NIHRDataInsights/HRCSData huggingface dataset:
Title: Precision type I interferon biomarkers for the stratification of autoimmune disease
Funder: JDRF

Abstract: What are the aims of this research? Interferon is a substance affecting the action of different cells of the immune system. Increased levels of interferon are thought to be important in contributing to conditions like type 1 diabetes and rheumatoid arthritis. However Interferon is also used to treat people with multiple sclerosis. Why interferon appears to have protective or harmful effects in different autoimmune conditions is not understood. This research aims to measure interferon levels in different autoimmune conditions to better understand the relationship between interferon and autoimmunity. Why is this research important? Understanding why interferon is associated with different autoimmune conditions in harmful or protective ways could help improve treatments for people with autoimmune conditions, potentially by blocking the harmful effects of interferon and harnessing the good effects that it can have on the immune system. This research will identify people with different autoimmune conditions, including lupus, rheumatoid arthritis, type 1 diabetes, Sjögren syndrome and multiple sclerosis. The research team will measure each individual’s interferon levels, using a variety of different tests, including a new test developed by this research team, to try and find new links between interferon and these different autoimmune conditions. How will the findings benefit people with autoimmune conditions? If this research can provide more information on the relationship between interferon and autoimmunity, it could ultimately mean that doctors could better identify which treatment a person would respond to best, as well as aiding the development of drugs that regulate interferon. It is hoped that this research will also confirm whether the new test for measuring interferon is effective in different autoimmune conditions, meaning it could become the first interferon test available in routine medical practice.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigating Novel Stress Response Pathways in Neurological Disease
Funder: Medical Research Council

Abstract: Oxidative stress (OS) is a hallmark of major neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), Parkinson’s and Alzheimer’s disease as well as ageing. Importantly, OS markers are present in cell populations selectively targeted in neurodegeneration, and pathogenic mutations occur in proteins that feature prominently in antioxidant pathways. OS is also an important feature of many other major neurological disorders including multiple sclerosis and epilepsy. This project, focussing on a particular protein family, is to determine how aberrant OS defence pathways lead to neuronal damage, and ultimately whether therapeutic up-regulation of antioxidants could be applied across neurodegenerative / neurological disorders. This 3-year Programme builds on data we have generated, demonstrating that a family of proteins, that includes oxidation resistance 1 (OXR1), is a critical component of the OS response in neurons. We have gone on to show that deletion of Oxr1 causes cell-specific neurodegeneration in mice, while the protein itself is also an early marker for cell death in the CNS. Furthermore, in investigating a specific neurodegenerative disease as a proof of principle, we now know that Oxr1 and related proteins can protect against OS when over-expressed in both cellular and mouse models of ALS. Significantly, one of these OXR1-related proteins, TBC1D24, has been discovered recently to be mutated in multiple inherited forms of epilepsy that are also characterised by neurodegeneration; nevertheless, how these mutations cause this range of serious neurological disorders is unknown. The aim of this Programme is to understand the function of OXR1-related proteins in the OS response and in neurological disease. The project will harness the power of mouse genetics at the Mammalian Genetics Unit (MGU) in combination with our specific expertise in studying the molecular mechanisms of neuronal function and degeneration. We are taking a systematic approach to understand the function of TLDc proteins, examining their potentially unique and overlapping roles in neuronal cells, in addition to determining how human mutations influence key aspects of these functions. Furthermore, we hope to determine whether phenotype-genotype correlations can be identified to assist future clinical outcomes in patients.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Intracellular immunity
Funder: Medical Research Council

Abstract: The human TRIM family comprise 70 members and are implicated in diverse cellular processes including cell proliferation, differentiation, development, oncogenesis and apoptosis. Our research program is designed to determine the mechanisms of function and dysfunction of two groups of TRIM proteins that are particularly crucial to human health – the antiviral and disease-associated TRIMs. Antiviral TRIMs operate intracellularly to restrict viral replication. The mechanism by which these TRIMs target virus and prevent replication is not known. To understand these mechanisms and how viral specificity is encoded, we are determining the detailed three-dimensional interactions that occur between the multiple domains of TRIM proteins, viral proteins and the host cell machinery. In particular we are interested in why human TRIM5alpha, which in primates limits SIV replication, is defective against HIV. Disease-associated TRIMs are those in which disruption of function has been shown to mediate disease. Dysfunction of these TRIM proteins can increase susceptibility to disease (e.g. TRIM20/pyrin), cause congenital defects (e.g. TRIM18/mid1) or mediate autoimmunity (e.g. TRIM21/Ro52). We are using a combined molecular and cellular approach to determine both the mechanisms of function of these TRIMs and their path


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Early Growth and Development
Funder: Medical Research Council

Abstract: Over the past decade, a large part of ING’s research has focused on the interaction between nutrition and immunity, driven primarily by a mission to understand in detail how nutrition at critical points during early-life can influence the development of human immunity. More recently, this theme of research has evolved beyond an interest only in the developing immune system to incorporate two other developmental outcomes in infants and young children - growth and brain development. Keeping in line with ING’s mission, we will concentrate on identifying the mechanisms through which nutrition may influence development and hence identify pathways by which nutritional interventions can be effective. This will build on work projects already ongoing at our field station in Keneba, The Gambia and on the evidence emerging from analyses of existing data from the MRC Keneba databases. ING brings to these areas of research an ability to interrogate research questions from the setting of widespread undernutrition and frequent, recurrent infections, coupled with the pronounced effect of seasonality.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;3.3 NUTRITION AND CHEMOPREVENTION
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Statistical ‘omics approaches to understanding autoimmune diseases
Funder: Medical Research Council

Abstract: Autoimmune diseases collectively affect 5% of the population, and clinical presentation of one disease alters risk of another, consistent with the reported overlaps between genetic association profiles of autoimmune diseases. Diagnosis frequently leads to lifelong chronic ill health and reduced lifespan while treatment options are limited. Identification of new pharmaceutical targets, such as the biological pathways through which disease risk is modified by genetic variation is a priority. Identification of genetically validated partitions of patients within a disease according to relevant risk pathways could enable stratified medicine: delivering the right treatment that has been mechanistically matched to the right subset of patients. GWAS studies have identified hundreds of associations of diseases with genetic variation, but translation to biologicial understanding and clinical impact has been slow. This programme aims develop and apply the integrative statistical methods needed to genomic data and immunological data to better understand the causes of the diseases and the heterogeneity between and within different clinical diagnoses. Research objectives are: 1. develop methods for fine mapping candidate causal genetic variants in full genotype or summary GWAS data that are not limited by assumptions of independence between causal variants and that leverage information across diseases; 2. develop statistical tools to integrate GWAS, eQTL, and promoter targeted, high-throughput chromosome conformation capture (Hi-C) datasets from primary immune cells to define candidate causal genes, cells and pathways for autoimmune disease; 3. use longitudinal gene expression data from humans subject to some immune stimulation (pharmaceutical intervention or infection) to define specific networks (pathways) of genes involved in immune responses; 4. identify which of these pathways are enriched for autoimmune disease-associated variation and compare the enrichment between diseases; 5. partition genetic risk loci into pathway-defined immune disease gene sets; These methods will be tested on simulated data and applied to genetic association data on ~100,000 subjects and smaller detailed cellular phenotyping dataset available publicly or through collaborations with the autoimmune disease research community in the UK and internationally.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Cutaneous Immunology
Funder: Medical Research Council

Abstract: Atopic disease affects 20-30% of the UK population and includes atopic eczema, asthma and rhinitis. Current treatments are suppressive, but not curative, and carry risks of side-effects. Since the identification of an association between atopic eczema and null mutations in the gene encoding filaggrin, it has become increasingly clear that events in the epithelium represent critical susceptibility factors in disease pathogenesis. We are working towards an understanding of the pathogenesis of atopic disease, in particular to explain how the epidermal dysfunction associated with filaggrin insufficiency contributes to atopic disease and whether this can be modified therapeutically. We capitalize on the ready access to lesional tissue in humans, and to function within networks and collaborations to maximize opportunities for success. The aim of the research is to understand the pathogenesis of cutaneous atopic disease in order to inform new approaches to disease prevention and treatment. The studies will also contribute to our understanding of the interaction between the epithelium and the innate and adaptive immune response. Emphasis will be focused on: 1) how filaggrin insufficiency promotes atopic inflammation and whether this can be therapeutically modified; 2) characterising innate IL-13 producing cells in human lesional atopic skin and after antigen challenge; 3) understanding mechanisms underlying antigen-specific immunotherapy to modulate immune responses in humans and to translate these findings to patient benefit; 4) investigating mechanisms underlying the cellular immune response to viral antigens in human skin. The experimental design is based on isolation of cells from blood and skin of patients and controls. The cells from skin include keratinocytes, dendritic cell family members (eg Langerhans cells), T cells, innate lymphoid cells. The patients will include those with cutaneous atopic disease and other inflammatory skin diseases, as well as individuals before and after cutaneous antigen challenge. Studies will be undertaken ex vivo and after culture. Interactions between keratinocytes, Langerhans cells and immune effector cells will include examination by expression analyses, mediator production and functional keratinocyte outcomes such as barrier function. Molecular mechanisms underlying these findings will be investigated. As well as contributing to disease and tissue specific questions, these studies will advance the broader University Unit aims of defining the interactions between the innate and adaptive immune responses and the local micro-environment, which in turn will support the development of new approaches to vaccination and treatment.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Nano-Immunology
Funder: Medical Research Council

Abstract: Single-molecule super-resolution microscopy of membrane dynamics: Many cellular responses lead to subtle changes on the molecular level, demanding not only for a superior spatial resolution of the analyzing method but also for the sensitivity to monitor single molecules over time and space. The combination of super-resolution optical fluorescence STED microscopy with single-molecule sensitive fluorescence-detection tools such as Fluorescence Correlation Spectroscopy (FCS) as well as the fast spatio-temporal tracking of single labeled molecules (single-particle tracking, SPT) allows for the disclosure of complex dynamic processes otherwise impeded by the limited spatial resolution of conventional far-field microscopy. For example, STED-FCS or SPT offer us the possibility to gain novel insights into important cellular processes, such as lipid-lipid, lipid-protein, and protein-protein interactions and the formation of so-called “lipid-rafts” in the cellular plasma membrane. These molecular interactions play an important role in the cellular immune response. We will therefore apply and further develop the STED-FCS and SPT microscopy techniques to highlight important molecular processes on the plasma membrane as well as inside the cell during immunological reactions. For example, these techniques will be used to shed new light on different molecular pathways triggered at the cell surface and intracellularly during antigen presentation by dendritic cells and T cell activation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Innate Immunity and Host Species Barriers
Funder: Medical Research Council

Abstract: In vertebrates, the interferon (IFN) response is the first line of defence against viruses, stimulating the production of diverse antiviral proteins encoded by hundreds of IFN-stimulated genes (ISGs). These host defences are engaged in continuous evolutionary conflicts with viruses, which have evolved a variety of evasive counterstrategies. Most viruses are only able to efficiently infect and replicate within a limited set of species, and multiple lines of evidence indicate that the IFN response plays a key role in limiting cross-species transmission. Sometimes, however, viruses do succeed in “jumping” from one species to another - indicating that host innate defences have been overcome. Since most emerging viruses (e.g. Ebola virus, coronaviruses, Nipah virus etc.) persist in animal reservoirs, it is vital to understand the barriers that normally prevent cross-species transmission. In this programme, we will first characterise the ISGs of a variety of animal species, including reservoirs of zoonotic infections. We will then examine a range of important human pathogens (e.g. Ebola virus, hepatitis C, Dengue and others) in vitro and in silico to (i) define patterns of antiviral restriction by “homologous” and “heterologous” ISGs and (ii) identify important host and viral determinants of cross-species transmission. We will develop experimental systems that will allow us to dissect the evolutionary history of antiviral genes, and explore the pathways and constraints to the evolution of viral counterstrategies. Altogether, these data will provide a powerful and flexible system for (i) constructing predictive models (a “zoonotic index”) to assess the risk of future cross-species transmission events and (ii) identifying novel antiviral genes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Characterisation of signal transduction pathways that restrict activation of the innate immune system to prevent inflammatory and autoimmune diseases
Funder: Medical Research Council

Abstract: We propose to develop our understanding of novel mechanisms we have identified that keep the innate immune system in check and prevent autoimmune and inflammatory diseases. Understanding how this system is controlled and its de-regulation in disease is a prerequisite for the development of new treatments for these conditions. We will study a protein kinase subfamily that we have found to restrict the production of anti-inflammatory cytokines. We will identify which members of this subfamily mediate this effect and the underlying molecular mechanism. We will develop specific inhibitors of these kinases via collaborations with academic colleagues as well as via a unique collaboration with the pharmaceutical industry, which we have renewed until 2016. We have discovered that the IKK-related kinases (IKKepsilon and TBK1) restrict pro-inflammatory cytokine production by inhibiting the activation of NFkappaB. We have also identified additional, putative substrates of these kinases, which suggest that they restrict innate immune signalling pathways in other ways. We will elucidate these mechanisms and establish their importance in keeping innate immunity in check. We will develop our discovery that polyubiquitin-binding to ABIN1 and ABIN2 prevents lupus and protects against colitis, respectively. We will elucidate how ABIN2 protects against colitis and the molecular mechanism(s) by which ABIN1 and ABIN2 restrict innate immune signaling pathways. We will also investigate whether the deubiquitylase activity of A20, a protein that interacts with ABIN1 and ABIN2, is critical for the functions of the ABINs. This multidisciplinary research programme will exploit state-of-the-art techniques in protein chemistry, enzymology, mass spectrometry, signal transduction, immunology, mouse genetics and molecular pharmacology and should lead to the elucidation of key mechanisms that restrict the activation of innate immune signaling pathways.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Elucidating the molecular mechanism of intracellular DNA recognition by the innate immune sensor IFI16
Funder: Medical Research Council

Abstract: The overall aim of this project is to investigate the molecular mechanisms that govern the innate immune response to intracellular DNA. During infection by DNA viruses, exogenous DNA can be sensed as a pathogen-associated molecular pattern (PAMP) by intracellular pattern recognition receptors (PRRs), which then promote the production of interferon-beta. This in turn acts to establish an antiviral state in the infected cell and its neighbours, and to recruit immune cells to the site of infection. We recently identified a novel intracellular receptor for viral DNA, IFI16, which is involved in the sensing of DNA viruses such as Herpes Simplex Virus 1. In this project, we will examine the function of IFI16 in human cells in more detail, and address some fundamental questions regarding the molecular mechanisms of DNA recognition. The specific objectives of this study are: 1.) Which cellular factors contribute to the sensing of DNA by IFI16? We will employ two large-scale unbiased approaches (a genome-wide siRNA screen and a proteomics approach to find IFI16 interaction partners) in order to identify novel factors that play a role in the recognition of viral DNA. 2.) How does the cell distinguish between viral DNA and its own DNA genome? We will test the hypotheses that exogenous DNA is either sensed by virtue of its cytosolic localisation, or by the recognition of particular DNA features as signs of viral replication. 3.) Is IFI16 invovled in the sensing of DNA as danger-associated molecular pattern (DAMP)? The innate immune system can also be activated by the body's own DNA, e.g. during DNA damage or when DNA from apoptotic cells is insufficiently cleared. We will determine whether IFI16 can sense DNA as a DAMP, and explore the mechanistic links between DNA damage, viral infection and innate immunity. This work will provide fundamental insights into the innate immune response to DNA, with relevance to viral infection, vaccination and autoimmunity.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Mechanisms underlying the physiological and cellular response to food allergen challenge in human subjects with peanut allergy
Funder: Medical Research Council

Abstract: AIMS 1) To investigate the pathophysiology of acute allergic reactions to peanut, and how this relates to severity of clinical symptoms, by assessing mucosal absorption of allergen, cellular activation and vascular physiology. 2) To understand the process by which exercise may alter the character of food allergic reactions. METHODS This fellowship will capitalize on a recently funded trial involving repeated double-blind placebo-controlled food challenge (DBPCFC) of peanut-allergic adults under controlled conditions. We will assess mechanisms of the acute reaction to a food allergen through: - assays for biomarkers (blood, saliva, urine) including kinins, complement, leukotrienes and mast cell proteases. Leukocyte activation will be determined by poylchromatic flow cytometry - Assessment of local and systemic changes in vascular flow and permeability, using established non-invasive techniques - the above techniques will be repeated with DBPCFC after exercise SCIENTIFIC AND MEDICAL OPPORTUNITIES 1) Investigate how the pathophysiology of acute allergic reactions to food differs from that of non-food triggers, which are not often associated with systemic effects. This will highlight new targets for future therapeutic interventions, as well as facilitate risk stratification of peanut allergic individuals 2) Determine the extent to which animal models of food allergy are applicable to man. 3) Allow for characterisation of peanut allergic individuals in terms of peanut-specific antibody production (IgE, IgG, IgG4, IgA, free Ig light chain) and how this relates to reaction severity 4) Validation of novel salivary markers of allergic reactions, improving diagnostic opportunities in patients in whom diagnosis is unclear 5) Synergistic collaborations with the pan-European project on Integrated Approaches to Food Allergen and Allergy Risk Management (iFAAM), which will investigate intrinsic and extrinsic factors affecting the severity of reactions to foods.


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