NIHRDataInsights/HRCSData huggingface dataset:
Title: Engineering genomic features to better understand the molecular basis of immune mediated diseases and their treatment
Funder: Wellcome Trust

Abstract: Genetic and transcriptional studies have demonstrated that shared aetiology between immune-mediated diseases (IMD) is reflected in shared patterns in both data types, and suggested new targets for treatment. However, the huge number of variants and genes measured mean that only a minority of potential information in these data has been harnessed, and disease prognosis and treatment success remains variable and unpredictable. My goal is to overcome this dimensional challenge by developing genomic feature engineering which exploits these shared patterns, to extract new insight from jointly analysing over a hundred existing datasets. I will generate summary features by tailoring dimension-reduction strategies and applying them to genetic and transcriptomic data from patients and cohorts with related traits measured. I will investigate how each feature contributes to rare and common IMD risk, and prognostic variability within diseases. I will correlate features with molecular measurements and clinical data to understand the gene products they represent, and the situations (cell type, disease state/subtype) in which they are relevant. Finally, through predictive modeling, I will explore the expected impact of targeting these gene products in different diseases and subtypes, to generate, and test, hypotheses about which targets might modify specific IMD activity or progression.

Lay abstract: Genetic and transcriptional studies of immune-mediated diseases (IMD) have demonstrated complex sharing of features between these diseases, suggested new treatments, and collectively generated data on 100,000s of IMD patients. However, successes have been limited because huge sample sizes are required to robustly assess the millions of genetic variants or thousands of genes measured. Disease prognosis and treatment success in IMD remain variable and unpredictable. I will mine these data across diseases, to generate orders of magnitude fewer summary features describing shared IMD factors in a more parsimonious manner. I will use molecular measurements and clinical data to understand the gene products the features represent, and their relevant contexts (cell type, disease state/subtype). Through this targeted feature engineering, I aim to describe the relationships between different IMD, both common and rare, and identify new therapeutic treatment targets or diseases/disease-subtypes where existing treatments may be newly applicable.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigating the cell biology of wound inflammation and its consequences
Funder: Wellcome Trust

Abstract: A robust wound inflammatory response is critical for survival of most organisms. We propose analysing how innate immune cells - neutrophils and macrophages - respond to wound cues, and once they arrive at the wound what are their varied activities and functions at the wound site, both positive and negative. We will use a marriage of Drosophila and zebrafish studies to model wound inflammation and to determine, what are the earliest damage signals that draw inflammatory cells to wounds and how these cells dramatically change their phenotype during their recruitment and throughout the period of wound repair in response to the dynamic wound environment. These signals and phenotypic “switching” events will be determined by a combination of FACS, genetics and live imaging approaches which are considerably aided by the translucency of our fly and fish models. We also want to determine how inflammatory cells influence other cell lineages at the wound site including fibroblasts and melanocytes and adipocytes, to the benefit and detriment of the wound healing process, with a view to developing therapeutic interventions that might alter these influences to enhance positive instructions and dampen the negative consequences of wound inflammation including excessive scarring.

Lay abstract: An effective inflammatory response after tissue damage is critical to prevent infection and help repair the wound. However, there are also negative consequences of wound inflammation including fibrotic scarring, and when inflammation is over exuberant it can lead to chronic wound healing and other pathologies. We will analyse how inflammatory cells respond to wound signals, and once they arrive at the wound, how they instruct other cell types at the wound, including blood vessel cells, fat cells, pigment cells and cells that make scars, to do both beneficial and damaging things at the wound site. We will use a combination of fruitfly pupae and zebrafish (which are both translucent and so let us watch these events in real time down the microscope) studies to model wound inflammation and to determine the molecular basis of these conversations between cells and how to change them to improve the repair process.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: B cell activation in human GALT: drivers and consequences
Funder: Wellcome Trust

Abstract: We have identified bifurcation in human B cell development from shortly after bone marrow exit. B cells following one trajectory express high levels of IgM and have a gut-homing phenotype when in blood. They selectively migrate through gut and ultimately give rise to marginal zone B cells (MZB). The other branch expresses low levels of IgM and is systemic. All stages of the gut-homing branch are vastly depleted in the autoimmune disease lupus nephritis. We will ask: 1. What drives the lineage split that commits a subset of developing B cells to migrate into GALT, and how does this fail in lupus nephritis? 2. What happens to MZB and their precursors in GALT? 3. Do MZB emergent from GALT enter spleen and respond to further tissue specific cues? We will apply cutting-edge technologies to identify the epigenetic marks and transcriptomes that reflect the key events in vivo and use these to compare pseudotime developmental sequences. We will merge deep single cell phenotype in tissues with paired transcriptomes of single cells in suspension to create a multidimensional map of events in GALT, and track subsequent clone evolution across tissues. This understudied area of basic immunology is fundamental to good human health.

Lay abstract: We have shown for the first time that the gut is involved in maturation of an arm of the human immune response that is critical for good health. Importantly, this gut-associated stage of immune maturation is missing in the life-threatening disease lupus nephritis. We want to determine what drives this arm of the immune response to mature in the gut and how this fails in lupus nephritis. We want to understand exactly what happens in the gut that supports this aspect of immune development. We wish to know if cells that mature in the gut and leave, undergo further modifications in response to local cues at destination. This work uses cutting-edge methods that have just become available to interrogate a relatively neglected study area that our work has opened up. Outcomes will have profound implications for basic human immune physiology and disease: lupus nephritis, and much more.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: RACE - Research into Inflammatory Arthritis Centre Versus Arthritis
Funder: Versus Arthritis

Abstract: The Arthritis Research UK Rheumatoid Arthritis Pathogenesis Centre of Excellence (RACE) comprises a partnership between the Universities of Birmingham, Glasgow and Newcastle. Our renewal will integrate the Kennedy Institute for Rheumatology, University of Oxford. Evidenced by publications, research income, training portfolio, and influence in the RA pathogenesis field, RACE has firmly established itself as a world-leading collaboration: critically, RACE has delivered added value by increasing collaborative outputs, but also by enhancing the productivity of each participant university. Thus far, we have explored the biology of RA across disease phases, especially the immunological events leading to breach of tolerance, early synovitis and progression to chronicity. Our second phase (RACE2) will further develop these themes but, informed by patient feedback, will additionally focus on established RA, in particular remission, flare and refractory disease. Across two themes, our programme of cross-cutting “research clusters” will include discovery molecular and cellular science, translational and experimental medicine, and clinical trials. RACE2 will focus primarily on “tissue pathogenesis” of RA in the synovium and wider lymphoid tissues, deconstructing disease pathology using optimal contemporary methodologies. Thus, we have created a fourth ‘cluster’ namely that of underpinning technologies that is truly state-of-the-art in empowering molecular genomics through cellular analyses to experimental medicine, all supported by bioinformatic and systems modelling expertise. RACE2 will deliver an expanded four-centre PhD training programme and maintain exemplary opportunities for post-doctoral scientific training within an innovative, team-based discovery-lead culture. Finally, RACE2 will extend our investigations into the parallel but discrete pathogenesis of seronegative arthropathies, including psoriatic arthritis, as critical comparators to RA. Our vision at the end of this renewal is to broker a national axis with harmonised purpose and strategy for the investigation of inflammatory arthritis, achieved by a knowledge-driven, inclusive approach within and outwith the Centre.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Somatic mutation in human macrophages: defining ontogeny and mechanisms of inflammatory disease
Funder: Wellcome Trust

Abstract: Acquired somatic mutation continually modifies the genomes of multicellular organisms, inevitably causing human disease. The over-arching aim of this proposal, is to define how somatic mutation impacts upon macrophages, immune cells that are critical for defence, regulation, and repair. Macrophages were thought to arise through continual recruitment of monocytes, but recent data indicate that they originate and renew in diverse ways. The first aim is to use silent mutation to study the origin of human macrophages. This will discern the difference between microglia, thought to arise exclusively from a primitive origin, self-renewing macrophages derived from definitive haematopoiesis, and macrophages that require a continual input of monocytes. The second ai, will study macrophages in clonal haematopoiesis. Somatic mutation in the bone marrow has the potential to alter macrophage function and accelerate prevalent diseases such as atherosclerosis. The final aim is to explore somatic mutation in clonal macrophage populations as a novel aetiology of idiopathic inflammatory disorders IgG4-related disease, granulomatosis with polyangiitis and sarcoidosis. These are noted for their overlap with histiocytosis, the archetype of a new class of inflammatory myeloid neoplasm. Together these studies will define novel functions of macrophages in pathology that reflect their independence or connection with haematopoiesis.

Lay abstract: When a cell replicates, its DNA code is altered, introducing ‘somatic' mutations. The descendants of that cell inherit new mutations, providing a molecular bar-code allowing us to track them. I use this barcode to determine whether macrophages, a class of immune cells, are formed in the embryo, or whether they originate later, from the bone marrow. Some critical macrophages, like microglia in the brain, may be embryonic. This could be important in understanding their role in dementia. With ageing, somatic mutations cause the bone marrow to develop abnormalities. I aim to find out if bone marrow-derived macrophages transmit these abnormalities to distant tissues, increasing the risk of vascular disease and immune disorders. Finally, sometimes somatic mutation activates cancer genes. If this happens in a macrophage, an inflammatory disease may occur. I aim to discover if this is the cause of spontaneous inflammatory diseases such as vasculitis and sarcoidosis.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Chemokine receptor regulation of monocyte/macrophage dynamics in the inflammatory response.
Funder: Wellcome Trust

Abstract: Inflammatory chemokines, and their receptors, orchestrate leukocyte recruitment to inflamed sites. These molecules are fundamentally involved in immune/inflammatory diseases and thus represent important therapeutic targets. However no molecules targeting inflammatory chemokine receptors have yet been licensed for use in immune/inflammatory pathologies. We believe that this, in part, relates to the complex nature of chemokine regulation of inflammatory leukocyte recruitment which is, currently, poorly understood. We have a particular interest in four chemokine receptors: CCR1, CCR2, CCR3 and CCR5 (collectively, iCCRs), which occupy a single genomic locus and play essential, but complex, roles in inflammation. We have generated three unique mouse models to allow us to analyse the individual and combinatorial roles of the iCCRs in inflammatory leukocyte migration. These include mice with the entire iCCR locus deleted; reporter mice in which each of the iCCRs can be individually tracked and mice in which the iCCRs can be switched on individually, and thus essential functions defined. We will use combinations of transcriptomics, in vivo imaging and infection models to rigorously define roles for the iCCRs in inflammation. We propose that the data obtained will be key to both understanding basic inflammation, as well as to the development of novel anti-inflammatory therapeutics.

Lay abstract: If not controlled, inflammation gives rise to conditions such as rheumatoid arthritis, multiple sclerosis and cancer. There are therefore good reasons to want to therapeutically suppress inflammation. In inflammation, white blood cells are recruited to tissues in response to locally produced molecules called chemokines. The chemokines act as 'beacons' attracting the white blood cells which carry detectors for chemokines. Therefore, there has been much interest in trying to therapeutically interfere with chemokines, and their detectors on blood cells, in inflammatory disease. This, so far, has not been successful and we believe that this is at least in part a consequence of the extremely complex nature of the way in which chemokines and their detectors work which we really do not understand. We now propose to use novel approaches to try to analyse this. We hope that our studies will lead to new insights into disease and options for therapy.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Discovering new pathways of lymphocyte specification and function
Funder: Wellcome Trust

Abstract: The co-ordinated development and differentiation of lymphocytes is critical to producing the bespoke immune responses required to combat specific pathogens, but also to maintaining tissue homeostasis and repair. However, dysregulated immune reactions underlie undesirable chronic inflammation and autoimmunity. Our discovery of type-2 innate lymphoid cells (ILC2) and the description of other ILC subsets has highlighted additional, previously unappreciated, complexity in the processes of lymphocyte specialisation. Our challenge is to unravel the microenvironmental cues, critical cell-surface receptors, and key transcription factor interactions that lead to lymphocyte specification, tissue-specific roles and cellular interactions. We will employ a unique repertoire of lymphocyte transcription factor reporter “polychromILC” mice in combination with CRISPR-mediated screens to identify new regulators of lymphocyte development, differentiation and function. To facilitate the investigation of these new pathways in specific lymphocyte subsets in vivo we will produce a new generation of mouse strains designed to limit off-target events by employing multiple positive and negative determinants, comparable to Boolean operators (AND, OR, noT or AND noT). Finally, using a combination of genetic screens and in toto adaptive light-sheet microscopy we aim to define molecules and cells that delineate the migration and development of ILC in the context of the stromal environment.

Lay abstract: The immune system helps us combat infection, but when it goes awry friendly-fire can cause chronic inflammation such as observed in the lungs of asthma sufferers. To perform successfully the weaponised immune cells must be selected carefully and recruited to precise locations so that they can attack disease or act as peacekeepers when necessary. This process requires a highly complex communication system that must act locally in the tissues, but also across the whole body. We discovered a new type of immune cell and want to understand how these specialised innate lymphoid cells (ILC), are instructed to develop and mature with distinct properties that allow them to co-ordinate discrete immune responses to specific infectious agents. We will develop methods to investigate how specific genes regulate immunity and help protect mice from experimental models of asthma and parasitic worm infection. Knowledge from these studies will inform on potential new therapies.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Defining the Fc receptor-mediated trafficking of IgG-antigen complexes in macrophages
Funder: Wellcome Trust

Abstract: Macrophages represent the most abundant antigen presenting cells in inflammatory infiltrates and tumors. An important immunoregulatory function of macrophages is to present antigen to cognate T cells. Antibody (IgG)-antigen complexes are internalized into macrophages through potential interactions with multiple different Fc receptors and are subsequently delivered to subcellular compartments where peptides derived from the proteolyzed antigen can be loaded onto MHC molecules. However, the multitude of possible Fc receptor interactions with the antibody-antigen complexes influences the spatial and temporal behavior of antigen and consequent peptide-MHC repertoire through a complex, and poorly understood, network of subcellular trafficking pathways. We have developed advanced microscopy tools to enable the analysis of three-dimensional, dynamic cellular processes at unprecedented levels of spatiotemporal resolution. We will combine these approaches with antibody engineering and analyses in mouse models of cancer and autoimmunity to elucidate how the combination of antigen delivery vehicle, microenvironmental factors and macrophage phenotype interplay to result in specific antigen presentation outcomes. The two long term goals of these studies are: one, to develop novel mechanistic insights into the fundamental cell biological processes determining the repertoire of presented antigens; two, to define how to deliver antigen to macrophages to orchestrate a predictable immune response.

Lay abstract: Antigen presenting cells form a key part of the immune system due to their ability to transmit information about the components of the body, including cancers, and foreign invaders or tissues such as bacteria, viruses or organ transplants. On the positive side, this leads to the destruction of infectious agents, whereas negative consequences are transplant rejection or the attack of body components during autoimmunity. Macrophages represent an important class of antigen presenting cells. These cells are present throughout the body and accumulate at sites of inflammation, tumors etc. Macrophages ingest proteins called antigens derived from pathogens or, in the case of autoimmune disease or cancer, from self-proteins. To understand how macrophages transmit information to other immune cells, it is essential to define how and where an antigen travels within the macrophage. Until recently, methodology to study processes such as the movement of antigens within cells that occur on microscopic scales (around one millionth of a centimeter) has been unavailable. We have developed the necessary microscopy tools for use in our proposed project to investigate these processes. Our studies are expected to reveal important information that will allow the development of next generation treatments for diseases such as cancer and autoimmunity.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Primary Immunodeficiency: mechanism and diagnosis via integrative clinical immunogenomics.
Funder: Wellcome Trust

Abstract: Primary Immunodeficiency (PID) has a devastating impact on the lives of patients and their families, and management is aided by genetic diagnosis. 80% of PID patients have no overt family history, and thus have been intractable to gene discovery. Our recent pilot study explored whole genome sequencing (WGS) to enhance diagnosis in PID, and found only 8% of such patients carried disease causing mutations in known PID genes. By applying new Bayesian analytical techniques, we identified multiple new PID-associated genes; causative deletions in regulatory regions; and interplay between novel high-penetrance monogenic and common variants, beginning to explain the variable penetrance of PID. We will expand this WGS PID cohort, already the world’s largest, and develop additional specialised statistical tools to incorporate deep clinical, immunophenotyping and antigen receptor repertoire data to enhance WGS analysis techniques. We will use genetic association data from immune-mediated diseases to increase power, and use genetic information to characterise the clinical features predictive of PID and enhance diagnosis. This collaborative effort will enhance understanding of PID biology, define phenotypic variability, discover new disease associated genes, increase diagnostic yield - but importantly develop mechanisms for WGS-based gene discovery in cohorts of sporadic patients, applicable beyond PID.

Lay abstract: Primary immunodeficiencies (PID) are a group of rare disorders that affect at least 1 in 350 people in the UK. PID encompass a spectrum of genetic diseases that can underlie susceptibility to life-threatening infections, autoimmune diseases and some cancers. However, variability in PID symptoms and severity makes it challenging to achieve the specific diagnoses required for the care for individual patients. Recently, we showed that combining clinical and genetic knowledge of 800 PID patients reveals novel genetic causes and aids diagnosis. Using this expertise, we will extend this approach by increasing the depth of genetic, clinical and molecular measurements collected across an expanded cohort of 2,000 PID patients, and combine these measurements to characterise the molecular events that are responsible for specific forms of PID. This will provide genetic diagnosis to more patients, and by increasing our understanding of the human immune system will help develop new treatments.

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