NIHRDataInsights/HRCSData huggingface dataset:
Title: MOLECULAR MECHANISMS OF MEIOTIC RECOMBINATION
Funder: Medical Research Council

Abstract: Sexually reproducing organisms rely on the process of meiosis for the generation of genetic diversity across generations. At the functional centre of meiosis is the process of genetic exchange between homologous chromosomes, of which the reaction of meiotic recombination is the physical manifestation. Despite its paramount role in meiosis, important aspects of meiotic recombination remain poorly understood at molecular level, including the specific architecture of the meiotic chromosome that must be achieved to promote genetic exchange, and the mechanism of the reactions of DNA-strand pairing and exchange that underlie recombination. Our proposed research aims to improve our knowledge of meiotic recombination, by focusing on two important, related questions that remain poorly understood at structural and mechanistic level: what is the role of the synaptonemal complex (SC) proteins in the three-dimensional organisation of the meiotic chromosome, required for recombination? And what are the molecular principles of meiotic recombination that necessitate the intervention of a specific recombinase, DMC1, acting cooperatively with its mitotic counterpart, RAD51? The current proposal builds on our long-standing interest in the field of homologous recombination and genomic stability, as well as our more recent focus on the structure and function of SC proteins in meiosis. To achieve our aim, we have designed a multi-disciplinary research plan that includes state-of-the-art biophysical and structural experiments, at ensemble and single-particle level. Our work will advance our understanding of the molecular mechanisms underpinning genetic recombination in meiosis and ultimately human fertility. Furthermore, it will illustrate molecular principles of DNA organisation that will be relevant to our understanding of chromosome structure and dynamics and of pathologies resulting from aneuploidy and incorrect chromosome segregation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Regulation of trophoblast differentiation by BAF complex chromatin remodelling factors
Funder: Medical Research Council

Abstract: Trophoblast stem cells (TSCs) are multipotent self-renewing cells giving rise to multiple trophoblast subtypes within the placenta, essential to maintaining a viable, healthy pregnancy. Mouse TSCs are a well-established model system that can be manipulated in vitro to interrogate molecular mechanisms controlling trophoblast differentiation. Pregnancy complications such as preeclampsia and HELLP (haemolysis, elevated liver enzymes, low platelet count) Syndrome are particularly linked to defective formation and behaviour of invasive endovascular trophoblasts that enhance maternal blood supply to the foetus. Our preliminary analyses (see Case for Support) suggest formation of this essential trophoblast subtype is heavily influenced by BAF complex chromatin remodelling factors. I recently showed the chromatin landscape undergoes widespread changes during TSC differentiation. We will continue to exploit mouse TSCs to understand how BAF chromatin remodelling complex bromodomain(BRD)-containing proteins BRG1, BRM and BAF180 influence the chromatin landscape and thus trophoblast cell fate and behaviour by: 1) Using CRISPR/Cas9 gene knockout and a highly potent and specific small molecule inhibitor specifically targeting BRG1, BRM and BAF180 BRDs, coupled with RNA-seq and qRT-PCR profiling of well characterized markers of individual trophoblast subtypes; 2) Profiling BRG1, BRM and BAF180 chromatin binding locations using ChIP-seq in control and BRD-attenuated trophoblasts; 3) Profiling BAF complex-dependent chromatin accessibility using ATAC-seq on control, BRG1, BRM, BAF180 and BRG1;BRM CRISPR knockout and BRD-inhibited trophoblasts; 4) Determining the composition of BRG1-, BRM- and BAF180-containing protein complexes in wild type trophoblasts using co-IP with mass spectrometry. This will provide valuable insights into trophoblast subtypes controlled by BAF complexes, how they control use of cis-regulatory sequences and their molecular mechanism of action.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: MICA: Understanding the glycemic profile of pregnancy: intensive CGM glucose profiling and its relationship to fetal growth.
Funder: Medical Research Council

Abstract: Aim: To characterise longitudinal changes in glycemia across gestation using continuous glucose monitoring (CGM), in order to understand the evolution of dysglycemia and its relationship to fetal growth. Methods: A multi-centre, prospective, observational, cohort study of 500 healthy pregnant women, recruited in the first trimester of pregnancy. CGM (masked) will be performed for a 14 day period on five occasions across pregnancy at 10-12,18-20,26-28,34-36 weeks gestation and postnatally. Routinely collected anthropometric and sociodemographic information will be recorded at each visit including: weight, height, blood pressure, current medication. Age, parity, ethnicity, smoking will be recorded. Blood samples will be taken at each visit for HbA1c and a sample stored. Details on fetal growth from ultrasound scans and the OGTT results will be recorded. Maternal and neonatal outcomes will be collected. CGM glucose profiling is the exposure of interest, and will be performed using standard summary statistics, functional data analysis and glucotyping. The primary outcome is large for gestational age (LGA) (>90th centile defined by customised birthweight centile) given its established relationship to maternal, neonatal and perinatal morbidity, adolescent obesity and T2DM. The relationship of glucose to key secondary outcomes will be explored. Outcomes: This will establish: 1) the prevalence of dysglycemia detected by CGM in pregnancy; 2) when it occurs and whether it resolves postnatally; 3) which glucose profiling technique is best at detecting it and how reproducible this is; 4) the relationship of maternal dysglycemia to fetal growth and outcomes in healthy 'normal' women, as well as those who go on to have diagnosis and treatment of GDM; 5) whether CGM glucose profiling can detect GDM before the OGTT; and 6) whether CGM glucose profiling may be more useful than the OGTT or HbA1c at detecting LGA and other perinatal outcomes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Zvatinoda! (What we want!): Increasing demand and uptake of sexual and reproductive health services by young people in Zimbabwe
Funder: Medical Research Council

Abstract: Uptake and quality of health services for adolescents and young adults (YP) is often poor, leading to preventable morbidity and mortality. Systematic reviews of adolescent interventions suggest mobile health strategies improve some YP outcomes but evidence of their effectiveness for improving health-seeking behaviour is limited. Building on evidence that physical support groups for those living with HIV can lead to improvements in medication adherence, we propose mobile phone discussion groups as a promising and novel approach to increase service uptake. We will develop and test an innovative approach, Zvatinoda! (What we want!) which aims to improve YP uptake of sexual and reproductive health services in Mutare District, Zimbabwe. Formative research and a participatory co-design workshop with YP and stakeholders will inform intervention design. Discussion groups for YP will provide information, peer support, and be led by a culturally appropriate mentor who can provide guidance and problem solve challenges to service uptake. Discussion content will be extracted and thematically analysed, and YP's needs and preferences shared with stakeholders to guide the improvement of services. We will conduct a 4-month feasibility study among 16-24 year olds living in the catchment of two health facilities in Mutare District. Findings will inform the main trial protocol. Research questions: 1.Why are YP not accessing health services? Which factors are malleable and have the greatest scope for change? 2.What are the most acceptable and feasible discussion group and health facility feedback formats? 3.What negative consequences might the intervention have and how can we mitigate against such events? 4.Is it feasible to implement the intervention among YP in the geographical catchment area of 2 primary care clinics? 5.How could we measure the effectiveness of Zvatinoda! on improving service provider practice and attitudes, and increasing use of health services by YP?


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Prevention of Neural Tube Defects by Inositol and Vitamin B12 (PONTib) - Development Trial
Funder: Medical Research Council

Abstract: Neural tube defects (NTDs) are common birth defects with a high prevalence in many low and middle income countries. NTDs can be lethal at birth (anencephaly) or cause severe disability (spina bifida). Primary NTD prevention is based on peri-conceptional supplementation with folic acid (FA), but considerable numbers of NTDs still occur, indicating frequent FA-resistance. Research in mice, and a pilot clinical trial in high-risk women, both show a potential preventive effect of inositol (vitamin B8) for FA-resistant NTDs. Vitamin B12 supplements could also enhance FA prevention of NTDs, although this is untested. This Trial Development grant will prepare for a future large scale, randomised controlled trial of inositol and B12, as a means of preventing a greater proportion of NTDs than with FA alone. China offers a unique opportunity for the study, given the large size of the reproductive population, high NTD rate, and well organised birth defects surveillance. Study particpantswill be women with a history of NTD-affected pregnancy who wish to become pregnant again. They will be randomised to four intervention arms: (i) inositol, (ii) vitamin B12, (iii) inositol + vitamin B12, (iv) no treatment. All women will receive FA (5 mg/day). We aim to identify ~ 460 women with a previous NTD-affected pregnancy, of whom we predict that ~320 will satisfy eligibility criteria. We aim to consent 200 women to trial entry in order to follow 140 pregnancies with a measurable fetal outcome (NTD or non-NTD). We will test key requirements for a subsequent, fully-powered phase III trial in China: effectiveness of the NTD surveillance mechanisms, proportions of potential subjects who are eligible to enter the study, consent to randomisation, comply with the study protocol, and have an informative pregnancy outcome. This study will be a vital step towards providing an evidence base for enhancing pregnancy supplementation worldwide, to further reduce the global burden of NTDs.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Investigating Kisspeptin Signalling in Sexual and Emotional Brain Processing
Funder: Medical Research Council

Abstract: Hypoactive Sexual Desire Disorder (HSDD) affects 17-40% of UK adults with devastating consequences to health, quality of life and fertility. Despite its significant psychosocial burden, our limited understanding of human sexual and emotional brain processing has constrained the development of effective treatments. The hypothalamic hormone kisspeptin has emerged as critical for integrating sexual and emotional behaviours with the reproductive axis. Beyond the hypothalamus, kisspeptin and its cognate receptor are expressed in key limbic brain structures, which govern emotional and behavioural responses. Using fMRI, recent work from my proposed laboratory has shown that kisspeptin administration in healthy men enhances limbic brain activity in response to sexual stimuli and modulates resting brain connectivity to enhance sexual and emotional processing. My pilot fMRI data reveals that kisspeptin administration in healthy men also enhances brain activity in aesthetic brain regions, including the medial prefrontal cortex, in response to female faces. To this end, these studies illustrate that manipulation of the kisspeptin-system may deliver therapeutic benefit for patients suffering psychosexual disorders, however its role in this context is undescribed. I therefore propose to use advanced fMRI techniques coupled with erotic stimuli, facial attraction, penile tumescence and psychometric tasks to determine how kisspeptin modulates limbic brain activity and associated behaviours in men with HSDD. Crucially, I will also perform in vivo rodent experiments using pharmacosynthetic techniques to establish the effects of endogenous kisspeptin activation and inactivation in specific limbic brain structures on sexual behaviour to provide mechanistic insights. Taken together, the data generated will provide fundamental insight into reproductive physiology, whilst laying the foundations for kisspeptin-based therapies for psychosexual disorders to address their significant burden.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Uterine natural killer cells, their expression and function through peptides and impact on reproductive success.
Funder: Medical Research Council

Abstract: Human reproduction is inefficient and abnormal implantation is a leading cause of maternal and foetal morbidity and mortality. Uterine Natural Killer (uNK) cells play an crucial role in regulating extravillous trophoblast (EVT) migration into the decidua and differences in uNK cell phenotype and function alter the risk of pregnancy complications. Unlike decidual NK cells, endometrial NK cells (eNK) in the non-pregnant uterus have been little studied. uNK cells express activating and inhibitory receptors for HLA class I, including the killer-cell immunoglobulin-like receptors (KIR), LILRB1 and CD94:NKG2A. The KIR gene family is highly polymorphic and immunogenetic studies have shown the combination of maternal activating KIR2DS1 in association with its cognate HLA-C group 2 ligand in the foetus, to be protective against pre-eclampsia and miscarriage. My hypothesis is that the balance between eNK cell activation and inhibition is disrupted in women with reproductive failures (subfertility, recurrent miscarriage, implantation failure), and that uNK cell activity can be modulated by peptides presented by EVT to KIR2DS1+ NK cells. I will characterise the phenotype and function of eNK cells in controls vs reproductive failure. This will be performed using multiparameter flow cytometry for markers of maturity and function including KIR2DL1/2/3, NKG2A, LILRB1 (inhibitory receptors) and KIR2DS1/S2/S4, NKG2C (activating receptors). The functional potential of eNK cells in response to HLA class I negative cells, and to antibody cross-linking of activating KIR will be investigated. The regulation of KIR2DS1 binding and activation by peptides presented by HLA-C on EVT will be defined by performing assays of HLA-C stabilisation, which will include exogenous peptide loading, KIR2DS1 tetramer binding and CD107a degranulation by flow cytometry. This work will provide novel insights into the molecular determinants of pregnancy outcome.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Targeting mitochondrial fusion to alleviate brain injury in infants
Funder: Medical Research Council

Abstract: Moderate to severe hypoxic-ischaemic (HI) encephalopathy, caused by birth asphyxia in term babies, affects 1-2 in every 1000 live births in the UK and far more in low-to-middle income countries. Therapeutic hypothermia represents the only intervention currently available for these infants and it is not universally successful. We therefore urgently require additional synergistic therapies in order to prevent the devastating life-long consequences which afflict this cohort. We recently found mitochondrial Optic Atrophy (OPA)1, is rapidly degraded following neonatal hypoxia-ischaemia (HI) in our rodent model, accompanied by increased mitochondrial fission. In vitro, OPA1 inhibition results in increased cellular vulnerability to oxygen-glucose deprivation. We propose that enhancing OPA1 integrity will provide additional neuroprotection for infants where therapeutic hypothermia alone is inadequate. Aim 1 will use mice with mild OPA1 overexpression to show that OPA1 integrity provides neuroprotection following HI in vivo. Histological analyses of infarct will be correlated with OPA1 integrity. Longitudinal in vivo spectroscopy and behavioural outcomes will determine the metabolic profile for OPA1-mediated survival benefits. Aim 2 will investigate the endogenous regulation of OPA1 in neurons and astroglia cells through a known target approach as well as by RNASeq and metabolomics to determine OPA1-mediated gene networks and metabolic profiles. Finally Aim 3 will investigate a novel, non-invasive diagnostic biomarker in order to stratify the severity of neonatal hypoxic-ischaemic brain injury and which we will validate using gold standard MRI. This project aims to produce a wide range of much needed resources and tools for use in both basic and translational OPA1 biology, instrumental in improving the outcome of term babies at risk of developing lifelong neurological impairment.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: The impact of metformin exposure on placental ageing, metabolism, and mitochondrial function
Funder: Medical Research Council

Abstract: The project aim is to evaluate the impact of metformin (N,N-dimethylbiguanide) on the human placenta. There is strong evidence from both meta-analysis of human trial data and from animal models that intrauterine metformin results in a pattern of low birth-weight and post-natal catch-up growth in metformin-exposed offspring. Metformin has multiple targets within metabolically active cells and is actively transported across the placenta via organic cation transporters. We hypothesise that reduced fetal growth in metformin-exposed pregnancies may be a result of accelerated placental ageing, metabolism, and mitochondrial function. The project aims are (i) to investigate the impact of maternal metformin exposure during pregnancy on placental ageing and metabolism, and (ii) to determine the direct effects of metformin on mitochondrial function in human primary trophoblast cells. A unique resource of placental tissue collected during two landmark studies: Efficacy of Metformin in Obese Pregnant Women, a Randomised controlled (EMPOWaR) trial and the Pregnancy Outcome Prediction (POP) study will be used to address the first aim. Placental ageing will be assessed by measuring telomere length, expression of ageing-associated genes, and end-products of oxidative stress. Detailed deep-phenotyping using multiomics techniques (RNAseq, lipidomics, metabolomics) will be performed to test the impact of metformin on lipidomic profiles and 1-carbon metabolism. The second aim will be addressed using direct metformin administration to in vitro isolated primary trophoblast cells isolated from donated healthy human placentas. We will thus test whether metformin acts directly on trophoblast through assaying cellular oxygen consumption rate and respiratory chain complex activities. The project results will add to current knowledge regarding energy production and nutrient transfer late in pregnancy, and will provide important new data to help guide safe use of metformin during pregnancy


Research activity codes: 4.4 POPULATION SCREENING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Exploring the potential for using parent experiences of pre-term birth to improve care in LMICs, using video narratives and digital stories.
Funder: Medical Research Council

Abstract: This project aims to identify the issues that are important to mothers of a baby born prematurely in Kenya, and assess the feasibility of using these experiences in the co-production of people-centred staff training. The research will span the continuum of antenatal, peripartum and post discharge care. We will identify a Stakeholder Group to guide the research, co-produce outputs and develop impact from the research in later workstreams. The group will be drawn initially from our existing networks to understand the key neonatal policy and implementation stakeholders at a national, county and hospital level. It will include healthcare staff, managers, policy makers and influencers, and crucially, mothers. The project will use the following methods to address its objectives. Obj 1. (i) We will conduct a secondary analysis of qualitative data collected by co-PI Oluoch for her longitudinal study of mothers' experiences of pre-term birth in two Nairobi hospitals. (ii) In two settings (Nairobi and Kilifi counties), we will supplement this sample, conducting semi-structured narrative interviews to collect detailed narratives from mothers to understand women's experiences of pre-term birth and subsequent care of their baby. Thematic analysis will identify and compare the issues important to mothers. Obj. 2 We will use the Experience Based Co-design (EBCD) approach to identify key service delivery 'touchpoints', and develop a series of video narratives and digital stories. Obj. 3 We will use EBCD in workshops to develop staff training and pilot with staff and medical students Obj 4. This initial use of detailed personal narratives will be the subject to a formative evaluation, using self-reported questionnaires and interviews to begin to develop a more generalisable understanding of their potential use and value.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH