NIHRDataInsights/HRCSData huggingface dataset:
Title: Biomechanical sensors and the maintenance of genomic integrity
Funder: Wellcome Trust

Abstract: 1. Development of novel therapeutic approaches for primary immunodeficiency: We will develop new gene transfer vectors for reduced mutagenicity but also for enhanced tissue-specific activity. These will be evaluated in cell culture and murine model systems. We will alsodevelop gene correction strategies, and application of alternative cellular targets based on reprogrammed somatic cells. Ongoing clinical trials will further inform areas of development and potential for broadened application to other disease candidates. 2. Studies on the Wiskott-Aldrich Syndrome Protein (WASp) and functionality ofthe immune system: we will determine the significance of WASp activation for functionality in murine model


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Development of novel therapeutic approaches for primary immunodeficiency.
Funder: Wellcome Trust

Abstract: 1. Diseases such as the Wiskott-Aldrich Syndrome are often lethal, and need complex treatment by bone marrow transplantation. However, if a good donor is not available, these techniques may be unsuccessful. Recent clinical trials have shown that gene therapy offers a real chance to fix the problem in the patients own bone marrow. However, to make this work more safely and with better effect, modifications need to be made to the formulation of the genetic medicines. This can be done in several wa ys, possibly even by correcting the actual genetic mistake in the bone marrow cells. 2. We will study how key regulators of our immune system contribute to the way in which we become protected against infections, and also prevent the development of disease such as autoimmunity and cancer. To do this, we will study a rare inherited disease of the blood called the Wiskott-Aldrich Syndrome, in which immune cells have difficulty in getting to the right place for these important tasks. Studying mode ls of this condition will provide new ideas for better therapies in WAS but possibly many other diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Anti-CD20 therapy in SLE patients: what can we learn from the B cells-repopulation phase.
Funder: Wellcome Trust

Abstract: Systemic lupus erythematosus (SLE) is a severe autoimmune disease which affect many parts of the body (skin, kidneys, joints, heart, lungs, brain). Although treatment for SLE has advanced considerably over the last few decades sufferers can still find the disease debilitating and for many it will be fatal. B cell depletion therapy is one of the recent breakthroughs in the alleviation of this disease. B cells are one of the major cell types of the immune system that can recognise and respond to infections by producing antibodies however in SLE these B cells are involved in a vicious cycle that is directed against the body. Removal of these B cells may break this vicious cycle and restore health. Unfortunately this does not always work, as not all patients respond to treatment. We intend to investigate the B cells that repopulate after being depleted, and effect these returning B cells have on other cells of the immune system. Comparing the differences between the returning B ce lls of responding patients with those patients who have not responded will further the understanding of both the contribution of B cells to the disease processes of SLE and how B cell depletion therapy works.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Meso-scale spatial reorganization of membrane proteins and the initiation of receptor triggering in T cells.
Funder: Wellcome Trust

Abstract: White blood cells are a key part of our immune response, responsible for clearing the body of infection. T cells are one type of white blood cell that goes around testing the surfaces of cells to determine whether they have been infected. While we understand many of the events that lead to identification of an infected cell we know less about the key initial events that start the response in which our T cells deal with the problem of the infected cell. This is of great importance since if the te sting of cells goes awry it can result in many diseases such as rheumatoid arthritis and multiple sclerosis, in which the T-cells turn on us. We propose to study how the proteins on the cell surface reorganise during the very initial stages of the response of the T cell. This will provide new insights into the molecular basis of triggering and may result in new ways to control immune responses and prevent disease.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Transcriptional regulation of human T cell differentiation.
Funder: Wellcome Trust

Abstract: CD4+ T cells differentiate into a number of effector types that define the immune response to different pathogens. Differentiation into specialized effectors is linked to changes in chromatin structure at key genes and transcription factors have been identified that are critical for this process. These epigenetic modifications provide a memory of cellular state passed onto cellular descendents. T cell effector types are also remarkably plastic and this combination of specificity and plasticity i s likely to be critical for the normal regulation of T cell effector function. We will identify the changes in histone methylation that occur across the genome during differentiation of primary human CD4+ T cells. We will test the hypothesis that lineage-specific gene expression is regulated primarily at the level of transcriptional elongation and determine the role of master regulator transcription factors. From these data, we will develop a conceptual framework that explains the specificity an d plasticity of the helper T cell response. All aspects of this proposal are underpinned by significant amounts of preliminary data. We will define these mechanisms with a combination of established in vitro and in vivo genomic, genetic and biochemical methods and this work will significantly enhance our understanding of human disease processes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The role of ATG5 in SLE
Funder: Wellcome Trust

Abstract: SLE is an autoimmune disease with frequently devastating clinical features, predominantly affecting women of Afro-Caribbean ethnicity. It has a strong genetic basis, inherited as a complex trait. Two recent large GWA studies have identified the gene ATG5 to be significantly disease-associated. ATG5 is a component of the autophagy system, by which cells recycle intracellular proteins. It is highly expressed in immune cells, and is required for apoptotic cell corpse clearance, type I interferon re gulation, and tolerance induction in the thymus. Its roles in immunity intersect with the proposed pathogenic basis of SLE. The study aims to confirm the association of ATG5 with SLE in European and Afro-American cohorts using a dense marker set of SNPs, and to resequence the ATG5 locus to identify rare causative variants. Using this data to select patients with risk haplotypes, the expression of ATG5 mRNA and protein in immune cells will be examined, and correlated with genotype. Finally, control of gene expression may be examined. The implication of autophagy in SLE would be a significant advance in the understanding of the pathogenesis of this disease. Autophagy can be manipulated pharmacologically, and could prove a valuable target in the treatment of SLE.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: T-cell regulation of CNS autoimmune disease.
Funder: Wellcome Trust

Abstract: Autoimmune diseases arise when an individual s immune system attacks the tissues of its own body. If this happens in the brain then he or she might develop multiple sclerosis, a disease for which there is currently no effective treatment. You can think of the immune system as a balance. On the one side there are cells (the effectors) that violently attack and destroy microbes such as viruses and bacteria. On the other side are cells (the regulators) that dampen down this violent response and hence prevent collateral damage to surrounding tissues. We have found ways to build up the regulator cells; we have now shown that one such approach, peptide therapy, is safe to administer to patients. As yet, however, we know very little about how the regulators appear in the body or how they function. By understanding how they are produced we may be able to use drugs to enhance both their generation and their regulatory function. We have identified two key proteins that control the regula tors; by studying their properties, we intend to ensure that induction of the regulators is both safe and effective for treatment of autoimmune and other diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Inhibiting TLR signalling by disruption of membrane microdomains.
Funder: Wellcome Trust

Abstract: Our immune system protects us from infections. It detects infections using a group of proteins called Toll-like receptors (TLRs). These sit in the membrane of the cell and bind to infectious particles. They then transmit signals into the cell to say infections are present. In addition to detecting infections, TLRs can also detect cell damage. They therefore help the immune system to clean up sites of damage and infection. If TLRs are activated when they shouldn't be, it can cause tissue damage and inflammatory diseases. We think we have found a way of stopping TLRs signalling, by modifying the cell membrane. This study will examine the potential to stop TLRs signalling by altering the cell membrane structure. We think that this approach may allow the safe inhibition of TLR function, with the potential to reduce excessive TLR signalling in disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The cellular and molecular basis for the impact of vitamin A on immunity.
Funder: Wellcome Trust

Abstract: Mankind suffers from of a litany of immune-related diseases. Over-activity of the immune system results in the development of autoimmune disease (rheumatoid arthritis, multiple sclerosis) while immune impairment results in increased susceptibility to cancer (melanoma, lymphoma) and infectious disease (influenza, AIDS). Drugs that can enhance or impair immunity have long been sought to intervene in these diseases. Vitamins (like Vitamin A) have been heralded as supplements that can boost the im mune system. A scientific breakthrough of how vitamin A controls immunity may allow us to use vitamin A-like drugs to set the level of immunity we need to control disease. We have discovered that vitamin A is essential for the function of cells that mediate inflammation. Therefore vitamin A-like drugs may be able to boost immunity to infectious disease and cancer. In another context, vitamin A enhances the activity of cells that suppress immunity, and therefore impair the development of auto immunity. To bring these aspirations to fruition we need to understand how vitamin A regulates immunity. The studies proposed will resolve the mechanisms through which vitamin A regulates immunity. Armed with this knowledge, drugs that target the vitamin A pathway can be intelligently developed and used to treat human disease.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The influence of eosinophils on intestinal macrophage and dendritic cell biology.
Funder: Wellcome Trust

Abstract: Inflammatory disorders are very common. It is well documented that having an inflammatory condition such as asthma, or inflammation of the intestine, alters the ability of the body s defence system to mount subsequent responses to new pathogens or other foreign entities. The mechanisms underlying these observations are not well understood but urgently need to be addressed, given the significant public health implications of pre-existing inflammation altering immunity to pathogens. Our proposal explores how immune responses in the healthy and inflamed gut are initiated and controlled. Specialised immune cells called Macrophages and Dendritic Cell (M/DCs) are needed to trigger an immune response. M/DCs are instructed by other cells in order to induce appropriate immune responses. We have identified a novel role for cells called eosinophils in regulating M/DC biology. Our research will define how eosinophils regulate M/DC function through the use of specialised mice which lack eosinophil s and two models of gut inflammation which use infection with parasitic worms to generate an inflamed environment.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Human and mouse genetics studies of filaggrin-related proteins in eczema and allergy
Funder: Wellcome Trust

Abstract: We recently identified the major gene for atopic dermatitis ( eczema ) a disease that affects 20% of children. The filaggrin gene defect is carried by about 10% of the population and impairs the skin s barrier function, which normally keeps foreign substances out of the body. The filaggrin gene defect also predisposes individuals to allergies, asthma and hay fever. Filaggrin is one of a family of related genes, all with similar functions. Little is known about what these related genes do n ormally or in disease. There is evidence from human genetics studies that genes filaggrin-related genes may also contribute to atopic diseases. We also have mouse mutants with defects in filaggrin and a related gene. Our main goal here is to analyse these filaggrin-related genes for disease-causing mutations. This will be done by state-of-the-art human and mouse genetics methods. Understanding all the genes involved in atopic disease will undoubtedly lead to design of better, more effectiv e treatments aimed at the root causes of the disease. Coupling new treatments and preventative measures with genetic testing may reduce the numbers of children who get atopic disease in the future.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Eastablishing the role of trans-endocytosis a new molecular mechanism for CTLA-4 function
Funder: Wellcome Trust

Abstract: We have generated a novel model for the function of CTLA-4. We have considerable evidence that CTLA-4 works by removing its ligands (by trans-endocytosis) fromantigen presenting cells. Consequently, it can suppress immunity by inhibiting CD28 costimulation- which uses the same ligands. We believe, that this model accounts for many of the key features of the CD28/CTLA-4 system, as well as the most robustexperimental data presently available. We now wish to extend these novel observations to address the predictions of our model and determine its functional impact. Accordingly, we will use a range of in vitro and in vivo studies to address: Under what conditions does CTLA-4 regulate T cell responses to Dendritic


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Signalling in T-cell immunity.
Funder: Wellcome Trust

Abstract: The overall goal of this application is to gain a better understanding of the T-cell signalling mechanisms that regulate T-cell immunity. The proposal will define the intracellular processes that control T-cell adhesion, migration and movement in lymph nodes in response to foreign antigen. Secondly, we propose to extend our initial exciting findings that an intracellular signalling protein termed SLP-76 can modify the make-up of nuclear pores that transport proteins in and out of the nucleus. La stly, we will define further our proposed model ('reverse-stop signal model') that controls the receptor induced autoimmunity, and determine how certain factors termed chemokines control this event. Overall, an understanding of these events is needed to understand the molecular basis of T-cell function, and to develop new strategies and therapeutics in the treatment of immune deficiencies, transplantation and autoimmune disorders.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: A highly dynamic role of corticosteroid-binding globulin in the stress-induced glucocorticoid hormone response
Funder: Wellcome Trust

Abstract: Glucocorticoid hormones, secreted by the adrenal gland, play in both animals and humans a very important role in the body's response to stressful events and therefore need to be tightly regulated. Glucocorticoid hormones in the blood are bound to a transport protein called CBG and only a rather tiny fraction of hormone is free, i.e. not bound and therefore available to enter the tissues and exert its function. Our recent discovery of a quick rise in blood CBG levels after stress brings CBG in th e centre of the biological control of glucocorticoid hormone function in the body. Now we wish to investigate how exactly stress affects CBG levels in terms of its time course, the identity of the hormones and other substances mediating the effect of stress on CBG, the regulation of the expression of the CBG gene (in liver), and how exercise affects these processes. Given that disturbed glucocorticoid function plays an important role in many stress-related diseases such as major depression, chro nic fatigue, cardiovascular disease and obesity (affecting a significant part of the population) and in view of the health benefits of moderate exercise (e.g. enhancing 'stress resilience'), research on the role of CBG is of great importance.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Understanding T cell receptor (TCR) signalling requirements for thymic gamma/delta cell development; are gamma/delta cells selected through their TCR?.
Funder: Wellcome Trust

Abstract: Gamma/delta T cells are key components of the immune system that fight a wide range of infection and cancer. Indeed, boosting gamma/delta T cell function is now being assessed in advanced clinical trials against several diseases. However, surprisingly little is known about their basic biology; for example, it is still not clear what gamma/delta T cells recognise on pathogens or tumours, or how they develop their useful characteristics. Clearly, this lack of knowledge will not benefit the optimis ation of gamma/delta T cell-based therapies in the clinic. Thus, this proposal focuses on how gamma/delta T cells develop in an organ called the thymus, which is found above the heart. It investigates whether certain gamma/delta T cells are selected based on their ability to recognise targets that are relevant to either infections or cancer. It also investigates whether this selection process also endows the selected gamma/delta T cells with the ability to produce substances that are tailored to fighting specific threats, e.g. against invading bacteria, or a recently established cancerous cell. We envisage that this improved understanding of basic gamma/delta T cell biology will provide an important foundation for the development of future therapeutic strategies for a wide range of human disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Integration of inhibitory NK cell receptors at the T cell immune synapse.
Funder: Wellcome Trust

Abstract: Cytotoxic T cells (CTLs) are a subset of immune cells which play a decisive role in fighting viral infection. During chronic disease infection persists despite a constant CTL response. Under such conditions CTL frequently express receptors which counteract and inhibit their activation. When inhibitory receptors are engaged the activity of CTL is reduced or dysregulated. Therefore the clearance of virus is less efficient, and this may contribute to the persistence of chronic infection. We aim to determine how different inhibitory receptors interact and interfere with the activation of CTLs at different levels. We will visualize the interference by inhibitory receptors with the process of CTL activation in live cells at the molecular level by means of novel high resolution, high speed microscopy techniques. Specifically, we will study 1) the disruption of processes at the CTL surface though which the CTL normally senses the presence of infection, 2) the mechanism by which inhibitory receptors achieve such disruption, and 3) the nature of the dysregulation of CTL as a result of interference by inhibitory receptors. By investigating how such inhibitory receptors work we will deepen our knowledge into the mechanism behind the immune response during chronic disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Regulation of adaptive immunity by proteolytic systems
Funder: Wellcome Trust

Abstract: Foreign pathogens come in all shapes and sizes need to be converted to a common currency to be recognised by the immune system. Proteins from bacteria and viruses are broken down into short pieces called peptides which are then presented to key immune cells called T cells. Vaccines also contain proteins and those also need to be converted to peptides so that protective T cells can be induced. Unfortunately, similar events of protein processing are also involved when the immune system is inad vertently activated in the absence of an infection, for example in allergies and autoimmune disease. We are studying the enzymes (proteases) that convert proteins to peptides for good and bad immune recognition. It is becoming clear that some of these enzymes control many other key events in the immune response and that there are also inhibitors that can modulate their activity. We believe that the more we know about these enzymes and their regulators the more possibilities there will be to enhance good immune responses, for example those induced by vaccines. It may also be possible to diminish bad immune responses since it is possible to develop drugs to block proteases.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM