NIHRDataInsights/HRCSData huggingface dataset:
Title: Novel biomarker platform for a 3Rs approach to assessment of developmental and reproductive toxicity
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Developmental and reproductive toxicity (DART) assessment presents significant challenges during the compound discovery pipeline, involving both one and two-generational testing of rats and rabbits, thus utilizing at least 2500 animals per compound. Our objective is to establish a novel non-vertebrate biomarker-based alternative testing platform to replace animals for compounds with medium to high risk of DART by identifying and eliminating them prior to animal testing. A combinatorial approach using Caenorhabditis elegans and Dictyostelium discoideum is envisaged in order to synergistically enhance predictive power. These simple eukaryotic organisms are genetically tractable and molecular developmental processes are well defined and conserved with mammals. We will establish a library of fluorescent reporter strains in both organisms that will be used as biomarkers of DART. These will represent a broad range of developmental and reproductive processes and pathways to define a molecular signature of development. These reporters will be arrayed in clusters defining molecular and developmental pathways and changes in fluorescence (levels and/or expression patterns) will act as read outs for potential DART. Phenotypic anchoring will inform cluster applicability to fine tune the assay where appropriate. Ultimately we will establish a novel biomarker based pipeline that will serve to replace vertebrate animals in the early stages of testing for compounds with high risk of DART as they can be eliminated without recourse to experiments on rats and rabbits. In the long term use of non-vertebrate models has high potential to replace vertebrates within the regulatory framework in DART identification.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Improve outcomes for infants following surgery in the first year of life by enhancing the evidence base for choice of surgical strategies
Funder: Department of Health (England)

Abstract: Dr Knight will lead research aiming to improve care for pregnant women and babies with life threatening illnesses, particularly focusing on helping babies to recover from early surgery.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;7.3 MANAGEMENT AND DECISION MAKING
Health categories: GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: The role of maternal and offspring metabolic and anthropometric gene variants in fetal and childhood growth.
Funder: Wellcome Trust

Abstract: Growth of a baby in the womb and growth in childhood are linked to many adult diseases and health outcomes. We propose that genetic factors are likely to explain many of these relationships, but at present the role of genetics in fetal and childhood growth is poorly understood. The relationships are complex: the growth of a baby in its mother s womb may be influenced by the baby s genes, and the environment surrounding the baby (which in turn may reflect the mother s genes). Similarly, the later growth of a child may be influenced by the child s genes and the childhood environment. However, in addition it may be programmed by early effects of the mother s physiology while pregnant. The aim of this project is to improve our understanding of how the mother s and baby s genes contribute to early growth. My project will focus on genes with proven effects on predisposition to type 2 diabetes, blood glucose, adult obesity and adult height as these are good candidates for affecting fetal and/ or childhood growth. The effect of each gene individually is likely to be small so it will be necessary to use large studies of mothers and children, and also to combine these studies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Studies of reproductive and stem cell biology at the molecular and cellular level using flow cytometry.
Funder: Wellcome Trust

Abstract: The Institute of Reproductive Biology and Development, Imperial College London comprises a number of researchers and clinicians striving to understand the science underlying a number of diseases related to reproductive health, pregnancy complications and to understand how stem cells can be used in broad areas of medicine. This application seeks funding to purchase a piece of equipment called a flow cytometer that will be an invaluable tool in understanding these diseases, and to use this informa tion to improve diagnosis and treatment. A flow cytometer is a system to analyse cells as they pass one at a time through two laser beams, which then captures the light that emerges from each cell as it passes through. As different genes in the cell can also be 'tagged' with different colours, this technique is a rapid way of obtaining a large volume of information (several thousand cells can be analysed every second) about cell numbers, shape, size and how different genes are regulated. The inf ormation obtained will help understand how various genes are controlled in normal reproduction, how cells lose their control mechanisms for dividing, as in cancer, or even identify new disease markers or drug targets.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Epigenetic and Signal Transduction Interactions in Development and Stem Cell Differentiation.
Funder: Wellcome Trust

Abstract: During early mammalian development, the embryo undergoes an important transition where cells become specialised and are orientated to be the building blocks of the future body. How this process is controlled remains understood poorly but it is important to study because it will provide insight in to how distinct cell types are formed in the embryo. Scientists are trying to mimic these events in order to control specialisation of stem cells. By better understanding how this process occurs in the embryo, we may uncover new ways to turn stem cells into useful cell types, such as heart and liver, that we can use for cell-replacement therapies. I have chosen to study a protein called Ezh2, which regulates what genes are turned on and off, because we know that it has an essential role during this transition in mouse development. By studying mouse embryos at a very early stage in development, together with stem cells in culture, I will uncover how Ezh2 is involved in this process and also what are the signals that control Ezh2 itself. Understanding the molecular mechanisms of how cell specialization occurs may lead to improved control over stem cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Dissection of Celsr1/Flamingo function in vertebrate morphogenesis.
Funder: Wellcome Trust

Abstract: An important process in tissues, known as the planar cell polarity (PCP) pathway, is critical for embryo development. PCP aligns tissue structures, for example ensuring the correct organisation of mammalian skin hairs. It also coordinates the complex cell behaviour necessary to achieve the elaborate structure of other vertebrate organs. When this process goes wrong severe problems with neural tube closure, which gives rise to severe birth defects, and lung development occur. It is not fully unde rstood how components which facilitate PCP achieve their significant tasks. We believe that the specific location of one particular PCP protein, called Celsr1, within certain cells, is critical for the orientation of cell division or migration of those cells. Differences in the location of this protein within cells of different tissues are associated with altered cell behaviour, which in turn affects the overall structure of the organ that the cell is in. We want to demonstrate that the position of this protein within a cell influences its behaviour or that of neighbouring cells. We also want to identify how the location of the protein is altered in different cells. These studies will significantly advance understanding of severe birth defects and of how complex organs develop.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: The specialised apparatus for meiotic chromosome segregation in oocytes.
Funder: Wellcome Trust

Abstract: Genetic information must be copied and partitioned accurately to each divided cell and to each subsequent generation. This partitioning is mediated by sophisticated molecular machinery. Surprisingly, the partitioning is particularly inaccurate during the specialised cell divisions that produce eggs. In fact, errors in this process are a major cause of infertility, miscarriages and birth defects, such as Down syndrome. Oocyte division uses a similar, but distinct machinery from other division s. Despite its medical importance, we know little about this machinery. This proposed research aims to study this specialised machinery at the molecular level using the fruit fly. As fruit flies shares many basic genes and molecules with humans, the information gained can be applied to humans. The use of fruit flies allows us to obtain mutants with abnormal division machinery, and the analysis of these mutants will lead to better understanding of how the machinery is built and operated in oo cytes from flies to man.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Maturation of the meiotic spindle in oocytes
Funder: Wellcome Trust

Abstract: Chromosome segregation in human oocytes is surprisingly error prone. Indeed it is reported that about 20% of all eggs are aneuploid. This is a major cause of infertility, miscarriages and birth defects including Down syndrome. The machinery of chromosome segregation in oocytes differs from mitosis, including a lack of centrosomes in oocytes. Furthermore, oocytes undergo arrest with a bipolar spindle in meiotic metaphase to wait for fertilisation. The bipolar spindle may require further stabilisation during the arrest, but little is known about whether such a stabilisation mechanism exists and, if so, what is its molecular basis. Our laboratory has found that some microtubule regulators change their localisation during the metaphase arrest in Drosophila oocytes, including the kinesin-5 Klp61F. The PhD project aims to understand how and why the meiotic spindle change the organisation and dynamic during prolonged arrest in oocytes. Firstly, the change of spindle organisation and dynamics will be assessed by live imaging from nuclear envelope breakdown. Secondly, the mechanism and biological significance of


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Strengthening health system promotion of maternal and child health through medical travel.
Funder: Wellcome Trust

Abstract: This 12 month grant focuses on strengthening health system promotion of maternal and child health through medical travel. It concentrates on South Africa and the effect on resident population of patients traveling to South Africa for treatment from neighbouring countries. It is a collaboration between the University of Cape Town and the London School of Hygiene and Tropical Medicine. The main objective is to identify how to assess and influence the effect of medical travel on the health system and maternal and child health in South Africa. There are three linked specific objectives. 1) To understand how inbound medical travel affects the maternal and child health of the resident South African population. 2) To identify and analyse current agreements between South Africa and neighbouring countries which govern and affect patients traveling. 3) To establish and review what kind of indicators and data are available at national and sub-national level to monitor health systems impact of medical travel on MCH. Research employs quantitative and qualitative methods. To assess effects on resident South African MCH, it examines indicators and experiences of health workers, patients and other actors in areas where health facilities are seeing a large number of medical travellers coming in and compare these with areas and facilities who do not. These will be identified through initial key informant interviews. Interviews will be in five communities/facilities where large numbers of medical travellers are received and five where there are not. Quantitative work will evaluate usefulness of core indicators for MCH and health systems access which are publicly accessible. Research will include the analysis of agreements governing medical travel between South Africa and neighbouring countries to identify policy recommendations on how such governance arrangements can best support health systems' promotion of maternal and child health. Findings, including reflection on methods, will inform a larger comparative research proposal with researchers in India and Thailand.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Experiences of gestational trophoblastic disease: reconciling cancer, pregnancy and loss
Funder: Wellcome Trust

Abstract: What are the implications for health professionals and patients when cancer develops during pregnancy? To what extent might existing care practices become reconfigured within this context? This Fellowship will address these questions through novel research exploring a rare condition: Gestational Trophoblastic Disease (GTD). GTD only arises following conception, and can result in the development of (pre-)cancerous tissue in place of a viable foetus. Nevertheless, in many cases women experience symptoms of pregnancy and anticipations for future parenthood. GTD disrupts conceptual boundaries between cancer and pregnancy as corporeal phenomena, posing vital questions around the status of foetal and malignant entities, and definitions of pregnancy and loss. An exploration of this unique condition through the lens of medical sociology will enrich social scientific explorations of foetal personhood and pregnant embodiment. Further, whilst cancer is often studied sociologically, this research will prompt dialogue around cancer and pregnancy. This clash of life potential with life-threatening illness provides unique opportunities to explore how experiences of anticipated parenthood, loss, and cancer ‘survivorship’ co-exist. Key goals will be the interrogation of societal definitions of pregnancy/cancer as reproduced and reimagined through the phenomenon of GTD, exploration of women’s experiences, and the generation of relevant insight for clinical practice.

Lay abstract: Gestational trophoblastic disease (GTD) is a rare condition arising from pregnancy, causing abnormal cells to develop within the womb. In some cases this leads to a tumour. GTD can mean that though a woman may receive a positive test and experience pregnancy symptoms, she will not be carrying a baby. GTD poses questions about what it means to be pregnant, and challenges how we understand cancer. Experiences of GTD are poorly understood because it’s rare, but also because it can be difficult for women and their families to talk about the condition. I will conduct observations and interviews with women affected and professionals treating GTD. I will talk to women about loss, treatment and follow-up to better understand their needs, and consider how the way society perceives pregnancy and cancer might shape understandings of GTD and care. I will share my findings with charities and healthcare-staff to inform GTD support.

Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH;CANCER AND NEOPLASMS
Title: Sexual Health and Families Programme
Funder: Medical Research Council

Abstract: In the last two decades sexual health has been a major public health priority across the world, primarily because of rising sexually transmitted infections, HIV, and unwanted pregnancies. There are continuing inequalities in sexual health, with marginalised groups (i.e., men who have sex with men, particular ethnic minorities and socially excluded young people) being disproportionately affected. The aim of the programme is to further the prevention of sexual ill health by understanding the determinants of sexual risk and conducting formative (i.e. preliminary or developmental) research to inform future intervention development. These are essential steps in the development of future sexual ill health prevention interventions and evaluations and to the delivery of these in ‘real world’ situations. The objectives are to: • understand the social and behavioural determinants of sexual risk and ill health; • investigate alternative research methodologies and the role of new technologies in sexual ill health prevention; and • develop and evaluate innovate strategies to improve sexual health at the individual, community and structural levels. The programme has three themes: 1. HIV prevention with vulnerable populations in the UK (gay and bisexual men and sub-Saharan African communities): 30 years into the HIV epidemic, there remains no cure or vaccine and 34 million people worldwide are estimated to be infected. This theme builds on the Unit’s past research, specifically the Gay Men’s Sexual Health Survey, while investigating new areas of concern. There have been exciting, but challenging, developments in HIV prevention (e.g., the use of antiretroviral drugs for the prevention of sexual transmission of HIV). The acceptability of these interventions to populations at risk is relatively unknown and is a key area we are investigating. 2. Inequalities in sexual health: As with many health outcomes, sexual health is patterned by socioeconomic inequalities, with those from deprived areas often being those most at risk of negative outcomes, such as sexually transmitted infections and unwanted pregnancies. This theme aims to explore the broad, negative sexual health related experiences of those in the most deprived areas, including the role of masculinities within these, and to use this information to inform the development of future sexual health interventions to reduce inequalities. 3. Alternative research methodologies in sexual ill health prevention: Sexual health can be a sensitive topic and our research relies on people’s willingness to participate, and the continual growth of digital media for social interaction and intervention opportunities also suggest the time is right to consider alternatives to our existing surveys. This theme aims to investigate the acceptability of different research methods and examines how to make better use of existing data, such as those collected by sexual health clinics.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH;INFECTION
Title: Malawi Centre for Research in Epidemiology and Public Health: addressing public health research priorities through partnership.
Funder: Wellcome Trust

Abstract: Building on 30-years of research in Malawi, we will conduct population-based epidemiological studies with integrated laboratory and genomic analysis. Our aim is to generate policy-relevant evidence for the region. We will: 1. Determine the burden, the risk factors and the barriers to accessing care for major non-communicable diseases (NCDs) in rural and urban settings. 2. Design intervention studies to evaluate different strategies for controlling NCDs. 3. Understand patterns of transmi ssion and the factors associated with virulence of M.tuberculosis in Karonga in a setting of unusually well implemented routine tuberculosis control in order to contribute knowledge towards the goal of tuberculosis elimination. 4. Determine the long-term impacts of antiretroviral therapy on mortality, reproductive health and family welfare in the rural population and investigate changes in treatment strategies that will maximise population level benefits. 5. Evaluate the impact of Malawi's newly introduced HIV test-and-treat strategy for pregnant women on retention in care and on mother-to-child HIV transmission in real-life urban and rural African settings. 6. Develop Malawian research capacity in epidemiology, medical statistics and demography. 7. Strengthen links with the Malawi Ministry of Health and the College of Medicine and form collaborations with public health institutions in the region.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES);3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH;INFECTION
Title: Mechanisms of stress-induced brain sparing during development
Funder: Wellcome Trust

Abstract: Growth of the developing brain is protected over that of the body when fetal nutrients and/or oxygen are compromised during intrauterine growth restriction (IUGR). This "brain sparing" phenomenon is well documented but the underlying mechanisms are poorly understood. Furthermore, even though ‘brain sparing’ protects overall brain size, it is imperfect - leading to long-lasting deficits in some adult brain functions. In this project, I set out to identify fetal brain sparing mechanisms and how they are linked to changes in adult brain anatomy. Neural stem and progenitor cells (NSPCs) are essential for the growth of the central nervous system in flies and mammals. Using a Drosophila model, the Gould lab showed that constitutive and starvation-resistant PI3K signalling in NSPCs is an essential part of the brain sparing mechanism. I now want to exploit a mouse IUGR model, established recently in the Gould lab, to pinpoint how NSPCs and their progeny change at the cellular and molecular level during mammalian brain sparing. To achieve this, I will examine PI3K and other candidate signalling pathways as well as using transcriptomics and metabolomics approaches. I will also follow up putative mechanisms for human brain sparing using in vitro models such as cerebral organoids.

Lay abstract: Intrauterine growth restriction (IUGR) occurs in about 5% of pregnancies. IUGR babies are underweight but often have a normal brain size. This ‘sparing’ of brain size helps safeguard cognitive development but it is not always 100% efficient, sometimes leading to behavioural impairments. This project aims to identify the mechanisms underlying the poorly understood process of brain sparing. To achieve this, I will assess how various types of stem cells and neurons in the developing mouse brain are altered by IUGR. I will also use state-of-the-art methods to identify genes and metabolites that change during IUGR. The clinical potential of my findings will then be tested using human brain cells grown in a Petri dish. A better understanding of brain sparing is a much needed first step towards treating IUGR babies and it may also shed light on the fetal origins of some behavioural disorders.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH;NEUROLOGICAL