NIHRDataInsights/HRCSData huggingface dataset:
Title: Isoform-specific Ras function during development.
Funder: Wellcome Trust

Abstract: Ras proto-oncogenes are key signalling intermediates controlling cell proliferation, differentiation and survival. Whilst most attention has focussed on the role of aberrant Ras signalling in cancer, normal Ras function is critical for embryonic development. Intriguingly, this process appears to be differentially dependent on individual Ras isoforms for reasons that remain unclear. Our study will characterise: 1. Tissue-specific gene expression and protein abundance patterns of Ras isoforms during early mouse development. 2. The contribution of Ras isoform-specific signalling networks to early embryonic development. 3. What signalling networks are engaged by Ras mutations associated with developmental disorders compared to those engaged by classical oncogenic mutations. This will allow us to ask whether and how different Ras isoforms contribute to the development of different tissue lineages and lead us to mechanistic insights into the specific pathways regulated by Ras isoforms to promote differentiation versus stemness. In later work we will develop isogenic cell models containing HRAS or KRAS mutations associated with developmental disorders. These mutations are believed to be less potent than oncogenic mutations; we will investigate whether this is the case and how this translates into differential coupling to Ras effector pathways.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: The relationship of the menopausal transition to healthy aging and chronic disease risk.
Funder: Wellcome Trust

Abstract: Women s reproductive health for example her age at first menstrual period, how many pregnancies she has and changes that occur during her pregnancies, the pattern of her menstrual cycles throughout her life and her age at menopause is associated with changes in other body systems, including bone and muscle health, cognitive function, heart health and mental health. How these associations occur and whether changing aspects of women s reproductive health will improve women s overall health is unknown. We have a number of grants that fund important work in this area, looking at the relationship of pregnancy and menstrual cycles with later health outcomes. We now want to consolidate this work and add to it by obtaining a Wellcome Trust programme. The new research in this programme will focus no determining how the transition from pre-menopausal to post-menopausal affects physical and cognitive capability, mental health and well-being, bone health and heart health. We will use data from a large cohort of women on whom we have collected a large amount of data (including blood samples and genetic data) since an index pregnancy 18 years ago. This research will help us to understand how to ensure women age healthily.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: The role of reproductive hormone metabolites in gestational alterations in lipid and bile metabolism
Funder: Wellcome Trust

Abstract: Pregnancy is a time of marked changes in a woman s metabolism. This project focuses on the causes of altered levels of bile acids and cholesterol in pregnancy. This is of relevance to diseases of the expectant mother and her baby during pregnancy and in later life. The cause of high levels of bile acids and cholesterol in pregnant women is not known. It is known that molecules made from progesterone (P4S) rise 100-fold in normal pregnancy and even further in a liver disease of pregnancy called i ntrahepatic cholestasis of pregnancy (ICP). ICP affects 1 in 200 women in the UK and can be complicated by preterm birth and stillbirth. We have discovered that P4S influence the way the liver controls blood levels of bile acids and cholesterol. This program of research will establish the precise mechanisms underlying P4S-induced changes in metabolism, including interactions between P4S and the main bile acid receptor protein. It will also investigate a drug that may improve diseases of bile aci d and cholesterol metabolism in pregnant women. We will also evaluate the role of P4S in other changes in the way a pregnant woman s body functions, e.g. the way the blood vessels accommodate changes in pregnancy.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Nikon A1R confocal system for the imaging of live embryos.
Funder: Wellcome Trust

Abstract: During embryonic development, cells act in an organized and coordinated manner to ensure the correct formation and function of tissues and organs. Embryonic development is controlled at two levels; cells become specialised (cell fate specification) and they acquire the ability to move and establish connections with other cells. Cells achieve the latter by altering their internal skeleton (cytoskeletal regulation). Furthermore, the mechanisms used to form the embryo are reactivated when adult tis sues are wounded in order to repair the damage. These processes are complex and dynamic and involve rapid changes in the location and activity of regulatory molecules. Therefore, we can only understand embryonic development and wound healing if we observe them in whole live organisms Recent technical developments in microscopy make it possible to observe the behaviour of cells and molecules in live embryos with high image quality. This grant will provide us with funds to buy a state-of-the- art microscope designed specifically for live imaging. This will enhance the scope of our research, allowing us to make faster progress on many fronts, giving us the ability to directly test hypotheses that currently can only be inferred and ensuring that our results are directly relevant in living organisms


