NIHRDataInsights/HRCSData huggingface dataset:
Title: Immunosurveillance by tissue-associated T-cells
Funder: Wellcome Trust

Abstract: We address two major issues. First, the controversial issue of immunosurveillance of non-microbial tissue damage; second the biology of tissue-associated unconventional T cells , of which gamma-delta cells are the prototype. Our current Programme saw us develop a transgenic system that seemingly establishes a rapid unconventional T cell response to a single molecular marker of tissue damage, Rae-1. But is this response simply local, or does it influence adaptive responses, possibly jeopardisi ng self-tolerance? Our current programme also saw us identify a new immunoglobulin superfamily, that we term Skint. The prototype, Skint-1, determines the unconventional gamma-delta T cell repertoire in mouse skin. Given our minimal knowledge of gamma-delta selecting elements, we shall investigate the biology and mechanism-of-action of this molecule. Furthermore, we have found that a close relative of Skint-1, Btnl1, is expressed on gut epithelial cells, binds activated intestinal T cells, an d is expressed differentially in mice with different gamma-delta repertoires. The study of Btnl1 may therefore extend our insight into gut immunosurveillance. Our three goals are to characterise: 1. tissue-associated, unconventional T cell responses to non-microbial stress. 2. the biology and mechanism-of-action of Skint genes 3. the biology of Btnl1 and its interaction with unconventional T cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: PI3K signalling; the rules of engagement.
Funder: Wellcome Trust

Abstract: Nearly all of the cells of our bodies contain three related proteins called, PI3Ks alpha, beta and delta. We now know these PI3Ks play a very important role in transmitting information from extra-cellular hormones to the inside of cells. This information is needed for the cell to co-ordinate various complex responses to the hormone, such as cell growth, survival or movement. Remarkably, when Genetically-Modified mice were created that lacked each one of these PI3Ks, they revealed that a single P I3K-type, despite its great similarity to the others, was responsible for controlling specific cell responses, eg one controlled cell-growth and another controlled cell movement. As a result, pharmaceutical companies are trying to make inhibitors of each of the PI3Ks to treat specific diseases, such as cancer (where PI3Kalpha is important) or inflammation (where PI3Kdelta is important)). We still do not understand how or why each PI3K does a unique job. Consequently, there is no way of predi cting which PI3K might be important in a new situation. Our application will enable us to understand the reasons why PI3Ks are apparently used specifically and hence begin to predict when each PI3K will be important.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: How do B cells control T cell pancreas infiltration?
Funder: Wellcome Trust

Abstract: Selection mechanisms in the thymus fail to remove all T cells that recognize tissue-expressed self proteins. Self-reactive T cells capable of autoimmune damage are therefore present in the periphery. Continual recirculation of such cells through blood and lymphatics poses no danger to the host. However, if such cells gain access to the self-antigen bearing tissue, immune-mediated damage becomes a possibility. Our laboratory has developed a transgenic model in which the factors that control th e entry of self-reactive T cells into the target tissue can be dissected. We have mice bearing T cells specific for a pancreatic antigen that fail to enter the pancreas. We have found that we can trigger T cell infiltration of the pancreas by a single injection of B1 cells. This proposal seeks to identify the mechanism by which B1 cells trigger tissue infiltration. We will test whether B1 cells act directly on T cells, whether they modify vessels within the tissue to allow T cell access, and whether they have an intrinsic capacity to initiate the formation of ectopic lymphoid tissue. We will also identify the timeframe in which B cell depletion is beneficial during the onset and progression of autoimmunity.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The role and modulation of Dectin-1 function in innate and adaptive immunity.
Funder: Wellcome Trust

Abstract: Fungal infections are an important cause of morbidity and mortality, and Candida albicans, in particular, is one of the most prevalent infectious agents of man. Our immune system relies on cell surface molecules called receptors to quickly recognise and respond to infection. These receptors drive immediate protective responses as well as responses which take longer to develop, but which are tailored to the specific pathogen. I have identified one such receptor, Dectin-1 which recognises fungal c ell wall sugar components called beta-glucans, that can stimulate immune responses in purified form. Using mouse models, I propose to explore the role of Dectin-1 in triggering the immediate and pathogen specific immune responses to Candida, and other selected fungal pathogens. The role of Dectin-1 in humans will be examined, determining the effects of genetic alterations that are associated with disease. The way that beta-glucans stimulate immune responses through Dectin-1 and how this protects against infection will be determined. The use of these sugars to drive immune responses in a desirable manner will also be explored. These studies will greatly advance our understanding of the role of Dectin-1 in immunity, and will provide crucial insights to the applicability of this receptor as a therapeutic target.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The filarial nematode immunomodulator ES-62 as a tool in novel drug development for mast cell-dependent inflammatory diseases.
Funder: Wellcome Trust

Abstract: Inflammatory diseases such as those associated with allergy (e.g. asthma) and autoimmunity (e.g. rheumatoid arthritis) have reached alarming proportions in the Western World. There is no current cure for these conditions and unfortunately existing drugs are not able to control disease in all patients such that long-term, significant ill-health is common and there may even be reduced life-span. It has been known for many years that allergic diseases such as asthma arise as a consequence of a cell called the mast cell confusing harmless materials such as pollen for an invading pathogen and thereby releasing chemicals designed to kill pathogens but that instead cause inflammation and the symptoms of asthma. It is now suspected that mast cells may also release such inflammation-promoting chemicals in autoimmune diseases such as rheumatoid arthritis. We have recently discovered that a product secreted by parasitic worms, ES-62, can inhibit human mast cell function in the test tube and also protect against development of allergy in mice. In this grant application, we therefore wish to establish exactly how ES-62 works in order that we can employ it as the starting point in the development of novel drugs targeted against mast cells in allergic and autoimmune diseases


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The patho-physiology of the ALX receptor in inflammation.
Funder: Wellcome Trust

Abstract: Inflammation is a life-saving response of our body to infectious and other foreign substances, that normally resolves over time with healing and restoration of function. In some cases however, this closely-regulated response becomes disturbed and the inflammation may become chronic leading to diseases like rheumatoid arthritis. Over the years our research has focused on characterizing molecules present in our body that prevent the inflammatory response from this unnecessary over-activity, li miting its duration and intensity. Proper functioning of these endogenous counter-regulatory systems is crucial for health and if they are absent or malfunction (as may be reproduced experimentally with genetically modified animals) a chronic illness may arise. Here we propose to study one of the protective mechanisms of our body, which involves a protein ( ALX ) on the surface of the body s white blood cells and elsewhere. The biological functions of this protein as a transmitter of anti-i nflammatory signals will be determined in experimental models of inflammation, with a particular focus on arthritis and events that occur in vessels following heart attack or stroke. This project could lead to the new ideas for using this protein as a novel target for anti-inflammatory and anti-arthritic drug discovery.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Novel resolution-phase macrophages restore post-inflammation tissue homeostasis
Funder: Wellcome Trust

Abstract: I am interested in the body s response to injury, specifically in how inflammation switches off. The importance of understanding resolution lays in the likelihood that failure of this process may result in inflammation becoming dysregulated doing more harm than good. Advancing our understanding of this process, I found that it s not enough to clear white cells that accumulate during inflammation, but that tissues need to revert back to their prior balanced state in order to fight future injuries in an appropriate manner. In other words, while tissues appear to resolve as determined visually by reduced swelling, redness and pain, for instance, there are discrete events occurring, unapparent to the naked eye that are critical for immune recovery. Central to this restorative process is the influx of white cells called macrophages to tissues as they recover from inflammation. I found that these novel macrophages re-equip injured tissues with specialised armamentarium to mount acute inflamm atory responses to future infection in a tempered manner. It is this reversion to homeostasis mediated by macrophages and the mechanisms that control it that is the focus of this application. Studying this hitherto unappreciated process will enhance our understanding of why we become susceptible to secondary infection.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Complement, SLE and modulation of the adaptive immune response.
Funder: Wellcome Trust

Abstract: The aim of this research is to understand some of the mechanisms for the development of an important autoimmune disease named systemic lupus erythematosus (SLE). In this disease, antibodies develop that react with molecules that are found in all the cells of the body. These are known as autoantibodies. When autoantibodies bind to self molecules, they may cause disease by inducing inflammation in the kidneys, skin and other organs. There is evidence that a group of blood proteins called the com plement system play a key role in preventing the development of SLE by facilitating the disposal of dying cells and regulating the immune response. We have previously developed mouse strains that lack the expression of complement proteins and now we aim to study how these genetic abnormalities alter the function of the immune system and hence predispose to the development of SLE. We will also try to explore the mechanism(s) by which a common genetic variant in one of the complement receptors m ay determine a significantly higher risk of developing SLE. These studies will advance our knowledge of the causes of SLE and may lead to the identification of new pathways with potential to be amenable for future therapeutic strategies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Defining the role of chemerin peptides and ChemR23 in the endogenous anti-inflammatory network.
Funder: Wellcome Trust

Abstract: Inflammation is the complex biological response of tissues to harmful stimuli and although it is generally a beneficial process, inadequately controlled inflammatory responses can damage our own tissues. It was recently discoveredthat the body is able to control the inflammatory response by making pro-resolving mediators which dampen inflammation and aid tissue repair. During my graduate studies I discovered a novel anti-inflammatory pathway thatinvolves molecules called chemerin peptides that can suppress inflammation and promote tissue repair processes. I plan to further study this promising and novel system, focusing on the effects of chemerin peptides in two mouse models of inflammation that reproduce some aspects of human disease. I will concentrate on ischaemia-reperfusion injury; a form of tissue injury caused when blood reenters a tissue after a period of oxygen deprivation such as a heart attack, and a model of rheumatoid arthritis; whereby the body s immune system attacks joints causing joint swelling and tissue damage. If chemerin peptides can suppress inflammation in these models then I will try to elucidate the mechanisms by which they do so. This study may contribute to the discovery of new medications to treat inflammation that may work with the body s own anti-inflammatory system.


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 dendritic cell motility within stromal niches of lymph nodes.
Funder: Wellcome Trust

Abstract: Our immune system is vital for us to recognise and fight infections that enter the body. However, the immune system must also be kept in check to stop immune cells from attacking our own tissues. One specialised type of immune cell, called a dendritic cell, constantly travels around the body surveying the tissues looking for signs of infection. The dendritic cells then relay messages about what they have found to the rest of the immune system, helping to decide whether to mount an attack or whet her to leave it alone. To act as efficient messengers, dendritic cells need to move around the body to find and interact with other cells of the immune system. They need to move quickly and know where they are going so that there is no delay in starting to fight a potentially dangerous infection. I plan to investigate the mechanisms regulating how dendritic cells move through tissues and vessels, a process that is critically important to how the immune system functions.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Equipment grant to fund the purchase of a multi-colour LSRII flow cytometer (University of Manchester, Faculty of Life Sciences, Immunology and Neuroinflammation groups).
Funder: Wellcome Trust

Abstract: Our body is composed of trillions of cells, which form the specialised tissues and organs that allow us to function normally. To understand how our body works, and what goes wrong in disease, it is critical to understand the biology of our cells; how they communicate with each other, how they perform their specialised functions, and how they change during disease development. Critical to the study of cell function is the ability to identify individual cells within complex samples, to tell us w hat molecules the cells are producing, what signals they are transmitting, and how these profiles change during disease. These measurements are achievable using a technique called flow cytometry. We are undertaking a number of well-funded research projects, focussing on understanding the cellular basis of immune regulation in health, and during infection and brain injury (for example, immune regulation of parasitic infection (Grencis, Else), mechanisms of autoimmune disease (Millar, Travis), im mune responses in stroke (Rothwell, Allan)). Many of the experiments we perform rely heavily on flow cytometry to detect our cells/molecules of interest. Progression of these projects would be greatly enhanced by state-of-the-art flow cytometry. This proposal requests funds to purchase a new flow cytometer for our groups.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: An RNAi screen for integrin regulation in T cells.
Funder: Wellcome Trust

Abstract: T cells are white blood cells that play a critical role in mounting immune responses against infections by viruses, bacteria and parasites. For these T cells to respond to the infectious agent, they must be triggered into action. This happens when they run into another cell that has the infection within it, for example a cell infected with a virus. For the T cell to be triggered into action to start fighting the infection, it needs to stick tightly to this infected cell. We are studying the process by which this tight sticking occurs. In particular, we are looking for proteins inside the T cell that play an important role in making sure the T cell sticks to the infected cell. Such proteins may eventually turn out to be good targets for drugs that would modulate the activity of the immune system, and would be applicable in conditions where the immune system is overactive, for example in rheumatoid arthritis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Understanding the basis and impact of gene co-evolution within the chicken MHC.
Funder: Wellcome Trust

Abstract: Of the many genes associated with disease, those found in the major histocompatibility complex (MHC) are among the most important. Unexpectedly, the human MHC associates strongly with autoimmune diseases, while the chicken MHC associates with resistance to infectious pathogens and responses to vaccines. Understanding this difference is important since chickens supply much food as well as carrying diseases harmful to humans (eg., avian influenza). The organisation of genes in the human MHC al lows multiple class I molecules which together provide a good chance of binding peptides from any pathogen and from self antigens. In chickens, the genomic organisation is different, so molecules which supply peptides interact specifically with a particular class I molecule, allowing only one well-expressed class I molecule, which may or may not bind an appropriate peptide to present to T lymphocytes. We wish to better understand the basis for and the impact of this co-evolution of genes, by studying the interactions of chicken class I molecules with the molecules supplying the peptides and with cells recognising class I molecules. The results will teach us fundamental rules about how genomic organisation affects gene function, as well as laying the basis for practical utilisation of this information.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Interactions between polymorphic human immune receptors.
Funder: Wellcome Trust

Abstract: We will study human immune genes of particular importance to disease, including autoimmune conditions, infections and cancer. The main set of genes, the MHC, is central to the way the immune system distinguishes diseased from normal tissue. We will examine functions of selected MHC genes as well as their related products, particularly those exhibiting person-to-person variation in relation to disease. One major aim will be to search for molecules that interact with the proteins we are studying. A key set of genes encodes receptors for MHC molecules, in a region of the genome called the LRC. A second aim is to obtain genetic evidence of interactions between these linked proteins in disease. We pioneered cloning of some MHC genes and have been studying them for over 25 years. Our success in this area in the last decade is due to flourishing interactions with colleagues in the Cambridge area as well as international collaborations.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Defining the signalling that leads to activation of lymphocyte integrins.
Funder: Wellcome Trust

Abstract: A successful immune response depends on the ability of the blood s white cells to crawl along the blood vessels and penetrate into an infected or injured tissue site. To attach to vessels, the white cells use sticky integrins whose behaviour is controlled by other molecules found inside the same cells. A molecule named kindlin-3 is important because it is mutated in patients suffering from life-threatening infections due to integrin dysfunction. The involvement of such controlling molecules h as been discovered through use of static assays that lack movement of fluid such as cells would experience in the circulation. Therefore our goal is to investigate molecules like kindlin-3 using an assay that mimics the flow of blood. Our primary goal is to develop the shear flow assay. We want to automate the analysis of the cell images allowing greater accuracy and throughput of results. The present analysis involves manually observing numerous individual cells and is laborious and inaccur ate. Secondly, we will use the shear flow assay, and compare it with the well-tested static assay, to investigate the molecules that control the behaviour of the integrins on the white cells, with emphasis on how kindlin-3 helps them to function.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The establishment of a large case collection of childhood atopic dermatitis: a resource for genetic research
Funder: Wellcome Trust

Abstract: Atopic dermatitis (AD; eczema) is the commonest inflammatory disease of childhood and causes a very significant burden of disease. AD leads to a markedly increased risk of associated food allergy, asthma and allergic rhinitis. While mutations in the skin barrier protein filaggrin are the strongest genetic risks identified to date, the genetic basis of AD remains poorly understood and there is a pressing need for additional large scale genome wide association studies (GWAS) on well-phenotyped, et hnically homogeneous populations to identify further genetic factors. This Biomedical Resources Grant has the key objective of generating a large collection of well-phenotyped paediatric AD cases suitable for GWAS and other studies investigating the genetic susceptibility of atopic dermatitis. In order to maximise efficiency, standardise clinical governance and quality of data and sample collection, the application will utilise established Clinical Research Centres including the Wellcome Trus t Clinical Research Facility in Manchester. To ensure the collection is processed rapidly, the collaboration will be performed in 9 clinical centres where large numbers of children with atopic dermatitis regularly attend for secondary and tertiary care. To ensure sustainability and compatibility with other collections, we will regularly collaborate with the two other leading groups in the field.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM