NIHRDataInsights/HRCSData huggingface dataset:
Title: How are chromosomes segregated correctly during sexual gene reassortment?-understanding how the meiotic chromosome axis functions in gametogenesis
Funder: Medical Research Council

Abstract: Chromosomes must break and recombine to segregate in meiosis. Hence, the programmed formation of DNA double-strand breaks (DSBs), catalysed by a group of proteins called the DSB proteins, is tightly regulated to achieve faithful gametogenesis. I found that meiotic chromosome axis components Hop1 and Red1 regulate DSB proteins in multiple ways to ensure recombination occurs at appropriate loci. Hop1 and Red1 recruit DSB proteins to chromosomes, with preferential recruitment to short chromosomes that ensures all chromosomes do recombine. Hop1 and Red1 can also act to repress DSB protein binding, since elimination of both proteins causes DSB proteins to bind chromosomes promiscuously. Finally, Hop1 and Red1 activate DSB proteins for cleavage, since DSB proteins bound without Hop1 and Red1 hardly initiate cutting. This study will elucidate the molecular mechanisms through which Hop1 and Red1 direct this control framework for meiotic DSB formation. Aim1 investigates how Hop1 and Red1 repress DSB protein recruitment, and examines how they switch from repressing to promoting DSB protein binding. Structure-function dissection will test if the Hop1-Red1 interaction functions as a switch, and if the repression function involves interaction with DSB proteins. Aim2 elucidates how Hop1 and Red1 activate DNA cutting by DSB proteins. Proteomics and genomics approaches will identify components and post-translational modifications that are lacking when the DSB proteins bind chromatin without Hop1 and Red1. Aim3 will reveal how intrinsic DNA sequence features of short chromosomes preferentially boost the recruitment of Hop1 and Red1 and consequently, DSB proteins. Advanced molecular genomics/proteomics will locate and characterise these intrinsic features, investigating their characteristics, the proteins that bind them, and their relation to other chromosome elements. Overall, this study will transform our understanding of how meiotic recombination is controlled.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Mapping the maternal-fetal interface at a single-cell resolution to interrogate the aetiology of severe pre-eclampsia and identify potential disease
Funder: Medical Research Council

Abstract: This project aims to achieve a better understanding of maternal-fetal interface interactions between cell types in pregnancies with severe PE. Cases and controls are matched by gestational age, delivery mode, ethnicity, age, BMI and smoking status. Sampling. From the mid-point of the largest distance between the cord insertion site and the edge of the placenta two samples are taken. One is placed in Hypothermosol Frs for single cell sequencing (SC) and the other is snap frozen for spatial transcriptomics (ST). From the mirrored area of the placental bed is two samples of are taken via a punch biopsy, for Sc and ST as above. Rolled chorio-amniotic membranes (CAM) are collected and divided for SC and ST as above. Maternal peripheral blood is sampled just before delivery. Tissues are dissociated in Accutase or Accumax, on an automated dissociator. PBMCs are isolated using density gradient media. Cell suspensions are processed using the Chromium Next GEM Single Cell 5' Reagent Kits (v2 Chemistry Dual Index). Snap frozen tissues are processed using 10X Genomics Visium Spatial Gene Expression Slides. Resulting libraries from multiple patients are pooled and sequenced on Novaseq S4 v1.5 (200cycle) kits. Maternal and fetal cells are separated using genetic variants. Unsupervised methods are used to obtain clusters, cell types will be assigned based on differentially expressed markers. Cell type composition is compared using scCODA. Gene expression for each cell type is compared using DESeq2. GSEA analysis is performed. Identification of genetic programs ("topics") that significantly change in severe PE is performed using ConutClust. Trajectories as well as their speed in pseudotime of different cell lineages, are inferred using Slingshot. Spatial mapping of cell types is inferred, using Seurat. Local distribution of cell types are quantified using spatial networks. We infer cell-to-cell signalling mediated by ligand-receptors pairs using CellPhoneDBv3 and Giotto.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: MRC Transition Support Award: Long-term health outcomes for women & their children after assisted reproductive technologies: a data linkage study
Funder: Medical Research Council

Abstract: This Transition Support Award will allow the applicant to consolidate the research outlined in an existing Career Development Award. The main aim of the project is to assess the long-term health outcomes of mothers and children after the use of assisted reproductive technologies (ART) in England. A linked dataset combining information from the Clinical Practice Research Datalink and the Human Fertilisation and Embryology Authority (HFEA) register has been created. Over 400,000 babies, born 1991-2018, and their mothers, who are registered at GP practices in England, will be included. Duration of follow-up varies from a few months to over 20 years, depending on date of delivery. The main 'exposure' is ART, which comprises IVF, ICSI, and ovulation induction; other techniques (e.g. cryopreservation) will be examined, where possible. Outcome data include all consultations, diagnoses, prescriptions and referrals recorded by GPs, supplemented by data on hospital episodes and mental health treatment. Key outcomes for children include growth, illness and infection, atopic and allergic conditions, behaviour and developmental outcomes; and for mothers, physical and mental health. Multivariable regression models will be used to estimate adjusted rate ratios and odds ratios as appropriate, comparing outcomes in the ART and non-ART groups. An economic analysis will compare differences in NHS expenditure on the long-term provision of care for ART and non-ART pairs, and model future costs. Concern among researchers that low consent rates since 2009 adversely affect the representativeness of the HFEA dataset, means that the newest data are under-utilised. Methodological work to explore the impact of missingness, and to develop methods to reduce the potential bias, will be conducted. This study will contribute to the evidence for the safety and costs of ART in England, and provide tools for future work using these rich data sources


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: MRC Transition Support Award:Maternal and perinatal Health Research collaboration,India(MaatHRI):improving outcomes in pregnant women with anaemia
Funder: Medical Research Council

Abstract: 1) Progress made to date: I have completed a majority of the fellowship work which established a UK-India collaborative platform for maternal and perinatal health research (called MaatHRI). I am starting to demonstrate my research achievements and leadership. Five papers from the completed fellowship work are published. A recent study has had a demonstrable impact on policy during the COVID-19 pandemic. The fellowship work leveraged additional funding and I have received recognitions and awards. However, my research momentum and consolidation of the fellowship was affected by a number of factors which delayed the completion of two ongoing studies. 2) Why I consider that I am not yet competitive for the next funding stage: Without completing the two primary ongoing studies and firming up the emerging hypotheses, I am unlikely to be competitive. Successfully completing the projects will consolidate the nascent multidisciplinary collaborations with national and international experts. This will facilitate a new phase of translational research. Several mitigating measures have been put in place including revising the samples sizes, increasing the frequency of monitoring participant recruitment and data entries. 3) Added value that the award would provide: The studies of global relevance currently being undertaken through MaatHRI cannot be carried out in the UK or in India without a large research infrastructure. Successfully completing the work will endorse the value of the platform. Limiting the studies will undermine the statistical power to produce meaningful results, thereby compromising the ethical obligations to existing participants, the value of the data already collected and the funds already spent. 4) Institutional support: I have strong continuing support from the Department to develop my research and academic leadership skills and profile. I have commitment for salary support and protected time to complete the remaining activities of the fellowship.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: An Investigation of Ethnicity Related Differences in Hypertensive Disorders of Pregnancy amongst Women living in the UK
Funder: Medical Research Council

Abstract: Background Hypertensive disorders of pregnancy affect one in ten pregnant women. Incidence and severity of disease varies significantly across ethnic groups. Women of African and Asian ancestry are more likely to be affected and experience adverse outcomes than White European women. The contributions of genetic as oppose to potentially modifiable environment and treatment-related factors is unknown. Objectives & Methods 1. To determine the relative contribution of clinical and socio-demographic variables, blood pressure control and genetic ancestry to ethnicity-related disparities in hypertensive disorders of pregnancy. The incidence and outcomes of hypertensive disorders of pregnancy in the eLIXIR cohort (a diverse South London pregnancy cohort, n=60,000) stratified by maternal ethnicity will be described. Mediation analysis will evaluate potential contributions of clinical variables, socio-demographic factors and blood pressure control to the relationship between maternal ethnicity with incidence and severity of hypertensive disorders of pregnancy. A genotyped study population (n=2000, ~50% hypertensive pregnancies) will be generated from genotyped eLIXIR maternal samples alongside samples and data from London and Manchester pregnancy hypertension cohorts. Adjusted statistical models and admixture mapping will test whether genetic ancestry is predictive of hypertensive disorders and disease severity, and detect specific disease susceptibility loci. 2. A feasibility study of antihypertensive agent treatment response in pregnancy. 96 pregnant women with hypertension >= 12 weeks gestation taking standard antihypertensive treatment (labetalol/nifedipine) as a single agent will be recruited to a single centre observational study. Following consent, women will provide a blood sample and be fitted with an ambulatory blood pressure monitor to measure a 24-hour BP profile. Modelling of genetic ancestry and post-dose blood pressure profile will be performed.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Investigation of the maternal immune phenotype in women with recurrent pregnancy loss due to chronic histiocytic intervillositis
Funder: Medical Research Council

Abstract: The overall aim of this project is to determine the cause of chronic histiocytic intervillositis (CHI), a rare placental disorder that causes recurrent pregnancy loss. Background: CHI is strongly associated with recurrent miscarriage, severe fetal growth restriction and stillbirth. It can only be diagnosed on postpartum placental histology and is defined by infiltration of maternal CD68+ histiocytes into the intervillous space. The cause is unknown but available evidence suggests an alloimmune aetiology, combined with abnormal endometrial immune cell function. There are no treatments proven to prevent recurrence in subsequent pregnancies. Objectives: Discover the pathophysiology of CHI by investigating the systemic and endometrial immune phenotype of affected women: 1. Demonstrate that women with CHI have abnormal antibody reactivity to placental antigen 2. Identify the causative placental antigen 3. Characterise uterine natural killer (NK) cell function in women with recurrent CHI Methodology: 1. Antibody discovery experiments will use established techniques including IgG purification, Western blotting and immunoprecipitation. Putative antigens will be characterised using mass spectrometry and identified using immunohistochemistry. 2. Uterine NK cells will be isolated from menstrual blood, using a novel non-invasive technique pioneered by our collaborators at the Karolinska Institute. They will be phenotyped using high-dimensional flow cytometry, uniform manifold approximation and projection (UMAP) and PhenoGraph cluster analysis. Scientific and clinical impact: 1. Findings will directly benefit academics working on CHI but could also translate into new discoveries in other placental, auto/alloimmune and histiocytic disorders. 2. This is a unique and original project that has real potential to benefit patients. Results will be used to identify biomarkers that predict recurrence of CHI and design novel targeted therapies to prevent recurrence.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: In Vitro Organ Imaging Device (IV-OID) with integrated Biosensing and Real-Time Imaging Capability: Proof-of-Principle using a Human Placental Model
Funder: Medical Research Council

Abstract: The most widely used in vitro models for human tissue-blood barriers are based on static setups such as the Transwell system, which poorly mimic physiological conditions, hence have limited translational significance. While efforts have been made towards the development of more predictive models, including that of a human trophoblast organoid, key limitations resides in (1) their inability to recreate the dynamic flow exchange existing at the placental barrier, or (2) their inability to replicate the mature developmental structure of the placenta, and, (3) the complexity of setting up the models in a research lab. Owing to the ethical issues associated with the study of human pregnancy and the caveat inherent to current experimental models, the understanding of the mechanisms governing placenta-blood barrier functions remains limited. The human placenta is an intricate organ made up of cellular and vascular networks that act in concert to promote fetal growth and viability. Trophoblasts represent the most outer layer of the placenta whereby chemical and gas feto-maternal exchanges are regulated. Here we propose to develop an unprecedented trophoblast-based microfluidic dynamic model, that mimics the feto-maternal interface. We will build on the use of hollow fibre technology to develop an artificial capillary system that will provide a three-dimensional, quasi-physiological environment where (fetal) endothelial cells will be luminally exposed to physiological levels of flow and co-cultured with abluminal trophoblasts to form a functional placental barrier. Our platform will be unique in that it will also offer real-time multi-photon imaging capability. Our easy-to-set up 3D-dynamic flow model may be used in a variety of research applications encompassing elucidation of vertical disease transmission mechanisms e.g., TORCH pathogens, maternal antibody placental transfer, pharmacodynamics of antibiotics and drugs.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Improving menopause treatment: Beta prototype development of a CBT-based digital therapeutic
Funder: Department of Health and Social Care

Abstract: What is the unmet health need being addressed? Lumino is scaling-up access to Cognitive Behavioural Therapy (CBT), adapted for menopause-related symptoms. 2.24 million UK women are currently experiencing hot flushes and night sweats1. 60 per cent of women with significant symptoms seek attention, but 3 in 4 are left untreated2. Untreated symptoms are associated with more frequent outpatient visits and associated costs3. Cognitive Behavioural Therapy has been proven to help4 5 6 7 8. However access is poor. Our own research demonstrates GPs report that treatment options other than HRT are limited and would welcome expanding this to include CBT9. Planned activity We have established proof of concept with the development of a fully functional alpha prototype, supported by Innovate UK. This is a Tier C intervention under the NICE framework, intended for NHS use. This project is to develop a prototype beta version product, ready for early user testing. Activity consists of the following work packages: Three rounds of user and stakeholder research (alpha feedback, prioritise features and content, beta prototype feedback). Clinician-led production of therapeutic content. High fidelity beta prototype. Funding need We are a pre-revenue company, incubated at the University of Cambridge. NIHR funding will increase our ability to raise private investment by de-risking the investment opportunity and increasing investor confidence. Further, NIHR support will allow us to keep pace whilst fundraising. Addressing barriers to innovation and adoption There are many promising ideas, but effective adoption of these ideas at scale is a challenge. Barriers include technical and cultural factors. By working with clinicians, including as part of our user research, we seek to better understand those challenges and develop plans to mitigate them. Further, by working with AHSNs and clinicians we will identify and support clinical champions who will assist in adoption plans.


Research activity codes: 5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: A point-of-care diagnostic for vitamin-k deficiency in neonates
Funder: Department of Health and Social Care

Abstract: Late-onset vitamin K deficiency bleeding (VKDB) has devastating consequences for newborns, with a mortality rate of 20%, and 50% of surviving babies suffering permanent handicaps [1]. VKDB, in the absence of the optional prophylactic injection given at birth has an incidence of 80 in 100,000, and with prophylactic injection the incidence is 0.4-3.2 per 100,000 [1][2]. Recent research from collaborator Dr Paul Clarke details of 45 premature neonates in the UK, 25% had developed vitamin K deficiency by age 2-3 months, despite administration of the prophylactic [3]. Developing world rates are approximately 20x higher than those from Europe [4]. If caught in time, administration of vitamin K will reverse bleeding within minutes [5]. Current assays for the vitamin K deficient marker (PIVKA-II) are conducted in a central lab in London, making routine screening unfeasible [6]; PIVKA-II screening of at-risk groups is recommended by numerous European committees [7]. Our aim is to commercialise a point-of-care PIVKA-II diagnostic allowing routine screening of at-risk neonates, eliminating VKDB. We have achieved proof-of-concept (TRL3) using lateral-flow to identify PIVKA-II in 1&micro;l of patient samples. A crucial challenge to effective impact is to understand where the diagnostic is best placed in the healthcare pathway, and how it should be used. The proposed project will answer this question through: A) health economic modelling (London IVD Co-operative) to understand where in the healthcare pathway the device needs to be integrated to maximise impact for patients and the NHS. B) Focus groups with healthcare professionals to develop minimal viable product requirements. The project is timely running alongside a study investigating regulatory scoping of a neonatal IVD. Project completion will provide evidence to secure further funding to commercialise the technology, as well as ensure adoption by the NHS to eliminate VKDB as a healthcare concern.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Progestogens for preventing miscarriage: a network meta analysis
Funder: Department of Health and Social Care

Abstract: Miscarriage affects 15% of pregnancies. Cochrane reviews on the use of progesterone for threatened (early pregnancy bleeding) and recurrent miscarriage (=3) suggested that progesterone supplementation may reduce the risk of miscarriage. However, there is a lack of certainty and a high degree of heterogeneity, with different regimens using different types of progestogen. In addition, the quality of these trials is a concern, with a recent trial being withdrawn due to concerns about its integrity._x000D_ _x000D_ Our group has recently published a large, high-quality trial on the use of progesterone in women with early pregnancy bleeding. A key finding showed that treatment was associated with increasing live birth rates according to the number of previous miscarriages. This latest evidence has now been considered by NICE and a decision made to update guideline NG126._x000D_ _x000D_ Our network meta-analysis will allow for comparisons and conclusions about which treatment is most effective amongst multiple options from 18 trials, to achieve a single coherent analysis. We will use a robust process to address the integrity of each trial and ensure only high quality evidence is included. Therefore, this review has been identified as extremely relevant and urgent by the Cochrane editorial team to inform the NG126 update.

Lay abstract: See summary

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH