NIHRDataInsights/HRCSData huggingface dataset:
Title: Analysis and mathematical modelling of T cell movement and interactions with antigen presenting cells, based on state-of-the-art dynamic imaging.
Funder: Wellcome Trust

Abstract: 1. How do T cells find APC in LN and somatic tissue? Development of a spatial mathematical model based on available and newly obtained imaging data (mouse models) and their quantitative computational analysis, identifying what the pattern of T cell movement towards APC is. Conversely, the design and implementation of imaging experiments based on model outputs. The same research concept will be applied to questions 2-5 and 7, with specific details below: 2. How do T cells scan the surface of APC they find? Similarly as in (1), to identify what the pattern and length of interaction is and how this relates to further fate of the T cell. We aim to investigate whether the individual T-APC interactions are coordinated (e.g. one interaction might predetermine the site and pattern of subsequent interactions, so that these would follow the same path on the APC surface ? ?conveyor belt? hypothesis) or whether these are independent. 3. How do T and B cells find each other in LN follicle? It has been observed that non-random migration of antigen-specific (but not non-specific) B cells to follicular border occurs, driven by a chemokine gradient, and that the antigen-specific interactions last longer than non-specific interactions [15]. We aim to model the impact of this migration to follicular border on the probability and duration of cognate interactions, and verify experimentally. 4. How do T cells find target antigens in somatic tissues? Expansion of the model framework from previous steps to discrete models for different tissues, to infer the search patterns and compare these for different tissues and LN. 5. How is the duration, frequency, geometry and intensity of cell movements and interactions influenced by the temporal (e.g. naïve, primary, secondary immune response) and spatial (secondary lymphoid versus somatic target tissues) context and by external factors like adjuvants and infection? Specification of models for different tissues and temporal contexts, based on imaging data from the specific scenarios. Again, the model outputs will guide advanced experimental efforts.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Role of the mammalian target of rapamycin (mTOR) in cytotoxic T cells
Funder: Wellcome Trust

Abstract: What is the impact of rapamycin and mTOR catalytic inhibitors on the dynamics of the human and mice cytotoxic T cell transcriptome and proteome? How does mTORC1 regulation of HIF1a/ARNT function regulate the transcriptional program and the proteome of CTL?


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Post-translational regulation of multicellular behaviour in Bacillus subtillis
Funder: Wellcome Trust

Abstract: The overall aim of the project is to investigate post-translational control of multicellular behaviour by Bacillus subtilis. More specifically, this study will seek to provide further functional insights into the novel role of bacterial tyrosine kinases in controlling two divergent multicellular processes - biofilm formation and swarming motility. Specific Aim 1: Biochemical and Genetic Characterisation of TkmA as a Sensor and Kinase Modulator The bacterial tyrosine kinase PtkA must interact with its sensor and modulator protein TkmA to phosphorylate downstream target proteins. The effects of mutation of the extracellular loop and C terminal domain of TkmA will be assessed for their impact on downstream kinase activation. Specific Aim 2: Identify Targets of PtkA Required for Biofilm Formation To identify targets of PtkA and TkmA needed for biofilm formation a phosphoproteomic screen will be employed to compare the phosphoproteomes of B. subtilis in the presence and absence of TkmA under biofilm forming conditions. Specific Aim 3: Tyrosine Phosphorylation and Swarming Motility Swarming motility is a complex behaviour exhibited by bacteria to exploit and colonise new environments. YvyG is a protein of unknown function that is essential for swarming motility and is a PtkA target protein. This project will investigate the role played by tyrosine phosphorylation during swarming motility, and more specifically how YvyG contributes to this multicellular behaviour.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Dissecting the role of lymphoid tissue inducer cells in lymph node responses.
Funder: Wellcome Trust

Abstract: Vaccination is the process by which immunity to a given disease is generated through exposure to a constituent of the disease-causing organism within a controlled manner. Immunity is conferred through the formation of a population of memory cells which are able to rapidly respond to the organism should it be encountered once more. These memory cells are critical for successful immune responses following vaccination due to their ability to help many other cells of the immune system. Therefore our ability to better vaccinate against many diseases will be greatly improved with understanding the signals required for the generation and survival of these memory cells. This project will investigate the role of a newly identified player in these reactions (the lymphoid tissue inducer cell), within certain tissues where immune cells preferentially reside (lymph nodes). This will be achieved through experiments using genetically modified mice in which the memory cell survival within lymph nodes either in the presence or absence of lymphoid tissue inducer cells will be analysed.


Research activity codes: 3.4 VACCINES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Unravelling the very earliest molecular events of T cell receptor triggering by super-resolution live microscopy.
Funder: Wellcome Trust

Abstract: The mechanism of the T cell receptor (TCR) triggering, leading from the biding of its ligand (an agonist peptide complexed with a Major Histocompatibility Complex [agonist pMHC]) to the transduction of the signal across the plasma membrane, is an object of controversy. Three main non-exclusive models have been proposed: aggregation, conformational change and segregation1. Our aims are to answer the following fundamental questions: 1. What is the natural state of the TCR at the membrane of a resting T cell? 2. What is the main mechanism responsible for the earliest molecular events of TCR triggering? 3. How are microclusters of TCR formed after contact with an antigen presenting cell (APC), before the formation of the immunological synapse (IS)?


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Chemical and biological actions of esterified eicosanoids generated by human immune cells: Understanding membrane signaling actions of novel lipid families.
Funder: Wellcome Trust

Abstract: Lipoxygenases (LOX) are enzymes that are found in all animals and plants. They generate signalling lipids termed eicosanoids and function in diverse physiological processes including wound healing and inflammation. For some isoforms, their biological role is unknown. Also, their signalling activity is not always accounted for by their known products, suggesting that additional uncharacterised LOX-derived lipids may be involved. In our laboratory, we identified and structurally characterised a fa mily of new LOX products, where the eicosanoid is attached into a complex lipid. These new lipids are much larger and behave differently to the already known structures. At the moment, we do not know their detailed functions. The proposed studies will determine the behavior and function(s) of the new molecules using a range of biological, genetic and biophysical techniques. The studies may aid design of new treatments for inflammation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Transcriptional analysis and biomarker discovery in autoimmune disease
Funder: Wellcome Trust

Abstract: Around 10% of people will develop an autoimmune disease in their lifetime - that is, a condition where the immune system reacts against self, resulting in inflammation, and significant disability and mortality. These ideases include lupus, rheumatoid arthritis, Type 1 diabetes, multiple sclerosis, inflammatory bowel disease and many others. Many of the problems associated with autoimmunity result from the toxicity of treatments used, as it is not possible to predict in advance who will need in tensive treatment, and who will do well with far less therapy that might allow them to avoid toxic side-effects. We have collected a unique cohort of over 500 patients and analysed gene expression from purified white blood cells to try and develop blood tests to predict outcome in these diseases at a time when patients first present. Very encouraging preliminary results have been obtained from initial analysis, and this application seeks funds to complete the processing and analysis of the dat a that we currently have, which we have good preliminary evidence to suggest will result in clinically useful tests.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Does the potential for proteins to be allergenic depend on structural homologies with IgE targets on metazoan parasites?.
Funder: Wellcome Trust

Abstract: IgE is found only in mammals, and is presumed to have evolved to combat metazoan endo- and ecto-parasites (helminths and arthropods). Recently, a closer molecular relationship between major allergens and metazoan products has become apparent. We have tabulated the known allergens and found that 8 of the 10 most abundant allergen protein superfamilies are represented in metazoan parasite genomes, although in only 3 cases have metazoan proteins been experimentally verified as IgE targets. We prop ose to study 5 metazoan gene families containing homologues of known allergens, to establish if these are indeed targets of IgE in natural and experimental infections. To fully validate the hypothesis that all allergens contain structural homology to metazoan antigens, we will also analyze the 2 gene families for which homologues with recognizable sequence homology have yet to be found in metazoan parasites. These will be subject to surface structural feature analysis, which will enable us to se arch metazoan genome databases for structural homologues which will then be tested for IgE reactivity. The technique will then be extended to provide a searchable database of the metazoan parasite surface features which can be searched to predict allergenic epitopes in food and environmental organisms.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Clinical PhD Programme at the University of Oxford: 'The identification of autoimmune susceptibility genes using ENU mutagenesis.'
Funder: Wellcome Trust

Abstract: The identification of autoimmune susceptibility genes using ENU mutagenesis The aim of this project is to advance the understanding of basic mechanisms in autoimmunity by studying ENU mouse strains that have a defective immune response to self-antigens. In order to increase the yield of autoimmune phenotypes in the inbred ENU pedigrees, a sensitized screen has recently been developed using the Y chromosome autoimmune accelerator (Yaa) introduced to the C57BL/6 (B6) mouse. The aim of this studentship will be: (i) to characterise Yaa strains that develop heritable systemic autoimmunity ? anticipated to be marked by antinuclear antibodies, immune complex formation and renal disease. (ii) To identify the causative mutations by mapping and sequencing using high throughput whole genome analysis and matching to reference genome. To develop a pipeline for sequencing that will reduce dependence on mapping. (iii) Combine the functional and genetic knowledge in order to understand new mechanisms of pathogenesis and normal regulation; this will involve in vitro and in vivo methods for studying gene function and expression. (iv) Relate the findings to human disease and models of self tolerance. The project will provide training in basic immunology and a wide range of laboratory techniques, as well as renal histopathology and sequencing work.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Understanding and re-engineering adenovirus late gene expression: controlling the gatekeeper to productive infection.
Funder: Wellcome Trust

Abstract: Successful gene therapy requires a vector to take DNA through the barrier of the cell surface. Several viruses have been modified as vectors, including adenovirus, which can be made incapable of growing and causing disease by removing selected parts of its genome. Another gene can then be inserted instead to create a delivery vector for the added gene. When the vector infects a cell, this gene becomes operative and has a beneficial effect. However, although adenovirus vectors can achieve this, t he effect does not last very long because they are eliminated by immune responses that are generated to small amounts of viral proteins that are still made from genes that remain in the vector genome. We have been working on a new way to prevent the production of these proteins when a vector is used in therapy, without actually removing all the genes. This means that the vector can still be grown easily in the laboratory. The trick is to prevent production of just two late proteins, which we ha ve discovered turn on the production of all the others. When these two proteins are provided, the vector grows well but otherwise, none of the late genes work.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: T follicular helper cells, a critical step in the pathway to CD4 T cell memory.
Funder: Wellcome Trust

Abstract: Making an immune response is a collaborative exercise between the main cells of the immune system. B cells can only make antibodies if they get help from T cells (so-called helper T cells). We have known for many years that there are several subsets of helper T cells, but only recently have we realized that one subset actually goes to B cell areas of lymphoid tissues (in lymph node and spleen) and performs some very specialized functions in these follicles and germinal centres. We wish to learn much more about the B cell-dependent development of this T helper subset, so as to boost its activity in vaccination and infection or to control its malfunction in autoimmune disease. We also wish to test theories arising from previous work in our lab about the importance of this subset in the generation of memory T cells, the basis of vaccine memory.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;3.4 VACCINES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The role of retinoic acid in T-helper cell differentiation and lineage commitment.
Funder: Wellcome Trust

Abstract: Over 10 million Vitamin A-deficient (VAD) children per year suffer from the heightened morbidity and mortality of increased infectious disease. This increased susceptibility is due to impaired immunity resulting from the lack of retinoic acid (RA), the active metabolite of vitamin A. Our research group has shown for the first time, that the immune system produces RA in response to provocation of the immune system and this production is essential for the body to mount an effective, inflammatory r esponse. A dysregulated inflammatory response underlies a number of diseases including autoimmunity and allergy. Understanding how vitamin A modulates the immune system will allow us to intervene better in (VAD) individuals to restore immune competence as well as develop therapies to manipulate the immune response. Targeting the RA responses in the immune system will allow us to inhibit unwanted immune responses after transplantation or enhance the body s ability to fight infection.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Regulation of the TNF-family cytokine TL1A in normal and pathological immune responses
Funder: Wellcome Trust

Abstract: For this research we wish to address the biology of the costimulatory ligand TL1A. Specifically the stability of TL1A mRNA in Dendritic cells (DC) and T cells and examine the biological significance of the membrane bound versus the soluble form of this cytokine.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Linking genotype to phenotype for the rheumatoid arthritis susceptibility locus 6q23: beyond genome wide association studies.
Funder: Wellcome Trust

Abstract: An intergenic region on chromosome 6q23 is associated with susceptibility to several autoimmune diseases. The aim of this project is to identify all causal variants in the region and determine how their function contributes to phenotype. The first step will be to understand the complete genetic architecture of the locus. I will use data from fine mapping (Immunochip) and resequencing studies of the region. Bioinformatics analysis will help to prioritize variants for subsequent functional char acterization. cDNA sequencing of the region will be undertaken to explore whether the intergenic region is truly noncoding, allowing simultaneous determination of the effect of different alleles on expression levels. I will test whether distant regulatory elements lie at the site of disease variants through chromosome conformation capture. I will perform formaldehyde-assisted isolation of regulatory elements and chromatin immunoprecipitation to test whether disease variants affect chromatin sign atures and binding of transcriptional regulators. The outcome will be the identification of all causal variants in 6q23 and the elucidation of their functional role. This will help to understand how intergenic variants regulate gene function. In addition, it will lead to a greater understanding of the aetiology of autoimmunity, and potentially, facilitate the development of new therapeutic targets.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: PI3K signalling in Immunity and Infection.
Funder: Wellcome Trust

Abstract: PI3Ks are a family of enzymes that have existed throughout animal evolution, from simple slime moulds to fruit flies, mice and humans. Originally, the PI3K pathway was used mainly by simple organisms to sense and respond to available nutrients. In vertebrate animals, the PI3K pathways have evolved new and interesting mechanisms that underpin the ability of the immune system to fight pathogens. With this proposal, we will study how the PI3K pathways has been adapted to ensure a fully functional i mmune system. A potential benefit of this research is that it may help find new strategies to dampen unwanted immune responses while maintaining the capacity to fight harmful bacteria and viruses.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The molecular rules that govern CD4+ T-helper cell recognition of peptide-MHCII.
Funder: Wellcome Trust

Abstract: The importance of T-cells to human health is immense. T-cells are essential for immunity to pathogens and cancer, and they hold the key to vaccination. T-cells also drive all autoimmune disease, play an important role in organ transplant rejection and are responsible for some allergic reactions. CD4+ T helper cells play a key role in orchestrating immune responses. The elimination of CD4+ T helper cells during HIV infection is the chief factor governing the devastating progression of AIDS. I plan to generate novel reagents that will be used to investigate the role of CD4+ T helper cells during immunity at the molecular level. These technologies are already highly anticipated by a number of world-leading laboratories and will have far reaching implications for the study of CD4+ T helper cells in human disease. I expect that my results will lead to improved understanding of the mechanisms that orchestrate human immunity. This work will also result in improved therapeutic interventions /diagnostics, such as vaccines. I anticipate that my findings will be utilised in many thousands of subsequent studies of these vital immune cells. The ability to track, understand and manipulate T-helper cells could lead to numerous benefits in a wide range of diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Pathways of CD4 T cell allorecognition in allograft rejection.
Funder: Wellcome Trust

Abstract: Despite the success of organ transplantation in transforming the management of patients with end-stage organ failure, most transplants eventually fail due to an immune process known as chronic rejection. The immune system comprises a large number of specialised T and B lymphocytes, and of these the CD4 T helper lymphocyte population has a pivotal role in initiating and then coordinating the immune response against foreign antigens. In transplantation, these helper T cells can be activated by two pathways (indirect or direct). It is believed that fundamental differences between these pathways have a profound impact in their duration after transplantation and in their ability to exert damage to transplanted organs. However, these differences remain unproven. This project will use mouse heart transplant models to study, in greater detail than is possible in human patients, the indirect and direct pathways, specifically concentrating on understanding what limits the longevity of these p athways, and establishing if these helper cells can in fact exert toxic effects against the transplanted organs. This will provide a greater understanding of the role of these cells in rejection and will likely make a significant contribution to the development of new therapeutic strategies.


Research activity codes: 6.4 SURGERY
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The biology of DEXI a novel candidate gene in autoimmune disease.
Funder: Wellcome Trust

Abstract: Autoimmune disease results in the destruction of healthy tissue in organs such as the pancreas in type 1 diabetes (T1D) or the nervous system in multiple sclerosis (MS), and has a strong genetic component. We have discovered that a genetic variant on Chromosome 16, associated with both T1D and MS, affects the level of expression of a small gene (DEXI) in monocytes, which are a type of white blood cell. The function of DEXI is unknown but higher expression in monocytes correlates with protection from autoimmunity. The aim of this project is to understand the biology of DEXI by determining where and when the protein is expressed in cells, as well as what happens within a cell when DEXI levels are reduced or increased. Key Goals: 1. Stimulate immune cells in culture (cell lines and cells from human blood donors) in different ways to understand what increases or decreases DEXI expression 2. Develop an antibody to detect amount and location of DEXI protein in different cells 3. Inve stigate the consequences of increasing or decreasing the amount of DEXI in cells 4. To make the DEXI protein itself so that we can study which other proteins it will bind to


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM