NIHRDataInsights/HRCSData huggingface dataset:
Title: Understanding the Relationship between the Synovial Fibroblast and the Mesenchymal Stem Cell in Rheumatoid Arthritis
Funder: Versus Arthritis

Abstract: In rheumatoid arthritis (RA), the fibroblast-like synoviocyte (FLS) causes joint destruction and spreads disease to unaffected joints. Its ontogeny, however, remains unknown. We previously reported the characterization of mesenchymal stem cells (MSC) from the adult human synovium. Recently, an in vivo double-nucleoside labelling scheme in mice allowed the identification within synovium of endogenous stromal stem cells with a MSC-like phenotype. Our preliminary work indicates that the stromal stem cells within synovium are heterogeneous with a subset co-expressing FLS markers. In this study, we propose to perform double-nucleoside labelling experiments in the collagen-induced arthritis model of RA in mice carrying genetically marked synovium and bone marrow stromal cells. By coupling cell-tracking techniques with marker analysis, we will determine whether 1) the FLS is a stromal stem cell that proliferates to sustain the synovial hyperplasia of the RA pannus and 2) the RA-FLS is a resident synovial MSC-like stem cell and/or derived from the bone marrow stromal cells. Finally, we will address whether functional properties of MSC and FLS reside in single stromal stem cells from human RA synovium. Understanding the relationship between FLS and MSC in RA is crucial for development of therapies to halt disease progression and restore joint homeostasis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Defining the Role of Cell Migration in the Initiation and Regulation of Pathogenesis in Inflammatory Arthritis
Funder: Versus Arthritis

Abstract: Current pathogenesis-based therapeutics have substantially improved outcomes in RA although a significant unmet clinical need remains. Despite tantalising advances, many fundamental pathophysiological processes underlying disease initiation and progression remain unknown. Increasingly, attention has focused on the initial events that subserve breach of tolerance, and articular localisation of disease. The molecular pathways that regulate dynamic recruitment, recirculation and retention of leukocytes between the musculoskeletal and lymphoid systems must underlie this process, but remarkably, remain understudied. We contend that a fuller understanding of these processes is fundamentally important in designing novel therapeutics and refining the application of existing agents to achieve remission. We therefore propose a programme to test the hypothesis that 'alterations in temporal and spatial control of cytokine and chemokine expression leads to disruption of normal synovial immune surveillance creating an altered synovial/draining lymph node microenvironment permissive to the establishment of chronic destructive inflammatory arthritis’.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Targeting fibroblasts in the treatment of inflammatory arthritis
Funder: Versus Arthritis

Abstract: Despite their biological importance, remarkably little is known about how fibroblast numbers and subsets change during inflammation. Difficulties in accessing patients with very early disease, sampling the tissue involved and the lack of good fibroblast markers have all proved obstacles to such work. We have addressed these limitations and using an unbiased screen identified three markers (CD248, FAP and gp38) that discriminate between fibroblasts in unaffected and inflamed synovium and salivary glands. These three markers associate with different diagnostic outcomes in synovial biopsies from patients with early undifferentiated arthritis. Using a combination of human explant tissue and mouse models of synovial and salivary gland inflammation, we will test the hypothesis that fibroblast subsets identified by CD248, FAP and gp38 determine whether inflammation persists or resolves. We will investigate the biological properties of these fibroblast subsets in human-SCID mouse models of migration and cartilage invasion. Using transgenic fluorescent reporter mice we will explore the origins and fate of the fibroblast subsets as inflammation progresses. Finally we will determine the effects on arthritis and salivary gland inflammation of systematically deleting fibroblast subsets using diphtheria toxin receptor transgenic mice.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Molecular requirements for the induction of tolerance in activated and memory CD4 T cells
Funder: Versus Arthritis

Abstract: Autoimmune diseases, such as rheumatoid arthritis, occur when an individual’s immune system responds to their own organs, causing tissue damage and painful inflammation. While current treatments can alleviate some of these effects, they cannot bring about an overall cure. A greater understanding of how to control the immune cells that drive rheumatoid arthritis, the specific CD4 T cells that respond to self-tissues, will provide the means to design targeted and rational therapeutics. Using cutting edge techniques to track responding cells types ex vivo and in vivo, I propose to examine how best to tolerize antigen-specific effector and memory CD4 T cells and to evaluate the mechanisms of this tolerization. By examining the alterations of cell surface and intracellular signalling molecules following tolerance induction, I will build up a signature of cellular tolerance that I will use to screen cells from rheumatoid arthritis patients. Together this information will provide vital details about how best to control or abolish the CD4 T cells that are at the crux of this autoimmune disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigating the role of omega-3 derived resolvins in inflammatory arthritis
Funder: Versus Arthritis

Abstract: Omega-3 polyunsaturated fatty acids are known to alleviate joint stiffness and pain in rheumatoid arthritis patients. Omega-3 derived lipid mediators,termed Resolvins, have recently been identified and shown to exert anti-inflammatory and pro-resolving properties, which could explain the benefits of omega-3 supplementation in inflammatory pathologies. Supported by an Arthritis Research UK foundation fellowship, I demonstrated that Resolvins inhibit PMN-endothelial interactions and dampen acute inflammation. With this novel fellowship I will test the hypothesis that Resolvins limit leukocyte recruitment to the inflamed joint and exert tissue protective properties in experimental arthritis. I will challenge the hypothesis that inadequate synthesis of Resolvins might contribute to the persistence of inflammatory arthritis. I will address the following key goals: I will profile the metabolites of omega-6 (arachidonic acid) and omega-3 (eicosapentaenoic and docosahexaenoic acid) by LC-MS/MS based lipidomics during experimental arthritis within the plasma (systemic inflammation) and hind limb (local inflammatory joint). I will also investigate the temporal expression of key enzymes involved in lipid mediator biosynthesis (including COX-1 and -2, 5- and 12/15-LOX) during early onset and established arthritis. Finally, I will test the translational potential of RvD1 on human synovial samples from RA patients in studies utilizing the human/SCID mouse chimera model.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: RITUXILUP - an open label randomised multicentre controlled trial of Rituximab and mycophenolate mofetil (MMF) without oral steroids for the treatment of lupus nephritis
Funder: Versus Arthritis

Abstract: The treatment of the multisystem autoimmune disease systemic lupus erythematosus (SLE) remains a challenge, particularly when there is renal involvement (lupus nephritis). For the last 60 years corticosteroids have been the backbone of the treatment of lupus nephritis but they are associated with significant toxicity. Although randomized placebo controlled trials of Rituximab in non-renal lupus and lupus nephritis did not meet their primary end-points, there is accumulating data that suggests that B cell depletion with Rituximab may be efficacious in lupus disease refractory to conventional therapy. Furthermore, our pilot data suggests that the addition of Rituximab to mycophenolate mofetil (MMF) without oral steroids is at least as effective at inducing a renal response as the standard of care therapy comprising MMF and high dose oral corticosteroids. RITUXILUP is a proof of concept, open labeled, randomized, controlled, multicentre trial that aims to demonstrate whether the addition of Rituximab to MMF therapy is useful in treating a new flare of lupus nephritis and whether it has a long lasting steroid-sparing, beneficial effect with equal efficacy and greater safety than a conventional regimen of MMF and oral prednisolone. If successful, this trial has the potential to dramatically change the management of lupus nephritis.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Rheumatoid Arthritis Centre of Excellence (RACE) - Towards a Cure.
Funder: Versus Arthritis

Abstract: We propose a conceptually unique Centre to implement a transformative programme concerning RA pathogenesis. Three Universities, with outstanding expertise and track records in the field, will together deliver a comprehensive ‘systems biology’ based evaluation of the disease, from pre-RA to chronicity, building upon existing funded programmes. Directly reflecting current unmet clinical needs, our goals are to elucidate mechanisms that underlie emergence of autoimmunity in RA and factors that mediate transition to, and maintain chronicity of synovial inflammation thereafter, representing failure of homeostatic inflammation resolution. Thus, we will unravel the complex interplay that exists between ‘professional’ immune cells and stromal cellular pathways that together contrive to perpetuate, or resolve articular inflammation. In so doing, we will establish a state-of-the art, integrated technical capability within which scientists and expertise can move seamlessly between groups, and an outstanding multi-centre PhD, and post-doctoral training fellowship programme to provide a unique national resource and programme for the development of future rheumatology research leaders. Each component builds on international pre-eminence and firmly established networks with other UK Centres and European leaders. We will therefore create a world-leading, first-in-class facility for the UK to enhance understanding of RA pathogenesis, to create novel biomarkers and curative therapeutics.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Understanding ectopic lymphoid structure development in the inflamed synovium – evaluating the prognostic and therapeutic potential of IL-27
Funder: Versus Arthritis

Abstract: Evaluation of early inflammatory arthritis patients through ultrasound-directed biopsy sampling of joints has allowed the stratification of disease according to histopathology. For example, the inflamed synovium can be classified as tissues rich in fibroblasts, myeloid cells and lymphocytic cells. The latter often form distinct lymphoid aggregates that resemble organised secondary lymphoid organs. Approximately 25% of rheumatoid arthritis patients develop these lymphoid structures, which are associated with severe disease symptoms. Studies outlined herein will identify mechanisms that underpin development of these ectopic lymphoid structures (ELS).


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Arthritis Research UK Centre for Genetics and Genomics
Funder: Versus Arthritis

Abstract: The applicants, with Arthritis Research UK support, have made enormous progress in identification of susceptibility loci for three types of inflammatory arthritis. This has been achieved through recruitment to an unrivalled collection of patient cohorts, leadership of national and international consortia, participation in a series of ground-breaking projects (WTCCC, Immunochip, Exome Chip) and leveraging of significant additional funding. Our vision for the Centre of Excellence will be to provide a national and international focus for advancing our understanding of the genetic contribution to onset, outcome, response to and toxicity of therapy in inflammatory arthritis (rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis). We will achieve this through a series of projects addressing two key goals: (i) an increased understanding of the heterogeneity of inflammatory arthritis using genetics, genomics and epigenetics and (ii) identification of predictors of disease outcome, including treatment response. Our aim is to ensure that patients will benefit fully from our discoveries through stratified medicine with safer use of existing therapies and through the identification of targets for novel drug design. Based in high quality genetic and genomic facilities, training for the next generation of researchers, and supporting the work of collaborators, will be central to our mission.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Epigenetic mechanisms of mesenchymal stem cell function in relation to inflammation, ageing and tissue regeneration
Funder: Versus Arthritis

Abstract: Recent research has provided strong evidence that epigenetics is a central mechanism which controls stem cell physiology and inflammation. Epigenetics also provides possible means to manipulate the complex interactions that occur in inflammatory disease, for example to suppress cytokine production, alter senescence behaviour, control differentiation and thereby understand and manipulate disease. Despite this progress a detailed picture and systematic understanding about which epigenetic factors are important are missing and we attempt to address this impasse in our program.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Functional genomic studies of PTPN22 in mouse models of arthritis
Funder: Versus Arthritis

Abstract: Genetic variants of PTPN22, encoding the protein tyrosine phosphatase Lyp in man (PEP in mouse), are associated with autoimmune diseases such as RA and SLE. The R620W variant is one of the strongest risk factors for RA outside the HLA region. Initial reports described Lyp/Pep as a negative regulator of antigen receptor signaling, and so functional genomic studies have focused on thresholds of TCR and BCR signaling. Since Src and Syk family kinases are important substrates of Lyp, PTPN22 variants could perturb intracellular pathways besides antigen receptor signaling. Our research will exploit new in vivo models and state-of-the-art imaging to identify and characterise pathways involved in the initiation and persistence of immune and inflammatory responses that are regulated by Ptpn22 in the mouse, and perturbed by Ptpn22 genetic mutants associated with autoimmune disease. Our specific goals are to:


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Childhood Arthritis Prospective Study (CAPS)
Funder: Versus Arthritis

Abstract: The Childhood Arthritis Prospective Study (CAPS), a unique cohort of over 1400 children with inflammatory arthritis recruited at presentation to paediatric rheumatology, was established to address an unmet clinical need; the lack of long-term prognostic information for children with arthritis. The study collects comprehensive demographic, clinical and psychological data alongside a linked bio-bank and aims to benchmark multiple outcomes (e.g. disease activity, disability, treatment response, quality of life) whilst also investigating predictive markers. CAPS has already provided valuable insights into short term outcomes. The challenge remains to provide long-term prognostic information which, given the heterogeneity of childhood arthritis, will require large sample sizes with complete follow up data. Despite the large size of CAPS, only a small proportion of children have completed even 5 years of follow-up thus far. Therefore, continued follow up of patients is crucial to meet this challenge and fulfil the goals of CAPS. This application for a further 5 years of funding will secure longer term follow-up in a substantial proportion of children already recruited to CAPS, thus maximising the ability of this resource to provide high quality, contemporary information on the long-term prognosis of childhood-onset arthritis and help better direct therapies in this chronic disease.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Targeted DNA sequencing in Indian and European samples contributes to causal allele identification for lupus
Funder: Versus Arthritis

Abstract: Main question: We seek to define the causal alleles for three risk loci delineated for lupus following GWAS, since extensive LD at each loci has hampered these efforts. Main methods: Using trans-ancestral mapping in a novel population we will narrow down the susceptibility intervals at three risk loci associated with lupus in multiple populations. Specifically we will re-sequence the associated haplotypes for TNFSF4, IKZF3 and UBE2L3 in Indian lupus samples and define alleles shared with other ancestries or population-specific, including novel coding variants. We will undertake association analysis in the Indian data and meta-analysis to compare the allelic/haplotypic diversity with existing genetic data in Europeans, Africans, Amerindians and South-East Asians. Conditional logistic regression will discover the markers showing the strongest association in each population. Bioinformatic prediction tools will be used to functionally annotate the identified variants. Anticipated outcomes: We will exploit the unique genetic diversity within Indian samples to identify causal alleles affecting biological function, variants affecting increased disease prevalence and markers of increased disease severity. Defining these classes of variation within associated loci and subsequent functional characterisation as part of the programme of research with the group will provide increased understanding of the molecular mechanisms underlying disease susceptibility.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Utilising the circadian clock to open new treatment avenues for rheumatoid arthritis
Funder: Versus Arthritis

Abstract: Cellular components of the immune system have autonomous clocks, which imprint 24h rhythms on immune function, thereby temporally gating inflammatory responses. Rheumatoid arthritis (RA) has long been associated with circadian variation, with patients demonstrating peaks in painful joint stiffness in the early morning. My previous studies with a murine model of inflammatory arthritis (collagen induced arthritis) reveal that the clock drives expression of a wide range of inflammatory mediators, imposing 24h rhythms in local (joint) and circulating levels of pro-inflammatory cytokines. Cytokine levels are significantly higher during the day, compared to night. In keeping with the human condition, this coincides with a morning peak in joint swelling. The clock is now recognised as a potential therapeutic target for the treatment of inflammatory disorders. In support I have shown that activation of the core clock protein CRYPTOCHROME (via a novel compound) has potent anti-inflammatory actions in joint-derived cells. This project will explore the hypothesis that the clock within the immune system controls disease expression and treatment responsiveness of inflammatory arthritis. Further, I will investigate whether tailoring existing and novel (clock-regulatory) treatments in phase with the immune clock can significantly improve therapeutic efficacy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The dissection of novel signalling networks controlled by the salt-inducible kinases during the resolution of inflammatory arthritis.
Funder: Versus Arthritis

Abstract: An enhanced understanding of the molecular mechanisms controlling the resolution of inflammation is expected to identify novel drug targets for the treatment of inflammatory arthritis. A key aspect of this process involves the switching of macrophages from a pro-inflammatory, classically-activated state to an anti-inflammatory, regulatory phenotype. My discovery that the Salt-Inducible Kinases (SIKs) regulate the formation of regulatory macrophages has raised many interesting questions about the role of this kinase family in macrophage biology and the resolution of inflammation. Moreover, the remarkable effects of SIK inhibitors on macrophage polarization mark these kinases as attractive targets for the development of novel anti-inflammatory drugs. My research goals are therefore to: 1) explain at the molecular level how SIKs promote the production of pro-inflammatory cytokines in macrophages to prevent the resolution of inflammation, and 2) establish whether the inhibition of the SIKs facilitates the resolution of inflammatory arthritis using animal models of disease. I will achieve these goals by exploiting novel SIK inhibitors and mouse lines carrying catalytically-inactivating mutations of the SIKs that I have been developing in Dundee in combination with state-of-the-art technologies in biochemistry, chemical biology, mass spectrometry and animal models of disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Understanding the effects of TNF on regulatory T cells in patients with rheumatoid arthritis
Funder: Versus Arthritis

Abstract: TNF is a pivotal pro-inflammatory cytokine contributing to the pathogenesis of rheumatoid arthritis (RA). However, there is conflicting evidence regarding its ability to boost or inhibit the function of regulatory T cells (Treg), which are considered vital for the effective resolution of inflammation. We and others have found that Treg function is impaired in patients with RA, and we subsequently characterised a potent population of Th17 suppressing Treg in the peripheral blood of RA patients responding to anti-TNF antibody therapy. Our goal in this proposal is to elucidate the interplay between TNF and Treg in RA patients in the context of therapeutic TNF blockade to define a roadmap towards tolerance. Building on pilot data we will identify the cellular and molecular components, including the downstream signalling pathways, that orchestrate the modulation of Treg by anti-TNF in RA. We will test whether an in vitro assay wherein anti-TNF drives Treg expansion can predict subsequent response to therapy. Our goal is to understand how blockade of TNF can enhance the function of Treg, to develop biomarkers of response and inform development of novel therapies that restrain inflammation whilst promoting tolerance.


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