NIHRDataInsights/HRCSData huggingface dataset:
Title: The cellular consequences of polymer accumulation in alpha-1-antitrypsin deficiency elucidated in molecular detail
Funder: Wellcome Trust

Abstract: Alpha-1-antitrypsin is a protein that is produced by the liver, is abundant in the circulation, and whose job it is to protect the lungs from enzymes that our body produces during an inflammatory response. Alpha-1-antitrypsin deficiency is a genetic condition in which some of the protein becomes trapped in the liver. The result is damage to both the lungs and the liver with increased risk of developing emphysema and liver disease. Some trapped alpha-1-antitrypsin forms clumps of protein in the liver, called ‘inclusion bodies’, and some clogs up parts of liver cells, causing them to change their behaviour. It has previously been possible to see fine details of these molecules only when they have been extracted from cells, which means a lot of information and context is lost. now technological advances allow us to see almost the same level of detail inside the cell. In our project we want to understand the effect of malfunctioning alpha-1-antitrypsin on the behaviour of the cell. To do this we will look at ultra-thin sections of cells using an electron microscope and reconstruct three dimensional representations of the alpha-1-antitrypsin molecules in the cellular environment.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Rebuilding a superenhancer to investigate the additive and synergistic effects of its individual components
Funder: Wellcome Trust

Abstract: Every cell in the body contains the same DNA; however each cell type "reads" and interprets DNA differently. Different regions of the DNA have different functions: some (genes) provide cells with instructions to make specific components, whereas others are regulatory, and simply tell cells which genes they should “read” and express. Enhancers are one category of regulatory DNA feature. They are regions of DNA which increase the expression of other specific genes, even when they are located a long way from one another. Superenhancers are groups of enhancers which combine to up-regulate expression of target genes to an even higher extent. Superenhancers often act to increase the expression of genes which are only active in certain tissues, for example we are studying the &alpha;-globin superenhancer which up-regulates &alpha;-globin, a gene which is only active in red blood cells. Currently, it is unknown exactly how the different enhancers within one superenhancer associate to increase target gene expression. We will study this by stripping down and rebuilding the &alpha;-globin superenhancer. This is particularly important, as most genetic diseases are caused by mutations in regulatory elements like enhancers, and mutations at the &alpha;-globin superenhancer are responsible for diseases such as &alpha;-thalassaemia.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Emergence and control of gene expression dynamics
Funder: Wellcome Trust

Abstract: During early embryonic development, stem cells need to differentiate to form different types of tissue. The mechanisms controlling this differentiation are not yet fully understood. The dynamics of gene expression are important for differentiation and cell state in many contexts, including neural differentiation. Intriguingly, gene expression dynamics and the timing of differentiation vary stochastically between cells — the biological benefit of this is unclear. We do not fully understand how dynamics are biophysically regulated within a cell, and how this influences cell state transitions. Here, we will develop a new computational tool that can learn kinetic parameters of gene regulation from protein expression time course data. We will illustrate the strength of this method by identifying and experimentally validating differences in gene regulation between cell states in the mouse embryonic spinal cord, however the method is generally applicable to time course data of gene expression for any self-repressing gene.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: A Multiscale Understanding of Patterning in Neural Development
Funder: Wellcome Trust

Abstract: For a functioning organism to form during development, cells must change from one type to another in a process called differentiation, and these changes must happen both at the correct time and in the correct place. During spinal cord development, progenitor cells which have the potential to produce various specialised neural cells, eventually differentiate and give rise to the functional cells of the spinal cord. The decision making required of these progenitor cells is controlled by internal and external biochemical signals, though there is difficulty in intuitively understanding how this process is orchestrated due to signalling pathways being highly interconnected. Mathematical modelling provides a useful and efficient method for analysis of these unintuitive dynamics and my work so far has involved implementing computational modelling as a means to understand how communicating cells in the spinal cord, each with their own internal signalling network, coordinate their gene expression during development. This work has identified that in the multicellular environment, various patterns of expression can arise across the tissue. The aspect that this PhD project aims to clarify is how each type of model behaviour influences the timing and amounts of functional cells that are produced during development.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Evolution of cell shape: epithelial-mesenchymal transition during gastrulation in insects
Funder: Wellcome Trust

Abstract: Cell shape plays a critical role in animal development and physiology. Consequently, shape deregulation can lead to pathological disorders. Epithelial-mesenchymal transition (EMT) is an evolutionarily conserved process in which epithelial cells, tightly connected to each other, transdifferentiate into more motile and spread mesenchymal cells. It is key to numerous developmental processes, such as heart formation, but it is also involved in cancer metastasis and organ fibrosis. The master genes controlling EMT are well characterised in many species and are relatively well conserved. However, how they drive the reorganisation of the cytoskeleton and the resulting shape change is poorly understood. Furthermore, the level of conservation of the downstream molecular pathways involved in cytoskeleton remodelling, and of the shape change itself, has not been investigated. The aim of my project is to investigate the evolutionary conservation of the morphological changes underlying EMT during mesoderm gastrulation, a process of cell internalisation in the early embryo. I will investigate cell shape changes, and cytoskeleton effectors that drive them, in two insects, to detect the level of conservation of the process. My project will shed new light on the evolution of a stereotypical cell shape crucial in both development and diseases.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Investigating pattern regulation during posterior body development in the zebrafish, Danio rerio.
Funder: Wellcome Trust

Abstract: Embryonic cells must have their identity specified in order to generate functionally distinct organs. Neuromesodermal progenitors (NMPs) are a progenitor cell population that resides in the tailbud of vertebrate embryos. The specification of the NMP population must be correctly balanced in order to generate axial body structures such as spinal chord, muscle and bone. Though little is known about how cell fate specification is regulated, it happens reproducibly and robustly in the majority of embryos, for example preliminary work I have done shows that normal development still occurs if a quarter of the NMPs are ablated. I aim to ablate NMPs in the zebrafish tailbud using targeted laser ablation. I will then use clonal analysis, live imaging, and quantitative gene expression techniques to observe and quantify the response to ablation. I will combine this with generating mathematical models to predict potential mechanisms. To explore the mechanisms which are involved in regulating the pattern of cell fate specification I will use quantitative live imaging and embryonic manipulation of transgenic fish lines. I expect this work to provide insight into how cell fates are decided in vertebrate embryos and how they are affected by internal or external perturbations.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Construction of multi-layer gene regulatory networks to understand the human immune system.
Funder: Wellcome Trust

Abstract: Every cell in the body has the same genes, but the level of activity of each gene varies due to factors such as cell type and environment. Genes can alter the activity level of other genes, for example in response to a change in environment. These interactions between genes can be described by networks called gene regulatory networks. It is thought that these networks are modular: genes involved in a particular function are contained in a module and there are many interactions within modules but few interactions between modules. By using gene expression data from patients with immune-mediated diseases as well as healthy controls, I aim to construct gene regulatory networks by first finding these modules. Investigating the modules that are linked to particular immune-mediated diseases will improve understanding of the immune system in both health and disease. Further, the gene regulatory networks constructed can provide insight into why a drug may not be effective for a particular patient, and help to suggest an alternative drug target.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Genome integrity and DNA damage response in Drosophila germline development
Funder: Wellcome Trust

Abstract: A large fraction of our genome consists of selfish DNA modules known as transposable elements (TEs) – mobile units that jump from one location to another. TEs contribute to genome structure and evolution, but their activity causes damage that must be tightly assessed and repaired. This is especially true in the germline, the cell lineage in which host and TEs compete for maximising their influence over the genetic information that will be transmitted to the next generation. We aim to understand how the germline assesses and responds to genome damage, using the fruit fly as a model system. Crosses between males that have TEs known as P-elements and females that lack them produces sterile progeny, with germ cells dying early in development. To define the time course of germ cell death, we will image fly embryos at different developmental stages. To gain insights into the changes occurring during germline arrest, we will isolate and sequence the genomes of individual germ cells. Finally, we will test how much DNA damage germ cells can cope with using genome editing tools. We hope to uncover fundamental mechanisms by which cells assess and respond to DNA damage.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Characterising the evolution and development of vertebrate nervous systems using cross-species comparative genomics.
Funder: Wellcome Trust

Abstract: The human brain is enormously complex, consisting of billions of cells, diverse cell types and complicated connectivity. One approach to understand such a complex system is to study instances in more primitive organisms, where homologous cell types and developmental processes can suggest how particular components of the brain may have originated, what purpose they serve and how they function. In this project, I aim to use single-cell RNA sequencing (scRNA-seq) datasets from multiple species to identify homologies across vertebrate and invertebrate nervous systems. To achieve this, I aim to improve existing methods for comparing, integrating and visualising cross-species genomics data, for which current solutions either do not exist or are unsuitable. This will include approaches for identifying gene orthologs, normalising expression levels, matching cell types and, perhaps most challenging, identifying equivalent developmental stages. This research will lead to greater insight into the evolution of neural cell types, gene regulatory networks and neurodevelopmental processes across species and provide general resources for comparative analysis of transcriptomics datasets. These resources may have a wider impact on other areas of biology and medicine, such as in cancer research, for which the same tools may be used, for instance, to compare transcriptomes across cancer samples.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Dynamics in the regulatory genome.
Funder: Wellcome Trust

Abstract: The human genome comprises multiple layers of information, from the basic DNA sequence, to the complex folding of DNA into 3D structures in different cell types. We have an extensive knowledge of the coding genome, and are beginning to build a better picture of how non-coding regions regulate gene expression. I am interested in the dynamic process of protein localisation and recruitment within the context of gene regulation. Pre-established techniques give a steady state, population view of which proteins and regions of DNA interact with one another. However, such processes are highly dynamic, occurring at different rates across the genome. A method that could demonstrate how interactions form dynamically and which genomic regions employ particular regulatory activities would further advance our understanding of genome regulation. My project will utilise a newly developed technique, called RAPID-release, that enables rapid induction of protein localisation which can be visually traced over time. I will integrate this with time-course Chromatin Immuno Precipitation Sequencing (ChIP-seq). I will use the combination of these techniques to generate genomic data from which a model for protein dynamics can be developed within the context of the regulatory genome.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Using phased multi-omic techniques to understand the regulatory landscape of the genome
Funder: Wellcome Trust

Abstract: Since the completion of the human genome project many genetic studies have discovered variations in our genetic code that are subsequently associated with common diseases. These can be insertions or deletions of genetic code or in-place modifications of the genetic code. Interestingly many of these discovered changes to the genome don't occur within genes but within the so-called "non-coding" regions of the genome. It is thought that these changes are in fact affecting the regulation of the genes -- switches that control gene activity. In this research I intend to build upon existing research that aims to understand how these changes are affecting the gene activity, which genes are affected and how. This is often complicated by factors such as these genetic-changes may well be very distal to the genes they affect in our 2-dimensional representations of the human genome. Overcoming these issues will provide clear insights into human diseases and hopefully will lead to improvements in our understanding of human disease and how to treat such diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: New approach to identifying epistasis using harmonic mean p-value
Funder: Wellcome Trust

Abstract: Epistasis refers to the phenomenon where the effect of one gene in a given trait is dependent on other genes. The effect of such interaction between genes is often ignored in studies that try to identify genetic risk factors in diseases and only the effects of individual genes are considered. Such an approach resulted in missing information and the heritability of genetic risks is only partially explained by these association studies. It is proposed that epistasis might be the missing piece of this puzzle. However, taking epistasis into account would increase the number of candidates dramatically. This presents a statistical challenge as the difficulty to find true signal grows when the number of candidates to be considered increases. In this project, we will leverage a recently published statistical method by Prof Daniel Wilson that can combine numerous signals into one representing signal and thereby reduce the number of candidates to overcome the challenge posts by epistasis. We hope to develop a framework to efficiently and flexibly identify genetic risk factors that includes epistasis in different human diseases.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: Modelling mitotic spindle dynamics in stretched epithelial tissue
Funder: Wellcome Trust

Abstract: Multicellular organisms are formed by cells dividing multiple times, with the direction of division determining whether tissues expand or new tissues are formed. The mitotic spindle forms during cell division and determines the direction of division. In vertebrates, nuclear and mitotic apparatus protein (NuMA) has been identified as an anchor at the cell periphery which allows motor proteins to apply forces to the spindle and position it appropriately. While current spindle orientation models focus on different characteristics of the shape of the cell as force determinants in single cells and invertebrates, preliminary data from a force-based model shows that spindle orientations best match those seen experimentally when force is amplified at the edges of cells with increased intensity of fluorescently tagged NuMA. We aim to develop this model to include time-dependent NuMA localisation as it accumulates at the periphery and observe the effect on spindle dynamics. We will use in-plane divisions in cells of stretched tissue to investigate whether NuMA localises as a result of the cell shape or applied forces and the subsequent effect on spindle orientation. These studies will go some way to explaining the fundamental process of cell division and its dependence on local and global forces.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Social tariffs, preference heterogeneity, and collective choice
Funder: Wellcome Trust

Abstract: Health economic evaluations are used to compare the costs and (health) benefits of different interventions. Their results often inform policy decisions about the allocation of resources within public health care systems. Since health is, to some extent, a social construct, measuring health requires making value judgments. In the UK, these judgments are supposed to be derived from the general public. To this end, it is established practice to survey a representative sample of individuals and to elicit their preferences over health states. Subsequently, individuals’ preferences are aggregated, using some statistical methods, into a single index of the societal value of health, which is then used to value health outcomes in economic evaluations. The proposed research project starts from the premise that no scientific method is value free, and that the aggregation of individual preferences into a societal preference is particularly contingent on underlying assumptions. The objective is to critically appraise what value judgments are inherent to the statistical models for health preferences that are commonly used in economic evaluations. Based on work in other fields, namely democratic and social choice theory, alternative conceptual and technical solutions will be developed, and their feasibility and impact will be empirically assessed.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Investigation of the role of small molecule ligands in Hedgehog signalling using molecular dynamics simulations
Funder: Wellcome Trust

Abstract: The hedgehog (HH) signalling pathway is involved in embryonic development, cell patterning and stem cell homeostasis1. Defects in pathway function lead to cancers such as medulloblastoma or developmental defects such as holoprosencephaly2. Several recent observations3–8 have led to the hypothesis that membrane sterols such as cholesterol play a crucial role in the function and regulation of key HH membrane proteins, Patched (PTCH1) and the Class F GPCR Smoothened (SMO). I will use computer simulations to study the role of sterols in PTCH1 function to inhibit SMO. This will include evaluation of protein dynamics within the cell membrane and calculation of energy changes along potential sterol transport tunnels within PTCH1 which I have previously identified9. Computer simulations will also be used to investigate how ligands bound within SMO may affect the movement of different regions of the protein. These studies will contribute towards understanding the function and regulation of key HH membrane proteins and how their conformational landscape may be exploited for targeting by drugs.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Sensitivity analyses for causal inference
Funder: Wellcome Trust

Abstract: Many epidemiological studies are interested in estimating the causal effect of an exposure on an outcome. While experiments in which exposure levels are randomly assigned to participants are the ideal setting for this purpose, it is often infeasible for financial, ethical or logistical reasons. Therefore, we are often limited to analysing observational data in which exposure levels across individuals are determined by many complex and often unmeasured factors. Drawing inferences from such data typically requires making untestable assumptions about the distribution of, or relationships among, the variables under study. Causal inferences which depend on these untestable assumptions are rarely convincing. In the last couple of decades, there has been increasing development of sensitivity analyses, which relax the assumptions and measure the extent to which the estimates change as a result. Estimates which have the same qualitative interpretation even when assumptions have been stripped back are much more persuasive. The aim of my PhD is to continue developing sensitivity analyses for causal inference, with particular focus on selection bias and measurement error, and to promote these methods among non-statistician researchers (e.g. epidemiologists, clinicians).


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE