NIHRDataInsights/HRCSData huggingface dataset:
Title: Exploring the genetic determinants of the portability of GWAS associations and polygenic risk score performance across populations
Funder: Wellcome Trust

Abstract: Over the last 10-15 years, large datasets containing genetic, physical and medical information for thousands of people (such as the UK Biobank) have allowed researchers to detect many genetic mutations that increase disease risk or explain variation in other physical traits.An important limitation of most of the studies conducted so far is that they mainly use data from people of European ancestry. This is significant, because there is increasing evidence that genetic differences between populations limit the validity and applicability of findings from European samples in other populations.We propose to address one aspect of this problem by exploring genetic variation that affects the accuracy of a set of relevant mutations in predicting a physical trait or disease within a single population. This is an important first step in understanding the causes of the poor portability of findings across populations.We expect that our work will identify relevant new genetic mutations, or interactions between them, which impact particular traits and diseases (as well as corroborate previous findings) and that this information will then improve our ability to understand the causes of, and predict, disease risk in understudied populations.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Liquid-phase Transmission Electron microscopy of RNA polymerase dynamics
Funder: Wellcome Trust

Abstract: Proteins control most cellular functions, made possible by their unique and diverse range of 3D structures and the dynamics within them. Methods to determine protein structure have revolutionised the understanding of cell function and dysfunction on the molecular level as well as drug design, however, these methods generally require static molecules. One rapidly developing method to probe protein structure uses transmission electron microscopy to take highly magnified images of cryogenically frozen proteins which can be computationally combined into a 3D model, however, freezing the sample prevents any real-time dynamics. We aim to optimise this method with new liquid-phase transmission electron microscopy technology, to film and understand structural dynamics of proteins in real-time in solution. This will require the development of electron microscopy techniques to image the protein clearly, image processing techniques to analyse the movies taken and molecular dynamics to understand and verify the results seen. We, therefore, aim to develop liquid-phase transmission electron microscopy as a technique to probe protein dynamics in solution, allowing the study of protein function, dysfunction and dynamic responses to stimuli, for example, drug binding. This will focus on RNA polymerase as a model system with physiologically relevant dynamics.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Structural and Biophysical Characterisation of ESCRT-0
Funder: Wellcome Trust

Abstract: In order to sense and respond to outside events, eukaryotic cells utilise many different proteins on their surface to finely control activities such as growth and movement. Key to regulating these processes is the uptake of these proteins from the cell surface, and their destruction at the lysosome in a process coordinated by the Endosomal Sorting Complexes Required for Transport (ESCRT) machinery. The first of these complexes, ESCRT-0, recognises a universal signal (ubiquitin), which is attached to these proteins and marks them for destruction by directing them to the lysosome where they are broken apart and recycled. In order to understand how ESCRT-0 works, we need to know what it looks like. We intend to investigate this by using the technique cryo-electron microscopy, which will allow us to understand the shape of ESCRT-0 at the atomic level. We will also use an array of biophysical techniques to investigate how the structure of ESCRT-0 changes when it binds to ubiquitinated proteins, and whether this binding helps to promote the subsequent stages of the ESCRT process. Together, this should tell us what the role of ESCRT-0 is at the head of the ESCRT pathway.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Mechanisms of Transcriptional Regulation by H3K4 Methyltransferases at CpG Islands
Funder: Wellcome Trust

Abstract: The genetic information of each cell is stored in the nucleus as DNA wrapped around histone proteins, a structure termed chromatin. Apart from packaging DNA into the confined space of the nucleus, histone proteins serve as a template on which chemical modifications can be placed. These modifications can determine whether the associated gene is actively being used to produce messenger RNA (mRNA) and subsequently its product. I am studying the four ‘writers’ of one such modification, tri-methylation of lysine 4 on histone H3 (H3K4me3). These four enzymes, SET1A, SET1B, MLL1, and MLL2, have major roles in activating genes, but they seem to do so in a way that is separate and distinct from their roles as the writers of this modification. To understand how these enzymes activate genes, I am using genetically engineered cells in which these enzymes can be rapidly degraded by treating the cells with a small molecule. By removing these enzymes separately and in combination, I can analyse how these enzymes contribute to the overall levels of mRNA and H3K4me3 of the cell using sequencing techniques. The results of this project will be expected to increase our understanding of how genes are activated.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Investigation of the structural and biochemical properties of mammalian tolloid proteinases
Funder: Wellcome Trust

Abstract: The family of BMP1/Tolloid-like proteases (B/TPs) is involved in a variety of important functions in mammalian tissue development. Firstly, B/TPs cut collagen precursors to allow their assembly in the extra-cellular matrix (ECM). Mutations or a loss of function of B/TPs result in several developmental defects or can result in death during the embryonic stage. The second role of B/TPs is activating different growth factors. These messenger molecules are involved in communicating with cells during the formation of different tissues, including bones and the brain. Our work aims to understand how B/TPs carry out their function and how mutations result in diseases. To do so, we aim to determine the 3-dimensional structure of two members of the B/TP family using cryogenic electron microscopy. Furthermore, we want to understand how B/TPs interact with their substrates, as well as known effector proteins. We hope our results will allow for a better understanding of B/TP function and regulation and provide potential basis for therapeutic approaches for B/TP-associated diseases.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Unravelling Mechanisms Controlling Gene Expression Noise in Saccharomyces cerevisiae during Rapid Adaptive Responses
Funder: Wellcome Trust

Abstract: The Nrd1-Nab3-Sen1 (NNS) complex terminates transcription of approximately 12,000 RNAs in Saccharomyces cerevisiae. During the stress response, the NNS complex changes its occupancy to reprogram gene expression. Some of the transcripts that are only targeted by the NNS complex during the adaptive response are specifically upregulated during glucose starvation. PIC2, which encodes for a mitochondrial copper importer, is one of these NNS stress-specific targets. Whereas lack of PIC2 expression leads to defective mitochondrial respiration in yeast and humans, overexpression of copper transporters makes standard copper levels toxic for cells. Accordingly, we hypothesise that PIC2 expression is tightly regulated by the NNS complex, which suppresses transcriptional noise during glucose depletion. We will compare the phenotype of strains encoding for wild-type and deleted PIC2 NNS RNA-binding sites in varying concentrations of glucose and copper, and determine whether the variability of PIC2 expression during glucose deprivation is higher when NNS regulation is impeded. Our results could validate the NNS complex as one of the first stress-specific suppressors of stochastic expression, outline a methodology to test this role in similar NNS targets, provide a synthetic biology tool to repress gene expression in yeast and shed light on how transcriptional noise elicits human disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Probing chromatin states with single molecule microscopy
Funder: Wellcome Trust

Abstract: Recent research showed that the emergence of resistance in fungi can be linked to epigenetic mutations. Those are not changes in the DNA sequence, but rather in the chromatin environment. Some parts of the genome are packaged in heterochromatin: in those areas, the DNA is bunched up much more tightly and thus not easily accessible, so genes are repressed. We want to investigate how specific heterochromatin regions are formed and removed. I am especially interested to find out why two seemingly identical cells can acquire differences in their epigenetic landscape and thus develop different phenotypes. To visualise cell-to-cell variations, I plan on using real-time fluorescent imaging, to track different proteins that are known to regulate heterochromatin. From the amount of protein and the movement of the fluorescent molecules, we can better understand how the heterochromatin distribution in individual cells changes in response to stress. Additionally, I am developing a probe, which can differentiate between different chromatin environments at specific locations.Understanding the development of these epigenetic differences is important, as they are likely involved in the development of antifungal resistance in pathogenic fungi.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Using Chemical Biology to Monitor Impact of Metabolic Perturbations on the Regulation of Chromatin State and Drug Action
Funder: Wellcome Trust

Abstract: Organisms respond to environmental changes by adjusting their physiological state, for example switching to oxygen-independent metabolism if oxygen provision is limited. Such coping mechanisms are encoded within the genetic information which provides the template for a cellular response. This is the reason why geneexpression and metabolism are highly interconnected via crosstalk between nutrient availability and the accessability of genetic information, the chromatin state. This interdependence has been shown to affect and contribute to many human disorders such as cancer and inflammatory diseases. Not surprisingly, alterations in metabolite pools can also have a significant impact on the therapeutic efficacy of drugs. With this project I’m aiming to develop methods and tools to monitor cellular responsiveness to drugs in the context of metabolic perturbations in cells to identify and define sensitivity patterns as well as factors that may provide novel therapeutic opportunities.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Developing small molecules to dissect the function and mechanism of m6Am methylation
Funder: Wellcome Trust

Abstract: RNA are widely modified and the modifications have a range of effects. One such modification found in animals is the m6A modification. It is found in wide variety of different types of RNA & is the most common modification in messenger RNA. While the modification has been known about for 30 years, modern methods have only just identified the enzymes that create it. I aim to study a couple of these newly discovered enzymes. We will look into their enzymology making use of the existing x-ray structures. We hope to develop small molecule inhibitors for the enzymes. I hope to apply these inhibitors & the enzymology to cell assays. We might then better understand why the m6A modification is made and what effect it has.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Development and utilisation of a ubiquitin directed photoreactive probe to identify endogenous E2-RING E3 interactions
Funder: Wellcome Trust

Abstract: Ubiquitin is a small protein, its addition to other proteins regulates many cellular processes such as protein homeostasis and cell signalling. The addition of ubiquitin to protein substrates is catalysed by an enzymatic cascade. Ubiquitin is transferred from a ubiquitin-activating enzyme (E1) to a ubiquitin conjugating enzyme (E2). The ubiquitin bound E2 interacts with an E3 ligase which catalyses the transfer of ubiquitin to the substrate. Methods to identify interactions between ubiquitin bound E2s and E3 ligases in cells are limited. To try to capture these interactions I will develop a ubiquitin directed photoreactive probe. The probe will consist of a photoreactive diazirine group chemically conjugated to recombinant ubiquitin bound to the E2, Ube2W. The ability of this probe to form covalent attachments with E3 ligases will be validated in vitro using the SUMO-targeted ubiquitin ligase RNF4. Following validation, multiple probes will be made using different E2s. These will be incubated with cell lysates and irradiated to form photo cross-linked products that will be identified using mass spectrometry. This approach could potentially identify physiologically relevant E2-E3 pairs and novel E3 ligases which would be beneficial for the development of targeted protein degradation strategies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Understanding and improving the fairness of risk prediction using health data
Funder: Wellcome Trust

Abstract: Computers can now create algorithms to give personalised predictions about an individual’s risk of developing diseases. These can be used to help make decisions about medical treatments and screening before the person gets sick. They could have a big impact on healthcare, because they can prevent illness and save healthcare systems money. It is also very important that these algorithms are fair. This means that they must be able to make equally good predictions for all races, ethnicities, genders, ages, and backgrounds. But this is not easy, and many give worse predictions for some groups of people. It is important to improve fairness in these algorithms as they are starting to be used to make real-world decisions. I will study definitions of fairness, and use these to look at how fair algorithms are, and how to improve their fairness. Then, I will create new algorithms which use medical and personal information and genetic data, with fairness as a focus. I will create multiple algorithms to make sure that each group of people have good predictions for their disease risk. The more fairness is studied and improved, the more sure we can be that these algorithms will benefit everyone in society.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Using electronic health records to help support the diagnosis of hard-to-suspect conditions in primary care associated with diagnostic delay
Funder: Wellcome Trust

Abstract: My project will support efforts to improve the quality and safety of medical diagnosis. I will focus on exemplar conditions known for their diagnostic difficulty - resulting in long periods between patients first complaining to their GP about symptoms relating to their condition and them receiving the correct diagnosis. It may be possible that some pathways to diagnosis can be improved by better decision-making by doctors, empowered by new knowledge that will arise from my research. I plan to focus on certain exemplar diseases (e.g., endometriosis, ankylosing spondylitis and chronic obstructive pulmonary disorder), known for their long diagnostic intervals. A patient’s electronic health record (EHR) contains lots of information about their medical history – for example, when, and how often, they visited the doctor and what symptoms they had. Using large collections of anonymous EHRs, I will identify different presenting features that patients shared before they were diagnosed and related healthcare utilisation events – so called ‘pathways’ to diagnosis. Having done that, I can examine patients who take similar pathways, and analyse whether different pathways have different diagnostic intervals. Associations between different presenting features and risk of as-yet-undiagnosed illness will also be examined in the latter part of the project.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: GENERIC HEALTH RELEVANCE
Title: Dynamic transcriptional regulation in neuromesodermal progenitor cell maintenance and lineage specification
Funder: Wellcome Trust

Abstract: After implantation in the uterus, embryonic cells diverge into a multitude of cell types during a process called gastrulation, which lays the foundation for later organogenesis. During this process, the three main lineages of the mammalian body, ectoderm, mesoderm and endoderm, are specified. Neuromesodermal progenitors arise early in gastrulation and retain their unique potential to generate both mesodermal and ectodermal tissues until late organogenesis. Genetic expression, termed transcription, in eukaryotes is discontinuous, and regulated by variable molecular processes ranging from milliseconds to days, whilst transcription itself occurs on a scale of minutes. How various transcriptional regulatory elements dynamically interact to direct cell fate decisions at the single cell level remains an open question. I therefore aim to establish a live single-cell approach to address how key transcriptional regulators dynamically modulate gene expression programs in neuromesodermal progenitors. I will use single cell super resolution live-imaging techniques and multiomic datasets to study live transcriptional dynamics, and model the relative contribution of the multi-layered regulatory components to transcriptional output and cellular identity. These studies will provide single-cell level information about transcriptional control in NMPs, providing a major advance on prevailing studies emphasising population-level dynamics, and contribute to the nascent field of transcriptional dynamics.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Exploring the use of routine health data in improving the efficiency of randomised implementation trials
Funder: Wellcome Trust

Abstract: Trials that assess methods to help implement health interventions of proven effectiveness are known as implementation trials. However, randomised trials tend to be expensive and take many years to conduct. The use of patient health data collected from routine practice, such as GPs, hospitals, and secondary care services, may make these types of trials more efficient. However, there are many challenges such as gaining access to such data and the data might be inaccurate.In this PhD I will explore how patient health data are used in implementation trials.I plan to start by reviewing reports of these types of trials and consulting the experts in the field. I will survey and interview those who have conducted or have been involved in such trials (e.g., trialists, IT staff, statisticians, researchers, patient participants etc.) and carry out some in-depth case studies. The involvement of patients and public representatives in all stages of the study will be vital.The key outcome will be a set of recommendations on the use of routine health data in studies implementing health interventions into practice. I hope the outputs of this PhD will increase the speed of adopting health interventions of proven effectiveness into real-world.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: The role of extracellular matrix during tissue repair
Funder: Wellcome Trust

Abstract: Epithelial tissues form boundaries between external and internal environments in organisms. When epithelia are injured, they must repair quickly and accurately to minimise damage and preserve organ function. Two possible mechanisms of wound repair are cell shape changes and rearrangements. Both mechanisms are linked to the basement membrane (BM), a layer of extracellular matrix (ECM) underlying epithelial cells, through cell-ECM adhesions. The BM has a key role in controlling the physical properties of tissues, but how the BM modulates its mechanical properties to control wound healing remains unknown. We will use Drosophila wing discs as a model system because they robustly repair wounds, are easy to genetically manipulate and have a simple 3D geometry. After wounding discs, we will visualise epithelia and BM and measure their mechanical interactions using quantitative live and fixed super-resolution microscopy, electron microscopy and biophysical methods. Machine-learning-based image analysis pipelines will be used to accurately quantify 3D cell shapes in dense live tissues. These experiments will inform parameters in 3D computational models, allowing us to further understand the forces between cells and BM components. This research will identify novel methods to edit the physical properties of cells or BM and design scaffolds for tissue repair treatments.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Mechanisms of 3D epithelial tissue organisation
Funder: Wellcome Trust

Abstract: Epithelial tissues line most of our organs. They have two distinct surfaces with the apical surface facing the inside of the organ and the basal surface facing the outside environment, including the extracellular matrix. While we understand how cells interact to organise the apical surface of tissues, we know very little about the pathways that organise the basal surface, and how morphogenesis is coordinated between the apical and basal surfaces to shape a tissue in 3D. The objective of my PhD research is to establish the pathways that induce basal surface organisation and reveal those that mediate coordinated movement and cell shape changes along the apical-basal axis to shape tissue in 3D. For my research, I will use Drosophila and take advantage of its genetic tools and imaging capabilities to manipulate and image cells in living tissues. Generating functionally distinct surfaces underpins epithelial shape and function. It is essential for nutrient absorption (intestine) and gas exchange (lungs) for example. Therefore, I expect my work to be broadly applicable to epithelial tissues, to both their formation and how this can go wrong in disease.


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