NIHRDataInsights/HRCSData huggingface dataset:
Title: Assessment of Potential Therapies for Pre-eclampsia and Fetal Growth Restriction using Murine Models
Funder: Medical Research Council

Abstract: Pre-eclampsia (PE) and fetal growth restriction (FGR) complicate up to 10% of pregnancies and are responsible for substantial maternal and fetal morbidity. In the UK, PE causes the deaths of 3-5 women and 600 babies per annum and FGR is associated with 1 in 4 stillbirths and 1 in 6 sudden infant deaths. The effects of PE and FGR are not limited to early life; survivors are at greater risk of cerebral palsy and neurodevelopmental delay. Furthermore, babies that are born small have increased risk of developing cardiovascular disease, chronic hypertension, diabetes and schizophrenia in adulthood. There is no curative treatment for PE/FGR and the only therapy is early delivery, which has its own risks of mortality and morbidity. PE accounts for the occupancy of 20% of all intensive care baby cots. Thus the health, social and economic burdens of PE/FGR are enormous. Despite the heavy burden of PE/FGR, there have been few therapeutic advances; only one new class of drug has been licensed for obstetric conditions in the last 20 years. Fear of fetotoxicity is one contributor to a lack of interest in drug development. Our proposal aims to develop treatments for PE/FGR by screening potential therapies in existing, and novel, mouse models of disease. Interventions that rescue utero- and fetoplacental vascular development and function in PE/FGR have immense potential for treatment of these serious pregnancy complications and are the focus of our research proposal. Through a multi-faceted programme of work incorporating a number of inter-related projects, using diverse methodologies, we will gain a thorough understanding of the vascular disease phenotypes of PE/FGR, and then rescue the vascular abnormalities using a range of potential therapeutic interventions, focusing on those which have already been approved for human studies outside of pregnancy. Treatments found to be effective in the mouse will be evaluated on the ex-vivo vasculature of women with PE/FGR thereby facilitating the identification of therapies for patient benefit. These pre-clinical studies will significantly advance our quest to identify therapies to arrest or alleviate the pathogenesis of PE/FGR. They will lead directly to Phase0/Phase1 Trials and promising novel interventions would interest pharmaceutical companies to develop further therapies and regimens.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: CSF1 and the control of postnatal growth and organ development in the rat
Funder: Medical Research Council

Abstract: In the third trimester of embryonic development, many major organs mature and develop functions that will be necessary for life outside of the womb. Most of the events that determine final body mass, as well as organ maturation, are controlled by Insulin Growth Factor-1 (IGF1). It is widely accepted that IGF1 is a circulating regulator produced by the liver in response to growth hormone (GH). We propose that through CSF1 activity macrophages contribute to the control the GH/IGF-1 system and thus contribute to the control of postnatal growth. Rats and mice that lack CSF1 signalling are macrophage deficient with many developmental abnormalities in common to animals deficient in GH/IGF-1 signalling. To confirm this view administering CSF-1 to new born mice had increased macrophage numbers and an overall increase of 30-40% in total body weight with corresponding enhanced maturity of organ function. Although this preliminary data is compelling, the challenge remains to understand the mechanistic regulation of the CSF-IGF-GH axis to underpin translation of this knowledge into application. To address these goals we aim to exploit new transgenic technologies in the rat to investigate the consequence of reducing CSF1 signalling on growth and elevating CSF1 levels as treatment of impaired growth. To do this we will exploit the lead position we have at The Roslin Institute in rat ES lines. Using this technology we propose to generate and evaluate both CSF1R-knockout and CSF1R-reporter rats to directly address these goals. This will provide a large animal model to evaluate CSF1-replacement strategies. There is a clear biological focus to this target in providing a basis for future therapeutic applications of CSF1 in humans, but it is also attractive as proof of concept for gene targeting in the rat system.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Roles and interdependence of calcineurin/NFAT and ERK pathways in pulsatile GnRH effects on gonadotrophin expression
Funder: Medical Research Council

Abstract: GnRH stimulates secretion and synthesis of gonadotropins and thereby mediates central control of reproduction. It is secreted in pulses, with pulse frequency varying under physiological conditions. Its effects are frequency-dependent as for example, LHbeta and FSHbeta expression are maximal with low-intermediate frequency pulses (0.5-1/hr) whereas alphaGSU expression is maximal at high frequency ( 2/hr). GnRH-regulated gene expression has been studied in detail but most work has involved constant stimulation. In spite of the physiological and pharmacological relevance of GnRH pulse frequency and the fact that gonadotrophs are viewed as a classic frequency decoding model, pulsatile GnRH signalling is poorly understood. This is largely because of the technical difficulty of monitoring signal dynamics with pulsatile stimulation. However, we have developed high throughput automated imaging systems (based on nuclear translocation of ERK2-GFP and NFAT2-EFP) that enable us to monitor GnRH signalling with pulsatile stimulation. These reporters were selected because a) ERK is a major mediator of GnRH effects on gonadotrophin expression with constant stimulation and is also necessary for GnRH effects with pulsatile stimuli, b) NFAT is activated by the Ca2+/CaM/calcineurin pathway and there is already evidence for involvement of this pathway in transcriptional effects of constant GnRH, and c) CaMs, ERKs and NFATs all act as frequency decoders in other systems These pathways are also interdependent in the immune and cardiovascular systems with ERK activation influencing NFAT activity just as Ca2+, CaM and calineurin influence ERK activation. Moreover, NFAT and ERK effectors characteristically converge as co-dependent regulators at the transcriptome. Accordingly, we hypothesise that these pathways act as interdependent regulators of GnRH action by virtue of cross-talk in the cytoplasm as well as by co-dependent effects at gonadotrophin promoters. We plan to test this using automated imaging to explore functional interactions between Raf/MEK/ERK and Ca2+/CaM/calcineurin/NFAT signalling, in parallel with molecular approaches for defining ERK and NFAT response elements in gonadotrophin subunit promoters, and involvement of these regions in mediating GnRH effects on transcription. Most of the work will be with LbetaT2 cells, a well characterised gonadotroph-derived cell line but we believe that sophisticated imaging strategies will also enable similar experiments with normal gonadotrophs within the mixed cell population of dispersed pituitary cell cultures. For this we plan to develop imaging readouts for gonadotrophin subunit expression (nitroreductase reporters) so that mechanisms of GnRH signalling and transcriptional regulation can be monitored with physiologically relevant stimulation paradigms and with native receptors in normal cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Novel biophysical and computational approaches towards understanding term and preterm labour.
Funder: Medical Research Council

Abstract: Preterm birth affects almost 60,000 pregnancies per year in the UK and is the most significant contributor to neonatal death and chronic disability. In order to design better treatment for premature labour, we need to develop quantitative models of the events controlling uterine smooth muscle excitability at a cellular and tissue level. Uterine contractions during labour are coordinated by spreading electrical activity and elevations of intracellular calcium in myometrial cells. However, quantitative details of the genesis and propagation of uterine action potentials are scarce. The aim of this project is to provide new experimental information and compute quantitative predictive models of the mechanisms of excitation governing human uterine contractility. The transmembrane voltage and intracellular calcium activities in myometrial tissues will be mapped macroscopically (cm), using epi-fluorescence imaging methods, and microscopically (orders of im), using confocal microscopy, each with high temporal resolution (msec). Morphological assessment of fibre orientations from the same biopsies will also be undertaken by optical clearing or diffusion tensor Magnetic Resonance Imaging. A principle aim is to use computational biology approaches to quantify normal (spontaneous) and agonist-induced coupling, synchronisation and decoupling of voltage and calcium changes in myometrial tissues of human and guinea pig (as an appropriate model of human uterine function) and examine the influence of gestation, term labour and preterm labour. The biophysical and morphological information will be utilised to construct, for the first time, a detailed mathematical model of the spatiotemporal characteristics of excitation in the uterus that underpins the contractile effort of labour; and the model will be validated with non-invasive multi-channel electromyography recording of uterine electrical potentials. The model will be used in exploring mechanistic details that initiate and underline normal and preterm labour, as well as to generate testable hypotheses as to how the excitation activities changes by different interventions. The medium-term benefits of this integrative computational biology approach will be to enable the in silico construction of quantitative predictions that can be experimental tested to enable the continued iterative advancement of the model and improved understanding of uterine physiology. The longer-term benefits will be to apply such in silico predictions/hypotheses, and subsequent experimental validations, to the assessment of new therapeutic agents for the treatment of premature labour and/or dysfunctional labour at term, as well as to improve interpretation of human uterine electrohysterography recording as a clinical prognostic tool, based upon putative modes of action on uterine electrical activities.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Maternal morbidity after caesarean section in developing countries: long term follow-up of a large factorial trial
Funder: Medical Research Council

Abstract: Caesarean section is one of the most common operations in the world, yet the techniques used to perform it have not been adequately evaluated in randomised controlled trials. Operative techniques vary between surgeons, and the frequency of the operation means than even small improvements in outcome may allow substantial improvements in the health of mothers, particularly in developing countries, where post-operative morbidity is high. The CORONIS trial will evaluate alternative techniques for the five most important aspects of the operation in a fractional factorial randomised controlled trial of 15,000 women: ?blunt? v. ?sharp? abdominal entry; extra-abdominal v. pelvic repair of the uterine incision; single v. double layer closure of the uterus; closure v. non-closure of the pelvic and parietal peritoneum; chromic catgut v. Vicryl for closure of the uterus. The short-term primary outcome of the study is serious maternal morbidity. This follow-up study will allow us to assess long-term outcomes at 3 years after the original caesarean section to determine the impact of the different techniques on outcomes including: involuntary infertility and outcomes of subsequent pregnancies including uterine rupture.


Research activity codes: 6.4 SURGERY
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Mammalian sperm-borne DNA binding proteins as reprogramming factors
Funder: Medical Research Council

Abstract: The most dramatic shift in cellular potency - from assured death to totipotency in a matter of hours - occurs in the formation of an embryo following fertilisation. This transitory phase, from gamete to embryo, includes exhaustive, replication-independent removal and rebuilding of paternal (sperm) chromatin. The mechanisms responsible for this reprogramming promise to inform the links between structural changes to chromatin and their functional readout that predispose to all increases in cellular potency. Our over-arching goal is a mechanistic understanding of genomic reprogramming following fertilisation. Current dogma assumes this reprogramming to be entirely mediated by maternal factors in the egg, but there is little supporting evidence for this view and we propose an overlooked, vital role for sperm-derived proteins. Preliminary data are presented to show that mammalian spermatozoa possess reprogramming factors that we propose to characterise primarily in the mouse. These unpublished data reveal abundant sperm-borne DNA binding proteins (sbDBPs) that enter the oocyte during fertilisation. A unique combination of molecular, cellular and embryological approaches are proposed to generate a complete profile of sbDBPs and to characterise sbDBP function. Novel DNA-bead and sperm head oocyte microinjection assays, transgene-expressing oocytes and anti-sbDBP antibodies will be employed alongside stringent controls to reveal the DNA binding characteristics, expression patterns and sub-cellular localisation in the testis, sperm and early embryo of sbDBPs. Mutagenesis and interaction strategies designed to interfere with function will complement studies on interactions between sbDBPs with each other and other proteins. These studies are expected to delineate sbDBP roles and reveal mechanisms in chromatin remodeling and exogenous (eg sperm) genome reprogramming. We have a head-start in an unexplored aspect of chromatin remodeling whose broad clinical potential makes it the subject of intense international competition. The work paves the way for novel diagnostic tools for idiopathic infertility and detailed exploration of the possibility that sbDBPs broaden cellular potency in multiple cell types via ectopic chromatin remodeling.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: The menopausal transition and healthy ageing and wellbeing
Funder: Medical Research Council

Abstract: Unlike most physiological systems in humans, which age slowly and continue to function to some extent until death, in women reproductive function is lost abruptly and completely in middle-age. The menopause is a clear marker of the end of reproduction and has important biological, health and social implications for healthy ageing. Our hypotheses are that (i) the menopausal transition (MT) will be importantly related to changes in health, social and economic characteristics; (ii) some of these changes will be temporary and some will be beneficial to long term health and well-being and others detrimental to it; (iii) health related changes will be influenced by lifestyle changes, menopausal hormonal changes and the influence of menopausal hormonal changes on DNA methylation and (iv) that lifestyle, social, economic and health related changes over the MT will influence body image, family relations, employment and income, and vice versa. Because of the complex interplay of lifestyle, molecular genetic, hormonal, health, social and economic outcomes that are likely to influence how the MT influences healthy ageing and wellbeing it is essential that a multidisciplinary and large-scale approach is used to address our hypotheses. Our proposal is unique in that it will be the largest study to date to explore changes over the MT (2800 women will be studied) and will be the only study with a wealth of previously collected (over 20 years) early adulthood data on reproductive health, general health and lifestyle before the menopause, existence of genome wide data and prospectively collected data on offspring and partners. Our research will clarify the relationship between MT changes and healthy ageing and wellbeing in women and how these relate to health and wellbeing in their partners and children.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Molecular and cellular control of oocyte maturation in mammals
Funder: Medical Research Council

Abstract: In the UK more than 10% of couples seek medical help to get pregnant. The extent of this problem points to a major problem in the ability to generate high quality oocytes capable of developing into viable embryos. This problem is exacerbated in older mothers because there is a well established exponential increase in the rate of chromosome abnormalities that starts in the mid-late 30s. The overall aim of this research is to investigate the cell biology and physiology that underpins the formation of a healthy fertile oocyte. To tackle this we will address four specific themes: 1. To investigate the role of the anaphase promoting complex (APC) in maintaining physiological meiotic arrest and its impact on long term fertility. 2. To investigate how APC regulation controls oocyte maturation and explain how aberrant APC activity impacts the first meiotic division. 3. To determine the role of cyclin A in meiosis I and whether aberrant control of cyclin A stability contributes to metaphase I arrest. 4. To understand how the oocyte deals with DNA damage and whether the G2 DNA damage checkpoint contributes to age-related increases in aneuploidy. These themes address aspects of the control of meiosis in mammalian oocytes. We will use oocytes from fertile mice, mice of advanced maternal age and in some cases conditional transgenic mice in which genes of interest have been deleted specifically from the oocyte. Human immature oocytes will be used in an effort to apply our advances to the human system as rapidly as possible. We will use microinjection, oocyte culture, confocal and conventional imaging techniques to explore how oocytes remain arrested in meiosis and how the transition through the first meiotic division is controlled. The experiments are expected to yield results that will benefit the treatment of infertility and reproductive medicine more widely.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: MRC Centre for Reproductive Health
Funder: Medical Research Council

Abstract: Reproduction is a fundamental feature of all life, essential for the continuation of our species. The remarkable integrative biology of human reproductive tissues is responsible for their outstanding resilience, characterised by long-term maintenance of stem cell populations and repeated episodes of regeneration and scarless healing. In Edinburgh there is now an exciting opportunity to understand the fundamental mechanisms responsible for the resilience and repair of reproductive tissues by bringing together, under new leadership and in a new Centre, outstanding strengths in reproductive health and tissue biology, the stem cell niche, resolution and repair of inflammation, developmental programming by steroids, epigenetics, systems and computational biology and tissue and organ imaging. The added value delivered will enable investigators and trainees in the proposed MRC/University of Edinburgh Centre for Reproductive Resilience (CRR) to address three linked questions of crucial importance in reproductive health and beyond: [1] What mechanisms deliver the optimal tissue niches for repeated regeneration of reproductive tissues? [2] How do reproductive tissues normally achieve scarless healing and what goes wrong when this fails? [3] How is reproductive resilience programmed by developmental effects of steroids? The proposed research strategy will offer unparalleled opportunities to understand fundamental processes with implications for resilience and repair in many organs. We will exploit this knowledge to develop novel treatments for the major unmet clinical challenges in reproductive health, to exploit this for impacts across medicine and to provide a rich environment for interdisciplinary research training. We specifically request funding to establish a new 4 year PhD training programme and for a postdoctoral fellowship for capacity building in this innovative area of medicine.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: The identification of novel biomarkers for the small for gestational age human fetus
Funder: Medical Research Council

Abstract: Small for gestational age infants (SGA) are at increased risk of a number of adverse outcomes. Screening for SGA has the potential to reduce the number of adverse outcomes, in particular population rates of stillbirth, which account for the death of about 4000 babies per annum in the UK. The 2008 NICE Guideline on Antenatal Care identified improving detection of SGA infants as one of 5 major research priorities. The current exemplar of pregnancy screening is Down?s syndrome, which utilises a combination of ultrasonic and biochemical markers and now detects 90% of cases for a less than 5% false positive rate. We have previously reported associations between a range of ultrasonic and biochemical measurements and the risk of delivery of a SGA infant, but none of these has the discrimination to provide clinically useful prediction. We have hypothesised that this may be achieved by combined ultrasonic and biochemical assessment of the fetus and placenta. The current project will use the Pregnancy Outcome Prediction study, a prospective cohort study of unselected nulliparous women. The study combines serial ultrasonic fetal biometry and utero-placental Doppler and maternal blood sampling at 12, 20, 28 and 36 weeks; and systematic sampling of the placenta following delivery. The study has already recruited 2800 women, has placental samples stored from 1900 women and continues to recruit approximately 100 women per month. The design of the study allows optimal phenotyping of cases of SGA (using both Doppler and growth velocity) and comparison with controls matched in relation to key maternal and obstetric characteristics. Preliminary analysis of the ultrasonic data indicated that an algorithm based on scan data alone only picked up about half of SGA infants for a 10% screen positive rate. The aims of the present study are (1) to compare expression gene array of placental samples from infants with different phenotypes of SGA at term and to compare them with matched controls, (2) to validate variation in placental levels of candidate biomarkers using qRT-PCR, Western blot and immunohistochemistry in a separate series of cases and matched controls, (3) to use a case cohort approach to compare maternal serum levels of candidate biomarkers and assess their screening performance in combination with serial ultrasound. The ultimate aim is to generate an algorithm for the identification of pathologically SGA infants that might ultimately be tested in a randomised controlled trial of screening the general population.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH