NIHRDataInsights/HRCSData huggingface dataset:
Title: How do KIR on uterine Natural Killer cells (uNK) regulate human pregnancy success?
Funder: Medical Research Council

Abstract: Our aim is to understand how the complex system of interactions between variable maternal KIR receptors on uterine NK cells (uNK) and fetal HLA-C ligands regulates trophoblast behaviour during placental development. Our genetic studies show that binding of the inhibitory receptor KIR2DL1 on uNK to the cognate HLA-C group 2 ligands (C2) on trophoblast increases risk of abnormal placentation, whereas binding of activating KIR2DS1 to C2 is protective. Both KIR and HLA-C are polymorphic and we will use mass cytometry (CyTOF) to determine how this variation affects the phenotype and responsiveness of primary uNK cells from the decidua compared with matched NK cells from peripheral blood (pbNK). This will be one of the first studies using high resolution CyTOF to directly compare matched uNK and pbNK responses from the same donor. Using in vitro assays that mimic different maternal KIR/fetal HLA-C combinations, CyTOF will enable us to study how functional responses of uNK depend upon KIR genotype and maternal or fetal HLA-C status across the full range of uNK subsets. We will employ degranluation assays (CD107), cytokine production and microarrays, to analyse how KIR2DL1+ or KIR2DS1+ uNK subsets respond to targets expressing C1 or C2 and to primary trophoblast cells expressing these epitopes. This will allow us to define novel responses mediated by these KIR in uNK and determine how responses differ between KIR2DL1 alleles that confer different risks to pregnancy. Finally we will examine how these KIR responses regulate trophoblast invasion and differentiation. These studies will lead to an understanding of how the functions of tissue NK cells are regulated compared to pbNK and how uNK regulate trophoblast behaviour during placentation in normal and abnormal pregnancies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Mechanical sensing in placental vascular endothelium
Funder: Medical Research Council

Abstract: Background Piezo1 is a mechanosensitive ion channel, which may have a critical role in shear stress sensing within endothelial cells. Isolated and cultured human placental endothelial cells (PlECs) and human umbilical vein endothelial cells (HUVECs) are positive for CD31, alignment to shear stress and respond reliably to vascular endothelial growth factor (VEGF) and the Piezo1 activator, Yoda1. Piezo1 mRNA has been detected in these cells. When PlECs and HUVECs undergo depletion of Piezo1, responses to shear stress, Yoda1 and, strikingly, VEGF are suppressed, suggesting an important regulatory role for Piezo1 in endothelial function within the placenta. Aims The aim of this project is to establish the importance of mechanical sensing and Piezo1 function in normal placental vascular function, and in preeclampsia and intrauterine growth restriction, and to determine the effect of Piezo1 modulation. Objectives and methodology The response of PlECs and HUVECs to shear stress will be measured in Ibidi chambers and the relative quantity of Piezo1 DNA and protein expression determined. Tube formation in co-culture, cell migration and apoptosis will be assessed the IncuCyte and complementary capabilities. Pressure and wire myography will be used to observe endothelium-dependent properties of fresh placental vessels with and without luminal flow and stretch. In partnership with Dundee Cell Products, phosphoproteomics will indicate protein differences in PLECs from normal versus IUGR-affected placentas. Piezo1 activity will be assessed by depletion (short interfering RNA), inhibition (GsMTx4 toxin), and Yoda1 activation. The InterPregGen database will be used to explore variations in Piezo1 expression between patients with and without preeclampsia. Opportunities This novel project will increase understanding of shear stress sensing within normal placentas and in vascular dysfunction. This could potentially lead to the development of new treatment targets.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: MICA: CB2 agonists as a novel treatment for women with endometriosis-associated pain
Funder: Medical Research Council

Abstract: Endometriosis is a chronic, incurable, inflammatory disorder affecting ~10% of women of reproductive age half of whom suffer from debilitating pelvic pain. Current treatments include invasive surgeries and hormonal suppression with the latter having undesirable side effects. Peripheral neuro-inflammation plays a pivotal role in activation of both central and peripheral pain pathways in endometriosis. We have shown that nociceptive ion channels are overexpressed in the peritoneum and endometriosis lesions of women with pelvic pain and inflammatory cells are abundant in their lesions. The endocannabinoid system is known to modulate inflammatory/immune mechanisms and pain processing. Endocannabinoids act via CB1 or CB2 receptors; CB1 is responsible for the psychotomimetic side effects of cannabinoids. CB2 has emerged as a key therapeutic target for a range of painful conditions but has not been rigorously tested as a treatment for endometriosis. We believe treatment with the CB2 receptor agonist LY2828360 offers a novel approach to treatment of women with endometriosis-associated pain. We will evaluate the impact of LY2828360 using a mouse model of endometriosis that replicates key features of the disease in women. A unique feature of our model is the introduction of 'menstrual' tissue into the peritoneum of immune competent mice. This menstrual tissue is cytokine-rich, with high concentrations of matrix remodeling proteins, mast cells and macrophages mimicking the endometrial tissue that is released into the peritoneal cavity leading to the establishment of endometriosis lesions that attract nerves and blood vessels. The lesions formed in recipient (ENDO) mice phenocopy those recovered from patients attending our pain clinic. Following establishment of lesions the ENDO mice exhibit altered pain behaviours (both spontaneous and induced) that can be quantified. The data from this study will be used to support a future clinical trial in women with endometriosis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: eLIXIR, Early Lifecourse data Cross-LInkage in Research; a Multidisciplinary Partnership
Funder: Medical Research Council

Abstract: This multidisciplinary academic Partnership (eLIXIR, early-LIfe data cross-LInkage in Research) intends to establish a unique life course approach to mental and physical health disorders by combining maternal, infant and child research in a single continuum. The study will be carried out in a deprived population of London (>600,000 people) served by three UK NHS hospitals (two Acute, and one Mental Health Care). Using methodology developed by partners at the KCL Institute of Psychiatry, Psychology and Neuroscience (IoPPN), a core research platform will be developed to link hospital records from pregnant women, infants and children with data from mental health records, primary care and national databases. Linkage will also be made to data from our partners' many observational and interventional studies in pregnant women, infants and children to enable long term follow-up of the mental and physical health of the mother and child. The development of a bioresource from routine blood samples from all pregnant women and infants attending antenatal care will provide a valuable biological resource to enable future large scale mechanistic studies to understanding the early life origins of disease, and to inform future intervention strategies. Whilst the technical feasibility and necessary permissions for data linkage have been established for similar purposes by our partners in mental health, the first stage of this project will be the acquisition of the necessary ethical and legal permissions for use of the de-identified patient data from each of the component databases for research purposes. This will involve extensive consultation with patients and the public. The sample collection will require 'consent to contact' to be established. These procedures and permissions will be facilitated by an accredited data 'Safe Haven'. Once completed and data linkages established, a pilot study will be undertaken before the resource is made available to the wider UK academic community.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Defining the prerequisites of naïve pluripotent human embryo cells for self-renewal in culture
Funder: Medical Research Council

Abstract: We recently developed a protocol for derivation of multiple clones of naïve pluripotent human embryonic stem (HNES) cells from a single embryo using serum-free culture medium supplemented with LIF and inhibitors of FGF signalling, GSK3, ROCK and aPKC. We propose to utilise this technology to sample the methylome and gene expression profile simultaneously from single cells of individual founder embryos before, during and after generation of HNES cell lines using the recently published scM&T-seq technology. The data generated will be used to explore the variation of gene expression and associated epigenetic modification, particularly of imprinted genes, between cells at each stage and during the process. In additional experiments, we will expand individual clones arising from cells separated from the same embryo to exploit the possibility to obtain a proportion of clones carrying chromosomal defects of potential medical interest that frequently occur intermixed with normal cells during assisted conception. HNES cells will be used as a model of the implanting human embryo to study the biomechanical changes associated with the transition from apolar inner cell mass to polarised epithelial epiblast. We will examine the expression and distribution of key cytoskeletal proteins during the transition from naïve to primed pluripotency and differentiation, primarily using immunocytochemistry and confocal analysis. For example, we will utilise specific small molecules affecting the actin cytoskeleton, such as Cytochalasin or Jasplokinolide. The readout from these experiments will dictate candidates that will be knocked down to confirm their specific activity and utilised to optimise future culture regimes. Use of compliant hydrogels to which specific extracellular matrix proteins can be tethered will enhance naïve pluripotency and reduce variables in the regime currently imposed by the fibroblast feeder cells currently required.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Improving HIV testing and care for adolescents in Zimbabwe: A targeted, community-based approach
Funder: Medical Research Council

Abstract: HIV infection is the leading cause of mortality among adolescents in Africa, and adolescents are the only age group in which HIV-related deaths are rising. Our aim is to improve the access to HIV testing and counselling (HTC) and treatment outcomes for adolescents in Harare, Zimbabwe. Our questions are: 1) Is targeted HTC an effective strategy for identifying undiagnosed HIV in adolescents (aged 7-18 years)? HIV-positive adults attending for care in the study clinics will be approached by trained lay counsellors. Consent will be obtained to visit the households of those who have untested adolescents to offer HTC, with an option to bring adolescents to the clinic for HTC if preferred. The outcomes will be uptake of HTC (proportion of those offered testing who undergo testing) and yield of HIV (proportion of those who test positive among those eligible for testing). 2) What is the impact of support provided by community health workers (CHWs) on linkage to and retention in care and virological suppression among HIV-positive adolescents? Participants who test positive through targeted HTC will be offered support visits at 1, 2 and 6 months following diagnosis from a CHW, referrals to support services and reminders about appointments. Outcomes will be proportion linked to and retained in care by 12 months and viral load at 12 months. 3) Are these community-based strategies cost-effective? The cost per individual tested and cost per HIV-positive adolescent identified through home-based HTC will be estimated. The cost per HIV-positive adolescent initiated on ART, and cost per HIV-positive adolescent virally suppressed on ART will also be assessed. 4) What implementation, mechanism and contextual factors affect the delivery and acceptability of targeted HTC and CHW support? A mixed-methods process evaluation of the intervention, mechanisms of impact and of local context will be conducted, to inform the components required for sustainability and scalability.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Improving adolescent access to contraception and safe abortion in sub-Saharan Africa: health system pathways
Funder: Medical Research Council

Abstract: 35% of adolescent pregnancies in sub-Saharan Africa are unintended. Adolescents account for 23% of the global burden of disease (disability-adjusted life years) due to pregnancy and childbirth. 10-19 year olds account for 25% of all abortions in Africa, higher than in any other world region. Unsafe abortion and its sequelae is a major public health problem, not only in countries where access to safe abortion services is highly restricted legally. Limited evidence focuses on adolescents' perceived barriers to accessing sexual and reproductive health services in general, and experiences of navigating these barriers (successfully or unsuccessfully) are under-researched. We propose a three country (Ethiopia, Malawi, Zambia) comparison of implementation research on contraception and abortion services for adolescents. Within each country, two contrasting study sites (tertiary hospital and designated ASRHS), have been identified. The study design permits 3 analytic levels: within-country by facility; cross-country; and cross-facility. The 3 countries represent a range of ASRHS and abortion legal frameworks and permit a maximum difference design. We will collect data from adolescents who have either sought a safe abortion or post-abortion care following an abortion initiated elsewhere. For implementation research on ASRHS, this is a critical population to understand (non-)use of services, including the barriers to access and care. By comparing adolescents treated for the consequences of unsafe abortion with adolescents who have navigated complex health systems successfully, we will identify factors critical for reaching this under-served and hard-to-reach group. Combined with key informant interviews and costing analyses, the evidence we generate will mean that we will be able to propose realistic and culturally-appropriate ways to address such sensitive topics as adolescent contraceptive use and abortion.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Menstrual health interventions and school attendance in Uganda (MENISCUs-2)
Funder: Medical Research Council

Abstract: Poor menstrual health (MH) is a global health and development problem. Our MRC-PHIND study (MENISCUS-1) was a series of sub-studies among girls aged 14-17 years old in Uganda to understand perceptions about menstruation, estimate an association with school absenteeism, and develop an intervention to improve school attendance (primary outcome) and secondary outcomes including school performance and prevalence of bacterial vaginosis. The study showed that menstruation is a key reason for school absenteeism. Among 40 girls who completed a daily diary, girls reported missing school on 28% of schooldays when menstruating compared with 6% on other days (p<0.001). In the proposed study (MENISCUs-2), we plan to pilot the MH interventions as a package delivered to all girls in one school year in two schools in Wakiso District. The intervention is: - Training of teachers to improve delivery of the Government guidelines for puberty education. - A drama skit to address issues around menstruation, engaging parents, boys and teachers. - Our implementing partner will train teachers and peers to teach girls how to use a menstrual cup and a re-usable sanitary pad. - Supply analgesics for cramps using vouchers - Improvements to school water and sanitation facilities The primary outcome is to review whether criteria for progression to an RCT are met. The criteria are that i) the education session and drama skit were delivered, the majority of girls used the Ruby Cup or re-usable pads, and accessed painkillers if needed, and that soap and toilet paper available for the majority of the time; and ii) the retention rate from one school year to the next is >80%. We will estimate the likely intervention effect size by comparing the absenteeism on period-days and non-period-days from diaries in MENISCUS-2 (intervention) and MENISCUS-1 (comparison) school. Finally, we will estimate the cost of the intervention delivery, and of monitoring trial o


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Developing personalized nanotherapies to target placental abnormalities causing fetal growth restriction
Funder: Medical Research Council

Abstract: Fetal growth restriction (FGR) is a serious pregnancy complication associated with significant risk of neonatal morbidity and mortality, and of non-communicable diseases in childhood and adulthood. Despite this burden of disease, there are no in utero medicines for correcting the underlying cause of disordered fetal growth: placental dysfunction. Our recent research using mouse models of FGR has identified a number of effective drugs, primarily designed for use in diseases outside of pregnancy, which have proven to be effective placental therapies. We have also developed targeted liposomes capable of selective delivery of drugs to the mouse placenta or uterine arteries, resulting in significant enhancement of fetal growth. The aim of this application is to test the hypothesis that targeted liposomes can selectively deliver drugs to either human myometrial vasculature or the placental syncytiotrophoblast (STB), improving functional effectiveness and safety, and enabling a stratified approach to treat FGR resulting from vascular or non-vascular placental pathology. Our objectives are to: 1. Assess the effect of targeted liposomes containing appropriate drug on healthy human myometrial vascular reactivity and STB function in vitro, and compare it to the effect of freely administered drug. 2. Determine whether targeted liposomes can selectively improve function in human myometrial vessels or STB from FGR pregnancies complicated by vascular or non-vascular placental dysfunction. 3. Use human placental ex vivo dual perfusion to evaluate maternofetal transfer of targeted liposomes and potential effects on placental endocrinology, cell survival and placental barrier integrity. This programme of study will allow us to fully exploit our proven strategy for fast tracking candidate therapies into obstetric clinical trials.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: IMPC: Essential role of the GPI anchor biosynthesis pathway for early placentation and its impact on heart and brain development
Funder: Medical Research Council

Abstract: Normal development of an embryo depends on a functional placenta, which is the organ responsible for all nutrient and oxygen supply to the growing baby during pregnancy. Placental development is tightly coupled to the development of embryonic organ systems. Mouse studies have shown that heart and brain defects in particular are often observed in association with placental failures. In some cases these embryonic pathologies can even be caused solely by the abnormal placenta and, consequently, can be rescued when placental function is restored. Despite this vital function, the importance of the placenta for healthy pregnancy and reproductive success has often been overlooked. In fact our efforts have identified that a far greater number of genes is involved in formation of a functional placenta than has been previously appreciated. In the course of our long-standing interest in this field, we have found that a particular molecular pathway that enables proteins to be anchored to the surface of cell membranes where they may function to recognize and direct specific signals into the cell, plays a pivotal role in placental development. Intriguingly, members of this same biochemical family have been associated in humans with congenital heart defects and neurodevelopmental pathologies resulting in mental retardation, opening up the possibility that these defects may in fact originate in an early placental abnormality. In this work, we will study two components of this pathway to identify their precise role in placental development, using the mouse as a model system. We will investigate very early stages of gestation in which the foundations are laid down for a healthy pregnancy later on, to determine which specific steps in placenta formation are affected. Taking advantage of mouse genetics, we will also study whether the defective placenta is the sole cause of the severe embryonic defects observed. In parallel, using genome editing technology we will establish placental stem cell lines that carry mutations in these factors, which will allow us to elucidate, in the longer term, which particular membrane-bound proteins and which signalling cues are crucial for these developmental processes. This work is of fundamental importance to gain a better understanding of placental development and its impact on formation of key organs in the baby, notably the heart and the brain.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH