NIHRDataInsights/HRCSData huggingface dataset:
Title: WTSI costs associated with "Immune function and pathology dissected by high throughput analysis of mice with targeted gene disruptions - an investigation by the Infection and Immunity Immunophenotyping (3I) consortium"
Funder: Wellcome Trust

Abstract: The immune system is fundamental to survival in the face of innumerable microbes and viruses. Hence, understanding immunology will clarify how we interact with the biosphere, and enhance our vaccine development. However, mirroring the complexity of the microbial world, the immune system is composed of myriad cell types that use complex, highly specialized mechanisms to respond to particular challenges, and to orchestrate appropriate defenses. Given this complexity, it is inevitable that our u nderstanding of the immune system is incomplete. Seeking to redress this situation, an efficient, economical and effective set of pipelines has been devised by which a thousand different strains of mutant mice (that are to be developed over the next five years as part of an ongoing programme) will be screened for defects in immune function. The knowledge gained should elucidate basic mechanisms in immunology, and also inform studies of cell and developmental biology. The findings will be useful beyond infectious disease and vaccine development, because faulty immune systems contribute to an immense spectrum of diseases, from obesity and cardiovascular disease, through neurodegeneration and allergy, to cancer. Hence, the study can at once provide basic new biological information with very real potential for clinical benefit.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Activation of the type 1 interferon response by nucleic acids: A fundamental mechanism causing human neuroinflammatory disease.
Funder: Wellcome Trust

Abstract: Brain inflammation is an important cause of disability and ill health among young and old people in the UK. In general, we do not understand the molecular mechanisms which cause the brain to become inflamed. In some cases of brain inflammation, patients have faulty genes called nucleases. These nuclease genes are responsible for breaking down nucleic acids like DNA and RNA. My hypothesis is that, as a result of these faulty nucleases, waste DNA builds up in brain cells. The brain cells then mistakenly recognise this waste as a virus and unleash an unwanted and damaging antiviral immune response in the brain. I will use mice and human brain cells which have the faulty nuclease genes to understand the molecular steps involved in causing disease. I will also ask if this pathway causes a broader spectrum of human autoimmune disease than is currently recognised. In this way I hope to identify critical steps which are involved in the development of these inflammatory brain d isorders and identify potential targets for treatment.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Mapping the genetic and cellular basis of human DC haematopoiesis.
Funder: Wellcome Trust

Abstract: Dendritic cells are immune cells that develop in the bone marrow, inhabit tissues and lymph nodes and are critical for the initiation of immune responses. The immune system plays an important role in many processes relevant to medicine but the development of human dendritic cells is not well understood. I aim to understand two important problems: first, what different genes are required for dendritic cell development and second, what discrete stages of cellular maturation must occur for bone m arrow stem cells to develop into dendritic cells. I aim to reveal the genes that specify dendritic development by solving the genetic cause of humans with dendritic cell deficiency. I propose new ways to identify immature precursors of dendritic cells by using their gene expression patterns to describe them more precisely, looking for new markers to purify them by comparing gene expression patterns across mouse and human and using advanced in vitro techniques that can evaluate the development of dendritic cells from single stem cells. Finally, I aim to analyse how genetic mutations that cause DC deficiency, interfere with the maturation of DCs from stem cells to produce an integrated view of human DC development.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The interaction between macrophages and fibroblasts in the resolution of inflammation.
Funder: Wellcome Trust

Abstract: Rheumatoid arthritis (RA) is a disabling condition, characterised by flares of inflammation. Inflamed tissue doesnt simply recover (resolve) automatically, but a process of recovery (resolution) needs to be actively switched on. We know that fibroblasts and macrophages (cells residing in the tissues) interact with each other, and can provoke more pro-inflammatory activity in one another. I expect to discover a normal process whereby fibroblasts and macrophages also work together to resolve in flammation and allow tissue repair. I suspect that in people with inflammatory diseases e.g. RA, this process malfunctions, so that the inflammation either takes longer to, or does not, resolve (e.g. residual swelling and pain following a flare of arthritis). The interaction of these cells is important, as drugs designed to make macrophages pro-resolution wont work if fibroblasts are continuing to instruct the macrophages to be pro-inflammatory, and vice versa. Finally, I aim to discover wh ether pro-resolution macrophages and fibroblasts (which have been taught to behave in a resolving manner) remember this, and resolve the inflammation efficiently during the next flare. Long term, this would open possibilities to design drugs which promote cells to obtain this pro-resolution memory, and so have long lasting effects.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: A comprehensive comparison of signalling used in the accessing and regulation of cytolysis in cytotoxic T lymphocytes and natural killer cells
Funder: Wellcome Trust

Abstract: Cytotoxic T cells (CTLs) and natural killer (NK) cells are essential defensiveimmune components which eliminate infected, damaged and tumourigenic cells. Both release cytotoxic granules in a highly specific manner to deliver a lethal hit to a single cell. Despite their functional similarities, different receptor repertoires mean the signalling pathways used by these cells to access and regulate cytolysis may be significantly different. Currently, a direct and comprehensive comparison of signalling in CTLs versus NK cells has never been performed, partly due to a lack of quantitative data regarding the highly complex signalling pathways occurring at the lytic synapse after targetcell recognition. Here we propose to utilise high resolution imaging protocolsdeveloped by the Wuelfing lab to generate an expansive data set on the spatiotemporal distribution patterns of signalling molecules at the lytic synapse1. Combined with biochemical studies and RNAi experiments, this approach will allow the construction of quantitative models describing key elements of cytolytic effector signalling in relation to function. Key differences in the signalling mechanisms used by CTLs and NK cells will also become apparent. We predict the unprecedented level of comprehension obtained by this study will contribute greatly to the field of cytolysis and therapeutic development.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Targeted gene addition strategies for the treatment of Primary Immunodeficiencies using X-linked lymphoproliferative disease (XLP) as a model
Funder: Wellcome Trust

Abstract: Gene therapy has been used to treat children with certain primary immunodeficiencies (such as severe combined immunodeficiency (SCID)) who lack a suitable donor for curative bone marrow transplant. However, some children treated in early clinical trials using a gammaretroviral vector to deliver a corrected copy of the gene to blood stem cells developed leukaemia as the vector integrated into the genome close to cancer causing genes. Using new technology (called TALENs which act like scissors to cut DNA at specified sites) we can direct addition of a normal copy of the defective gene to its normal location in the genome. This will ensure the gene functions only in the kinds of cells that it would in a healthy person and should be safer when compared to older techniques. We will also look at ways of directing gene integration to a specific safe site in the genome where we think gene insertion will not affect function of neighbouring genes. We will test this technique in the context of an inherited immune disorder called X-linked lymphoproliferative disease (XLP) to see whether we can correct the immune defects seen in patients with this condition, first in cells and then in a mouse model.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Identification of Atypical Ubiquitylation and its Role in Inflammatory Signalling.
Funder: Wellcome Trust

Abstract: The overall aim of my research is elucidate key mechanisms governing inflammatory signalling and innate immune responses to invading pathogens. Pathogens are a constant threat to human health, particularly in the gastro-intestinal system. Accordingly, deregulation of inflammatory signalling leads to immunodeficiency, chronic inflammation, and cancer. Uncovering basic mechanisms controlling these processes may thus contribute to understanding the aetiology of human diseases. Pattern recognitio n receptors (PRR) recognise pathogens, and in response form multi-protein complexes where assembly and disassembly of ubiquitin chains (polyubiquitin) by ubiquitin ligases and deubiquitinases orchestrates the signals that control the subsequent inflammatory response. How polyubiquitin encodes specificity into the signals to secure an appropriate inflammatory response is not well understood. Eight types of polyubiquitin exist our cells but the cellular function of most them, termed atypical polyu biquitin, remains poorly defined. I envision that atypical polyubiquitin, like the well-studied K48- and K63-linked polyubiquitin, has important functions in innate immune regulation. In this proposal I will investigate the function and regulation of atypical polyubiquitin in PRR-dependent inflammatory signalling. I will particularly focus on signalling by bacteria-sensing receptors NOD2, TLR4, and TLR2, which have important functions in intestinal immunity. I anticipate that our results will uncover mechanisms in PRR signalling that addresses fundamental questions relating to how sensing of pathogens is translated into specific and appropriate cellular responses. Specific project aims: -Identify atypical ubiquitylation after PRR stimulation -Determine ubiquitin ligases and deubiquitinases regulating atypical polyubiquitin -Define the function of atypical polyubiquitin in pro-inflammatory signalling


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigation of the extent and outcome of neutrophil 'retro-transmigration' to draining lymph nodes
Funder: Wellcome Trust

Abstract: Neutrophils are white blood cells that play a key role in the immune system. Little is known about how neutrophils are removed from inflamed tissue, a critical process for the resolution of inflammation. One proposed pathway is 'retro-transmigration', where neutrophils leave inflamed sites and migrate to the lymph glands that drain tissue fluid, allowing neutrophils to interact with other immune cells resident in lymph glands. Using the live cell imaging techniques of intravital microscopy an d attaching a radioactive label to track neutrophils, this project investigates the theory that the outcome of neutrophil retro-transmigration is different with different triggers of inflammation. My aims are to: 1. Determine the time course of neutrophil retro-transmigration and how this contributes to the resolution of inflammation. 2. Compare how different types of inflammation triggers affect retro-transmigration and their location within the lymph glands. 3. Assess the interactions of ne utrophils with other types of immune cells in the lymph glands. 4. Examine how migrated neutrophils affect the function of a specific type of immune cells called B-cells. Studying the pathways involved in the resolution of inflammation is important in our understanding of chronic inflammatory diseases.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Autophagy and Metabolism in B Cell Immunity.
Funder: Wellcome Trust

Abstract: For our immune system to recognise new threats, and to respond better to ones already combatted, we constantly produce lymphocytes with random receptors. For a lymphocyte to survive, it needs to encounter a matching target. Most never do, and die. But those rare few that are able to bind a target, with the right support, proliferate massively and become specialised dependent on the nature of the infection. As the fate of a lymphocyte plays out, so its source of energy must drastically change. Th ere is emerging evidence that the the energy source itself and the metabolic state of the cell may play a role in the outcome of the immune response. We have previously demonstrated that in the often severe autoimmune disease lupus, B lymphocytes show signs of metabolic stress, with activation of an emergency energy source known as autophagy (self-eating), in which a cell breaks down its own substance to be used for fuel. We propose that as a consequence of this stress, the normal safety mec hanisms that stop B cells from recognising and attacking our our tissues are bypassed, leading to disease. Targeting cell stress may thus lead to new therapeutic agents for autoimmune conditions.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The Role of Regulatory T Lymphocyte Fibroblast Interactions in the Resolution of Inflammation.
Funder: Wellcome Trust

Abstract: Rheumatoid arthritis (RA) leads to progressive joint damage and disability. Fibroblasts are cells within the lining of the joint, which in healthy individuals support the structure and function of the joint. Following injury, white blood cells accumulate within the joint in a process referred to as inflammation. If inflammation becomes abnormally persistent (as occurs in RA) irreversible joint damage occurs. Our work has shown that fibroblasts in the joint can be good and protect the joint or ba d and amplify inflammation resulting in damaged joints. We think that the balance between good and bad fibroblasts in the joint determines if inflammation gets better or becomes abnormally persistent. It is difficult to know whether new therapies should get rid of the bad fibroblasts or attempt to retain and enrich the good fibroblasts. Our approach is to understand how and why these cells change their behavior in the joint. If we can understand why a fibroblast becomes bad we can develop treatm ents that promote good fibroblasts and block the bad fibroblasts, thereby reducing joint damage. This may provide a potentially novel therapeutic approach for arthritis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The roles of protein arginine methyltransferase, Prmt1 in hematopoiesis
Funder: Medical Research Council

Abstract: Protein arginine methyltransferase I (Prmt1) is an important epigenetic modifier that mediates asymmetric dimethylation of arginine 3 of histone 4 (H4R3), a critical mark for transcriptional memory and maintenance of cellular identity during normal development. In leukemia, Prmt1 is hijacked by MLL fusion proteins for oncogenic transformation, which can be suppressed by specific knockdown of Prmt1 in transformed cells. Prmt1 also activates expression of genes,which are critical for normal hematopoiesis. While Prmt1 is an important molecule for transcription regulation and a potential therapeutic target in leukemia, its functions in normal development has not been defined. Thus the primary goal of this project is to characterize the roles of Prmt1 in normal hematopoietic development by both knockdown and conditional knockout mice approaches. The proposed research should define and give significant insights into the functions of Prmt1 in various stages of normal hematopoiesis (from hematopoietic stem cell to progenitors), which will also provide crucial information for current effort in developing specific inhibitors targeting Prmt1.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;BLOOD
Title: Clinical PhD Programme at the University of Edinburgh: "Analysis of the early development of human haematopoietic stem and progenitor cells".
Funder: Wellcome Trust

Abstract: Blood stem cell transplantation is an important and potentially curative treatment for many conditions such as leukaemias and lymphomas. However, there is currently a shortage of suitable stem cells which are collected from the peripheral blood and bone marrow of children and adults and from the umbilical cord blood at birth. Attempts have been made to manufacture blood stem cells in the laboratory but the procedure is currently very inefficient. Blood stem cells are first found in the early human embryo. Compared to those found in the adult, these first stem cells are much more efficient at recovering a previously destroyed blood system upon transplantation. We aim to study and learn about the genetics of the stemcells found in the human embryo and umbilical cord blood in order to improve the current protocols for manufacturing blood stem cells in the laboratory. We will try growing our stemcells alongside other cells taken from the early embryo in order to attempt to increase the potency of the stem cells and the efficiency of their production.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;BLOOD
Title: Tissue- and stage-specific roles of the unbiquitously expressed transcription factor Sp1 in hematopoietic development
Funder: Wellcome Trust

Abstract: This proposal will use the formation of haematopoietic precursor cells from mouse embryonic stem cells as a traceable model system to gather insights intothe molecular mechanisms of cell differentiation in a system-wide fashion. We have previously shown that knock-out of the transcription factor Sp1 leads to a progressive deregulation of gene expression and failure to complete terminalhaematopoietic differentiation. All four Hox gene clusters as well as their upstream regulators, the Cdx genes, are direct targets of Sp1 at an early, butnot at a later differentiation stage and the regulation of a subset of these genes is affected by Sp1 inactivation. This indicates that the deregulation ofgene expression caused by the lack of Sp1 is cumulative and that at developmental genes Sp1 interacts with different transcription factors in a stage-specific fashion. Currently, we do not know (i) at which precise developmental stage Sp1 is crucially required and (ii) which different transcription factor complexes are formed on developmental genes, such as the Hox clusters. This grant will use Sp1 knock-out ES cells and cells carrying an


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;BLOOD
Title: The Epigenetic Control of Gene Expression in Leukaemia and Haematopoiesis
Funder: Medical Research Council

Abstract: The Mixed Lineage Leukaemia 1 protein (MLL1) protein is important for the epigenetic regulation of gene expression during stem and progenitor cell development but is also mutated in a subset of aggressive human leukaemias. The most common leukaemic disruptions of the MLL1 gene are chromosome translocations that fuse the N terminus of MLL1 in frame with over 40 different partner genes creating novel fusion proteins. Recent work has suggested that wild type MLL1 and MLL1 fusion proteins cooperate in leukaemogenesis by together causing aberrant epigenetic profiles at target genes in vivo. Epigenetic changes are often defined as heritable changes in gene expression or chromosome stability that don’t alter the underlying DNA sequence. We are interested in identifying the key molecular events in MLL1 mediated leukaemogenesis in order to fully understand the epigenetic basis for this disease. This major goal has been divided into three key questions: 1) What key downstream gene targets are essential for MLL1 mediated leukaemogenesis?; 2) how do MLL1 and MLL1 fusion proteins control epigenetic gene regulation on a molecular level?; and 3) how are MLL1 and MLL1 fusion proteins recruited to important gene targets in the cell? To answer these questions, we are using xenograft transplant assays to identify Leukaemic Stem Cells (LSCs) in MLL1 patient samples, ChIP-seq to identify and characterise direct gene targets in specific haematopoietic cell populations, small molecular inhibitors and siRNA combined with ChIP and ChIP-seq to determine how MLL1 fusion proteins regulate gene targets in the cell and MLL1 domain analysis coupled with genome wide techniques to determine how MLL1 is recruited to gene targets in the cell. Answering these questions may not only be useful for future therapeutic strategies, but will also inform our basic understanding of epigenetic gene regulation during normal stem and progenitor cell development.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;BLOOD;CANCER AND NEOPLASMS