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Regulation of gonadotroph function by c-type natriuretic peptide (CNP) in humans, mice and zebrafish
Funder: Wellcome Trust

Abstract: At least 15% of the UK population have trouble conceiving. Although many therapies are used to treat infertility and other reproductive disorders, understanding control of reproduction remains poor. An important reproductive hormone, Gonadotrophin releasing hormone (GnRH), is released from the hypothalamus in pulses to control gonadotroph cells in the pituitary gland. Depending on the frequency of these GnRH pulses, gonadotroph cells will release hormones that control fertility. Our previous wor k has shown another pituitary hormone, called C-type natriuretic peptide (CNP), is made in large amounts in gonadotroph cells, and can stimulate the process by which reproductive hormones are made. We have also shown that CNP could be important in the normal development of gonadotroph cells in humans, mice and fish, and in human pituitary tumours. However, the mechanisms by which these effects occur are not known. We propose to examine how CNP affects GnRH action and gonadotroph function in hum ans and mice. We will use the versatile Zebrafish to examine the consequence of having too much or too little CNP, on gonadotroph function. These experiments would yield important information to help treat fertility disorders in humans, to treat pituitary tumours, or even design new contraceptive therapies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Immunogenetics of KIR and HLA-C variants in Ugandan women with disorders of pregnancy.
Funder: Wellcome Trust

Abstract: How does the mother's immune system respond to the presence of a different individual - her fetus - and its need to access maternal blood for nutrition? Special immune cells (Natural Killer cells, NK) populate the pregnant uterus of women and of laboratory mice and through receptors (NKR) they sense molecules called MHC on the fetal cells that bud off the placenta (trophoblast cells). The mother s NKR and the baby s MHC are both genetically variable meaning they will differ in each pregnancy. W e will explore how variability of these immune system genes affects reproductive success by comparing NKR and MHC in normal pregnancy to those with pregnancy disorders such as pre-eclampsia or recurrent miscarriage. These findings will be correlated with direct measurements of the uterine blood flow to the fetus and placenta. We will also mimic the good or bad human NKR/MHC combinations in mice so that we can directly examine the uterine blood vessels and the growth of the placenta and fet us. These studies will for the first time investigate exactly how maternal immune cells and fetal placental cells co-operate for


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Functional immunogenetics of fetal and placental development: the regulation of placentation by NK cell receptors and their trophoblast ligands
Funder: Wellcome Trust

Abstract: How does the mother's immune system respond to the presence of a different individual - her fetus - and its need to access maternal blood for nutrition? Special immune cells (Natural Killer cells, NK) populate the pregnant uterus of women and of laboratory mice and through receptors (NKR) they sense molecules called MHC on the fetal cells that bud off the placenta (trophoblast cells). The mother s NKR and the baby s MHC are both genetically variable meaning they will differ in each pregnancy. W e will explore how variability of these immune system genes affects reproductive success by comparing NKR and MHC in normal pregnancy to those with pregnancy disorders such as pre-eclampsia or recurrent miscarriage. These findings will be correlated with direct measurements of the uterine blood flow to the fetus and placenta. We will also mimic the good or bad human NKR/MHC combinations in mice so that we can directly examine the uterine blood vessels and the growth of the placenta and fet us. These studies will for the first time investigate exactly how maternal immune cells and fetal placental cells co-operate for reproductive success. The results of our experiments should help understand and prevent common and distressing disorders of pregnancy.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Taurine transport proteins in the placenta: novel targets for correcting trophoblast cell turnover in pre-eclampsia?
Funder: Wellcome Trust

Abstract: 1 in 15 mothers suffer from a serious illness during pregnancy called pre-eclampsia (PE) and for reasons unknown, obese women are more likely to get PE. As obesity is becoming more common, cases of PE are likely to increase and currently there is no treatment. Cells which make up the maternal-facing part of the placenta (the organ which connects a mother to her baby) behave abnormally in PE compared to healthy pregnancy and scientists believe this leads to the illness. Factors have been identifi ed that affect the behaviour of placental cells and their ability to take in nutrients known as amino acids. Taurine is an amino acid that can itself control cell behaviour. We therefore predict that factors present in mothers who are obese or have PE affect the amount of taurine found in placental cells and it is this that causes their behaviour to change. We will perform experiments to find out if our theory is correct and investigate how this situation arises. We hope to also identify ways of correcting abnormal cell behaviour. This work will help develop future treatments for PE which would reduce death and health problems in mothers and their babies caused by this illness.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Pregnancy changes and future health of mother and offspring.
Funder: Wellcome Trust

Abstract: This sabbatical award will allow a group of scientists to start working together so that they can find out important things about how changes that occur during pregnancy and soon afterwards can identify mothers and their children who might be at risk of later health problems We will work together to examine whether it is possible to use routine data collected in antenatal clinics in different countries (initially UK, US and Australia, but we hope eventually to broaden the collaboration to other countries, including poorer countries) to identify which women and their children are more likely to become obese and go on to have diabetes and heart disease later in life. We will also examine whether it is possible to use information collected at the time of antenatal clinics and just after the birth of the child to identify children who might have developmental problems or problems doing well at school. Lastly, we will work out why pregnancy changes are related to later health and well-bein g in the mother and child so that it is possible to develop interventions that make sure all pregnant women and their babies get the best chances of good health.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Gender inequalities in early life health outcomes: are they important, and can they be modified?.
Funder: Wellcome Trust

Abstract: Male infants are more likely than female to be born early and to die as babies. There is evidence that they are also at greater risk of complications in pregnancy. The extent of this male disadvantage is still unclear, and it is not known whether worrying local trends, such as the increasing proportion of stillborn boys in Japan, are found elsewhere. The first part of our study will discover how much more at risk baby boys are than girls. It is not yet known whether the male disadvant age is purely driven by the genetic differences between boys and girls, or whether the environment experienced by the developing infant in the womb might also be important. Research in animals suggests that the mother s environment might affect the way in which genes are activated during early life. Our work will find out whether environmental factors known to affect health in pregnancy, such as smoking and social class, are worse for male than female babies. If they are, then early interven tions may be effective in improving the health of males.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Making sense of the ethics of gestational time in the abortion clinic: A comparative analysis of clinical and lay understandings.
Funder: Wellcome Trust

Abstract: The proposed research will explore how the moral significance of the gestational timing of routine abortion provision becomes defined by health professionals, and by women with unwanted pregnancies. Building on my doctoral work, which revealed the ethical frameworks through which individual health professionals privately approach this issue, it will investigate how the moral significance of gestational time becomes defined in public professional spaces (for example, through training and in peer- reviewed literature). Additionally, it will explore how the meaning of the timing of an abortion is conceptualized by British women with unwanted pregnancies, as well as how their experiences of this issue are/are not shaped by their encounters with health professionals. In parallel with this analysis, I will investigate the conceptual frameworks through which feminist bioethical and philosophical work has theorised the morality of gestational time and abortion. The overarching aim of the resear ch is to explore, with abortion providers, potential routes towards improving patients and health professionals experiences of the management of gestational time in abortion provision, and thus, the delivery of an important aspect of women s reproductive healthcare.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: A proteomic and cell biological approach to understand the molecular mechanisms of meiotic chromosome segregation.
Funder: Wellcome Trust

Abstract: Meiosis is a special type of cell division that is necessary for sexual reproduction. In animals, meiosis produces sperm and egg cells, while in other organisms, such as fungi, it generates spores. Meiosis begins with one diploid cell (the mother cell) containing two copies of each chromosome, and produces four haploid cells (daughter cells) containing one copy of each chromosome. My aim is to understand in molecular detail how chromosomes are segregated during meiosis in a way that daughter cel ls with half the number of chromosomes are produced. When errors are made during this process, sperm or egg cells with too many or too few chromosomes are produced that can lead to infertility and birth defects such as Downs syndrome. This is why understanding meiosis is important. In particular, I will study the role played in this process by kinetochores, the structures that during cell division connect chromosomes to the filaments that pull them to daughter cells. I will conduct my studies in fission yeast, a single-celled non-pathogenic yeast whose simplicity and extensive similarity of basic cellular features to humans make it an ideally placed model organism for such studies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Transacting Reproductive Materials: a South Asian perspective on ethical, legal and social aspects of new reproductive technologies.
Funder: Wellcome Trust

Abstract: Despite the increase in the use of New Reproductive Technologies in Sri Lanka,there is a significant gap in knowledge about ethical issues and concerns in relation to the reproductive material transaction practices and guidelines that the practitioners adhere to. Therefore, this project aims to study the views of different stakeholders involved in reproductive tissue transactions in Sri Lanka in order to develop policies appropriate to local needs.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: The role of cervical innate immunity in preterm birth.
Funder: Wellcome Trust

Abstract: The ultimate aim of this research is to reduce the number women delivering prematurely. The study has two aspects that are of particular clinical relevance: (1) it seems likely that early identification of women who are at risk of bacteria triggered PTB will be essential to intervening in a timely fashion ? phenotyping maternal antimicrobial defences at an early gestation offers a logical way to do this; (2) the idea of therapeutically augmenting cervical antimicrobial activity using vector mediated gene delivery to cervical epithelium is a highly novel approach that has the potential to prevent ascending bacterial colonization of the placenta and membranes. As such, the project is poised at the interface of clinical and basic science and may make a significant contribution to reducing the risk of preterm birth and subsequently both neonatal morbidity and mortality, and the serious long term disability associated with prematurity.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Investigating Reproductive Ethics-in-Context: The Indian Experience.
Funder: Wellcome Trust

Abstract: RESEARCH QUESTION ABSTRACT ONLY How and in what ways do cultural expectations, conventional practices and beliefs shape motivations to access ART services amongst the rural and urban poor of India; and the ways in which clinical ART services are then marketed and delivered to such constituencies? To what extent do the existing National Guidelines for Accreditation, Supervision & Regulation of ART Clinics in India and the Draft ART Bill take account of these cultural specificities and the ethical issues to which they give rise and how might they be profitably revised to more effectively address them in strengthening ethical oversight of ART provision?


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Future Families: The social and psychological outcomes of emerging assisted reproductive technologies for individuals, families and society.
Funder: Wellcome Trust

Abstract: Advances in assisted reproductive technologies in combination with recent legislative changes are giving rise to new family forms that would not otherwise have existed such as gay fathers with children born through surrogacy and egg donation; single mothers by choice who conceive their children by donor insemination and intentionally parent alone; and donor siblings who are conceived using the same donor but raised in different families. Moreover, a growing number of families are being created t hrough egg sharing, egg freezing and intra-family donation. The aim of the reseach is to examine the impact of advances in assisted reproduction as they emerge in order to address the ethical issues that they raise and inform the development of policy and practice. The overarching question to be addressed is What are the social and psychological outcomes of of emerging assisted reproductive technologies for individuals, families and society?


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: The Donation and Transfer of Human Reproductive Materials.
Funder: Wellcome Trust

Abstract: Our ability to transfer reproductive materials, both to facilitate reproduction, and to underpin biomedical research, has grown dramatically in recent years. A coherent, comprehensive and philosophically defensible ethical framework with which to think about the donation and transfer of human reproductive materials is of the highest importance. This programme aims to develop and to provide rigorous arguments for such a framework, and to examine its implications for clinical practice, law, publ ic policy, and regulation. Such a framework will be capable of: (a) providing clinicians, policymakers, health professionals and scientists with greater clarity and with a more precise set of arguments, concepts, and terms; (b) informing and improving policy and regulation in the UK (and beyond); and (c) increasing public confidence in, and understanding of, these areas of research and practice. 'Human reproductive materials' is understood broadly here to include not only central cases (e .g. human embryos, ova, and sperm) but also artificial gametes, human reproductive tissue (e.g. ovarian tissue grafts or uterine transplantation), and mitochondrial transfer. Donation and transfer is understood similarly broadly and includes 'rewarded' as well as altruistic transfer, and the use of materials for research and clinical practice. This application builds on the applicants' already extensive research on the ethical and legal issues raised by assisted human reproduction; it provid es the Wellcome Trust with a rare opportunity to facilitate the coming together of two leading scholars in bioethics and medical law, in order to undertake a sustained and potentially ground-breaking programme of work.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH