NIHRDataInsights/HRCSData huggingface dataset:
Title: Actin-dependent mechanisms of chromosome segregation in mammalian eggs
Funder: Wellcome Trust

Abstract: Chromosome segregation is conserved throughout eukaryotes. In oocytes, a specialised form of cell division called meiosis segregates the chromosomes. Chromosome segregation errors are remarkably high in oocytes and give rise to aneuploidy, which generally causes embryo deaths and accounts for nearly 35% of miscarriages. When compatible with life, aneuploidy in embryos frequently leads to genetic disorders such as Down’s syndrome, which affects about 1 in 1,100 live births worldwide. The rate of chromosome mis-segregation increases even further with advancing maternal age. My research aims to uncover the mechanisms that safeguard accurate chromosome segregation in oocytes to enable successful fertilisation and healthy embryogenesis. I recently showed that actin filaments promote accurate chromosome segregation in mammalian eggs by bundling microtubules into functional kinetochore-fibres (Mogessie and Schuh, Science, 2017). In the present proposal, I aim to address two fundamental questions in the field. Firstly, I will investigate precisely how spindle actin is assembled and the mechanisms whereby it stabilises k-fibres in mammalian oocytes. Secondly, I will examine a novel contribution of actin to pathways that tightly hold oocyte chromosomes together before segregation. This programme of work will advance our understanding of the safety mechanisms that prevent aneuploidy in mammalian eggs.

Lay abstract: Every human life starts when an egg is fertilised by a sperm. For poorly understood reasons, eggs frequently contain an incorrect number of chromosomes. This chromosomal abnormality is a leading cause of embryo deaths in humans – it accounts for nearly 35% of miscarriages. Chromosomal abnormality in embryos also leads to genetic disorders such as Down’s syndrome, which affects about 1 in 1,000 live births worldwide. My research is aimed at understanding which cellular processes protect eggs from having an incorrect number of chromosomes before fertilisation. In this regard, I recently discovered an unexpected function of a protein called actin in preventing chromosomal abnormality in eggs. I now wish to investigate in depth how this protein performs this critical task. In the future, knowledge obtained from my research programme could be exploited to improve the outcomes of fertility treatments as well as prevent pregnancy loss.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Leveraging genetic variation to understand chromosome pairing, meiosis and the evolution of human disease risk
Funder: Wellcome Trust

Abstract: We have the following specific aims: 1. To discover how normal pairing (synapsis) of homologous chromosomes during mammalian meiosis is genetically controlled in fertile and infertile individuals, and how synapsis first initiates, and then spreads. To do this, we will leverage naturally occurring genetic variation. Errors in recombination, and in synapsis, result in aneuploidy events, and chromosomal rearrangements due to NAHR, that cause many human disorders including infertility, pregnancy loss, cancer, and developmental syndromes. 2. To quantify how the chromatin accessibility and gene expression environments change during meiosis, using single-cell ATAC and RNA sequencing, and learn how proteins binding to DNA coordinate the onset and progression of meiosis, recombination, synapsis and impact fertility, and are impacted by genetic variation and chance. 3. To build from our existing approaches to understand population structure, in order to infer trees revealing the historical relationships relating hundreds of thousands of modern and ancient individuals, in humans and other recombining species. We will use these trees, which change along the genome due to recombination, to investigate how variation impacting complex diseases and other traits has arisen and been acted upon by natural selection, how selection changes through time, and how the rate of evolution itself evolves through time.

Lay abstract: In healthy reproduction, meiosis - producing sperm and eggs - requires our paternal and maternal chromosomes to pair (synapse) and swap DNA (recombine). Errors in this process are responsible for a wide range of human diseases. It has been unknown how chromosomes pair, but recent work in our lab has helped to show how a particular gene called Prdm9 aids this process. Building on this, we will perform experiments to understand how synapsis succeeds/fails depending on how Prdm9 binds. We will examine single cells, to explore how binding of many proteins, including Prdm9, co-ordinates meiosis. Recombination means the evolutionary trees relating individuals vary along the genome. Extending previous work on human migrations, we will develop new approaches to identify these hidden trees for hundreds of thousands of individuals across different species - to define whether mutations affecting disease risk are mainly young or ancient, and how this reflects natural selection.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: X-gene functions in spermatogonia, and their role in idiopathic and sex chromosome aneuploidy associated infertility.
Funder: Wellcome Trust

Abstract: The sex chromosomes underscore basic differences between males and females, and the X and Y chromosomes have specialized functions in the gonad and germ cells. Sex chromosome aneuploidies, i.e. Klinefelter (XXY), Turner (XO) and double-Y (XYY) syndromes), form the largest group of chromosomal abnormalities and are associated with infertility. While recent studies have defined the mechanisms for germ cell loss in XO and XYY mice, Klinefelter syndrome (KS) infertility remains poorly understood. KS males experience an early spermatogonial block and germ cell loss initiates in utero. The early loss of gonadal function has significant long-term consequences. Gametogenesis in males occurs throughout their lifespan and relies on germline (spermatogonial) stem cells (SSCs), differing with females. Recent work from our group has identified the concerted activity of gene networks in driving spermatogenesis, and unique regulation of X-linked genes during this process. We observe that a number of X-genes express specifically in SSCs. However, regulation of SSCs self-renewal vs. differentiation dynamics, and the functional importance of X-linked genes in this process, remain poorly understood. We aim to understand physiological gene regulatory networks functional in SSCs using a combination of single-cell methods, to explain how perturbation in X-gene dosage in SSCs may cause infertility.

Lay abstract: In mammals, females have two X chromosomes (XX) while males have an X and Y (XY). The presence of the Y determines male development. However, a mismatch of sex chromosome complement with phenotypic sex, sex chromosome aneuploidy causes infertility i.e. Klinefelter syndrome (‘KS’; XXY), Turner syndrome (XO) and, Double-Y syndromes (XYY). These are the most common group of human aneuploidies. Sperm production in males relies on spermatogonial stem cells (SSCs) and occurs throughout their lifetime. The ability of SSCs to self-renew, and also differentiate to sperm is poorly understood. KS infertility in particular remains poorly characterized, and men with KS experience a block in SSCs development early in life. This loss of gonadal function has lifelong health implications. We have recently described unique X-gene activity during normal spermatogenesis, and specific expression in SSCs. We now wish to understand how perturbation of X-gene dosage in SSCs may cause infertility.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Epigenetic inheritance: the influence of variable silencing of the repeat genome.
Funder: Wellcome Trust

Abstract: Evidence from epidemiological studies and experiments in animal models suggests that effects of environment and lifestyle can be transmitted across generations via non-genetic mechanisms. Such mechanisms are challenging to unravel in mouse and man. In mammals, non-genetic inheritance is best exemplified by the Agouti viable yellow (Avy) mouse where phenotypic differences in genetically identical animals are caused by insertion of a retrotransposon - an endogenous retrovirus (ERV) that provides a cryptic promoter driving ectopic expression of agouti. This ERV is variably DNA methylated in different individuals causing inter-individual variation in coat colour – a non-genetic influence on phenotype. Remarkably, a memory of parental coat colour is transmitted to subsequent generations. Variable expressivity can be modulated by in utero environmental exposures. ERVs represent ~12% of the mouse genome. Inspired by Avy, we propose a research programme, supported by preliminary data, to address the following questions: Aim 1 – To what extent do mammalian ERVs exhibit variable epigenetic silencing and what is the mechanism? Aim 2 – Is this transmitted as non-genetic memory across generations? Aim 3 – Are they sensors of environmental compromise? Aim 4 – Are there implications for phenotype? Aim 5 – Does a related phenomenon occur in humans?

Lay abstract: Only a small portion of our DNA contains genes. In fact, more than half of our DNA is repeated multiple times over; and some have thought this to be ‘junk’ DNA with no function. We have identified some unusual repetitive elements that behave differently in different individuals and which have the potential to influence our genes by a mechanism that we do not understand. We propose to determine whether these special repeat elements play a role in regulating our DNA, whether they can act as biosensors for environmental compromise (like a canary in a coal mine), whether the inter-individual differences they induce can contribute to why one person might be different to another, and whether their properties can be transmitted from one generation to the next. Understanding the function and regulation of these special repeat elements will provide new and important insights into the function and regulation of repetitive DNA.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Genetic control of cell fate decisions in the developing mouse embryo
Funder: Wellcome Trust

Abstract: Understanding the logic of transcriptional networks that control temporally and spatially correct patterns of gene expression required to establish cell identity is the central challenge in developmental biology. My research has provided fundamental insights into regulatory events during axis patterning and cell lineage specification in the developing mouse embryo. A consistent theme is that a handful of so-termed “master regulators” govern the transcriptional networks that coordinately regulate cell type specific target gene expression in diverse tissue contexts. The proposed experiments are interconnected by the cross-cutting question: how do the master transcription factors Eomes, a T-box family member and the zinc finger transcriptional repressor Blimp1/Prdm1 control cell fate decisions? The first goal of my proposal is to define the underlying transcriptional networks and time window(s) when Eomes-dependent progenitors of the node, midline and DE become lineage restricted during gastrulation. We also aim to characterize Eomes requirements during specification of the hemogenic endothelium giving rise to the first wave of primitive blood. Secondly we will further characterize Blimp1 functional contributions, define upstream signalling pathways governing Blimp1 tissue-specific expression and identify its key downstream transcriptional targets in trophoblast sub-populations and decidual cells at the maternal-fetal interface.

Lay abstract: Regulatory cues controlling growth and development of the early embryo within the maternal uterine environment remain poorly understood. The specialized extra-embryonic tissues giving rise to the placenta, are set aside at the very earliest stages after the embryo implants into the uterus. We are studying how key transcription factors expressed within these cell populations activate expression of downstream genes that guide correct morphogenesis of the early placenta. In parallel we also want to understand how cell fate decisions within the embryo proper establish the body axis and regulate formation of specific cell types and tissues as the embryo gains complexity. My goal is to provide fundamental knowledge about how mutations in these pathways can cause debilitating conditions affecting pregnancy such as pre-eclampsia as well as birth defects.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Make childbirth and surgery safer by preventing accidentally retained surgical items
Funder: Innovate UK

Abstract: A major risk of childbirth/surgery is the possibility that foreign objects may be accidentally left inside. Around 1 in 12 people require surgery or go through childbirth each year in the UK. Surgery is the mainstay of treatment in many health conditions such as cancer and chronic diseases and childbirth brings joy. Every year in the UK, there are around 12 million operations and 750,000 maternity events.Surgical swabs(also known as sponges) are the most common 'retained foreign object', which is also the most common procedural 'never event'. Other retained items such as needles and instruments are rare. There is good data that these events are under-reported globally due to litigation and their indefensible nature. First reported in 1884, this should simply not continue to happen in this day and age. Patients are not made aware of this during the consenting process as it is considered preventable. Retained swabs can cause extreme harm such as reoperations, severe infections, damage to organs (permanent damage in 16%, death in 5%). They can also cause cancer due to chronic irritation. The costs due to this problem to NHS amount to around £2 billion annually. Data shows that 1 in 11 procedures have counting errors and as high as 1 in 500 procedures can have a swab left inside. This is more common in complex unpredictable areas with distractions and interruptions such as childbirth and difficult operations. There is a need for a low-cost medical device to create a robust system to prevent accidental retention. We have developed a docking device that allows users to monitor swabs before, during, and after a procedure, including a method to measure blood loss. This simple, cost-e?ective solution with a UK IPO 'granted' patent is designed to make it impossible to leave a swab behind, vastly improving safety and efficiency. Eureka's vision is to make childbirth and surgery safer. When tested in real-life like conditions in University Hospitals, Birmingham the device system proved to be to be significantly more reliable and accurate than counting (current NHS practice).This will lower costs and reduce the need for a second checker, a practice that is prone to human error and confirmation bias. This grant will allow Eureka to collaborate with KIMAL, an established device manufacturer and Royal Wolverhampton NHS Trust, a large teaching hospital towards refinement of design towards manufacture, product development with patient and public involvement as well as real-world testing.


Research activity codes: 5.4 SURGERY
Health categories: GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: ‘Femtech’ and the process of becoming a 'better' woman: how should law and regulation respond to health technologies targeted at improving women’s health and well-being?
Funder: The British Academy

Abstract: This research is motivated by the concern that law and regulation fail to adequately protect women as users of ‘Femtech’. Femtech is a relatively new personal health technology (PHT) aimed at women, however it has been met with little legal or ethical scrutiny. I suggest that - if women are to continue to be marketed technologies which aim at improving their bodies and biological processes (e.g. fertility and sexual pleasure) - then we need a framework that adequately reflects their needs and priorities as Femtech's users. How might we do this? In answer, I will investigate and test a novel framework for regulation that accounts for biological processes and technological change. By exploring Femtech in this way, my research will generate a bedrock to (i) specifically influence Femtech policy and development, and (ii) inform broader contemporary debate about the law and ethics of PHTs, as these directly impact women's health.


Research activity codes: 5.3 MEDICAL DEVICES;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Safe and efficient training in epidural placement: commercialising a back manikin with realistic tissues
Funder: Division for Social Care and Health Research (Wales)

Abstract: Epidural injection provides pain relief for surgery and childbirth. Epidural insertion relies on anatomical knowledge and the feel of a needle as it passes through the back. It is a blind technique taught to doctors and patients. A serous complication occurs if the needle passes a few mm too far, giving a dural tap, causing a debilitating headache lasting up to a week, lengtheneing hospital stay and causing pain and distress for the patient. This often necessiatates a major treatment called a ‘blood patch’. Epidural simulation training models exist, but are either expensive high fidelity, or simple plastic and rubber models. However, even the highest fidelity models lack the accuracy of the feel of real skin and tissues. T his realism is essential for the correct feel as a needle passes from the skin towards the epidural space. IN partnership with MBI (Wales), Cardiff University have developed the early stages of an epidural training model, with realistic tissues. With each iteration, realism has been assessed by Consultant Anaesthetists. Feedback and subsequent modification of tissues has been undertaken. The current stage of the project involves assembling all five layers of tissue with a model including the spine, producing a basic prototype. This will be completed by September 2012. The next stage is to develop the prototype to a fully commercial model which requires the up-scaling of production of artificial tissues. Tissues must behave in a similar manner to our one-off prototype, when produced on a larger commercial scale. This commercial version will be tested by the NHS Consultant Anaesthetists in five centres throughout the UK. In addition, the removable parts will be tested to destruction assessing durability. Ten completed models will be produced for market testing. An economic assessment of the simulator will be made, and a business plan produced for final commercialisation.


Research activity codes: 6.3 MEDICAL DEVICES
Health categories: GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Programming the paternal nucleus for embryonic development
Funder: Medical Research Council

Abstract: This project investigates the nature of paternal nucleus programming that underlies successful embryonic development. We have shown that mature sperm is 5 times better than spermatids in supporting Xenopus embryo development, illustrating the programming process associated with sperm maturation. We will use this unique system, where these two haploid cells exhibit different developmental potential, to reveal the nature of sperm programming. The deposition of epigenetic marks on paternal chromatin during sperm maturation will be analysed by ChIP-Seq on sperm and spermatid. Subsequently, we will compare the presence of these marks with the differential embryonic gene expression observed in sperm- and spermatid-derived embryos. Next, we will test what fraction of epigenetic marks present in the paternal nucleus is carried over to and propagated by the embryo. Ultimately, we will functionally test the role of gene marking in the sperm on the future embryonic gene expression and we will investigate what are the egg factors responsible for the recognition and maintenance of the paternally-inherited marks. Our results will provide functional evidence for paternal programming, and will also allow the generation of epigenetic maps of sperm/spermatids and corresponding embryos in Xenopus. We believe that the final outcome of our research - understanding the way the paternal nucleus is programmed, has the potential to improve several aspects of human health. First, knowing the epigenome of a cell that is efficiently reprogrammed by the egg will help the design of strategies altering the epigenome of a somatic cell in order to increase the efficiency of nuclear reprogramming. This would improve derivation of patient-specific cells for cell replacement therapies and drug screening. Second, our work will shed light on a recent area of research - the paternal inheritance of epigenetic features across generations, which is likely to influence the public health policy.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: PARP1 is essential to maintain the epigenetic hallmarks of imprinting control regions
Funder: Medical Research Council

Abstract: The focus of this proposal is to elucidate the molecular mechanism of Parp1 function in epigenetic gene regulation and imprinting control, and its physiological significance. Using ES cells as a powerful tool, we will assess the progression of epigenetic reprogramming at ICRs upon Parp1 deletion and the factors involved. In a series of intercalated experiments, we will elucidate whether Parp1 is an integral component of the ICR chromatin protein complex, or whether it is the conferred post-translational modification of ICR complex members that is critical for imprint maintenance. We will also test whether the few genomic regions that are hypomethylated in Parp1-/- ES cells in addition to known ICRs demarcate yet unknown imprinting control regions that may identify novel imprinted genes. In parallel, the impact of Parp1 deficiency on imprinted gene regulation in vivo will be scrutinized. We will assess existing knockout models (of mild severity level) of Parp1, the highly related Parp2, and double mutants. The analyses will include to determine, in candidate and genome-wide approaches, the effect on DNA methylation, histone modifications (H3K9me3) and imprinted gene expression during gestation and postnatally. This will be complemented by a detailed analysis of developmental progression, postnatal and adult health, including assessment of the putative link to obesity that has been previously noted. Germ line mutants will serve to determine whether Parp1 (& Parp2) play a role in the establishment as well as the maintenance of gametic imprints, in epigenome surveillance and protection from transgenerational inheritance of epimutations. This research is pertinent to our understanding of imprinting disorders and how they might arise for example in infertility treatments. Thereby, it will identify novel avenues for potential therapeutic intervention. It also provides direct links between epigenome (dys)regulation and cancer biology, in which Parp1 is a major player.


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