. Knowledge derived from this project will shed light on pathophysiology of diabetic wound healing and potentially lead to the development of novel treatments for diabetic foot ulcers, a major clinical problem in diabetics. Considering that that PTP1B inhibitors are in phase 2 clinical trials for diabetes treatment, these could easily be repurposed for diabetic foot ulcer wound healing.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE;SKIN
Title: A systematic review and individual patient data meta-analysis of prognostic factors for foot ulceration in people with diabetes: the international research collaboration for the prediction of diabetic foot ulcerations (PODUS)
Funder: Chief Scientist Office (Scotland)

Abstract: Design: A systematic review and meta analysis using individual patient data(IPD)Search strategy: A detailed electronic search strategy has been developed forMEDLINE and EMBASE AND CINAHL. Fourteen cohort studies of predictivefactors for foot ulceration in diabetes have been identified using a search ofMEDLINE (1966- February 2005) EMBASE (1980-February 2005) and CINAHL(1982- February 2005) databases and from contact with authors.Review strategy: 2 reviewers working independently will apply the revieweligibility criteria and assess quality of the included studies.Statistical analysis: Acquiring IPD from multiple cohort studies will allow us toconstruct a prognostic model using data from patients worldwide.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE;SKIN
Title: Over three years for defining surgical indications for children with flexible flat feet.
Funder: Action Medical Research

Abstract: Background Most children under the age of two have 'flat feet' and the arch develops as they get older. Estimates suggest that nearly one in five children has flat feet and it is the most frequent condition seen in Paediatric Orthopaedic clinics. There are various definitions, but essentially it means the height of the arches of their feet is lost when standing. A flexible flat foot is where the arch height is recreated when the child stands on tiptoes. Most children with flat feet are fine, but others go on to experience ongoing pain and disability, such as pain around the foot and ankle when walking long distances or even when walking short distances. Children with more severe problems can find it difficult to take part in sports or some games and may feel left out and isolated. Long term problems include nerve entrapment, secondary arthritis in adulthood and there are possible links with knee, hip and back problems These children may benefit from surgical treatment to re-create the arch but there are risks to surgery such as infection, damage to nerves and blood vessels, recurrent deformity and stiffness. At the moment there are no useful measures to help the surgeons know which children will benefit from the surgery. The research project The aim of this proposed research is to compare children with flat feet with those who do not have flat feet and see how their structure and function is related to any perceived disability. This will further define what causes and constitutes a flat foot and also what factors result in increased disability. This research should highlight key objective criteria that can identify potentially problematic feet. In turn these criteria will form the basis of tool that can be used by surgeons to help decide which children do not need surgery and which children need an operation on their foot to recreate an arch.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Over three years for improving the diagnosis and preventing the development of Perthes' disease.
Funder: Action Medical Research

Abstract: Background Perthes' disease is a very poorly understood destructive disease of the hip joint that affects children, especially boys, between the ages of three and 14 years. The condition appears to be caused by a restriction in the blood supply to the upper end of the thigh bone (the femoral head) which forms the ball part of the ball-and-socket hip joint. The reduced blood supply prevents proper bone development and causes the existing bone to collapse, leading to a misshapen femoral head. As the child grows, blood supply is usually restored and the bone may then return to a spherical shape, but often it remains permanently deformed, resulting in disability and possibly premature arthritis. The condition affects up to 16 children in every 100,000 with current surgical and non-surgical treatment methods being very unreliable. The research project Until recently, the reason for damage to the blood supply to the femoral head was unknown. However, using computer modelling, the researchers have identified a mechanism where abnormal forces within the hip joint cause the head of the femur to deform and block the key blood vessels. These forces arise as a result of an apparent abnormal geometry of the hip joint seen in some children. This study will use computer modelling alongside X-rays and clinical assessment to further investigate the biomechanical forces within the hip joint which trigger Perthes' disease. This information will then be used to develop guidelines for the early identification of those children most at risk. The researchers will also investigate exercise-based methods to prevent the disease from becoming established in at risk children (for example, activities such as horse riding and swimming which are attractive to most children), whilst waiting for the biomechanical conditions at the hip to improve so that normal development can be resumed.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL