NIHRDataInsights/HRCSData huggingface dataset:
Title: The role of cell surface metalloproteinases in the development of rheumatoid arthritis
Funder: Arthritis Research UK

Abstract: The joint pathology of rheumatoid arthritis (RA) is characterised by formation of inflamed pannus tissue containing numerous inflammatory cells and cartilage invasion by the pannus. However, mechanisms of these events are not clearly understood to date. Our recent studies indicate that membrane-type 1 matrix metalloproteinase (MT1-MMP) is a pivotal enzyme that promotes both pannus formation and its cartilage invasion. We reported that MT1-MMP is an essential promoter of cartilage invasion and is highly expressed in cartilage invading synovial cells and macrophages. Our recent data suggest that cartilage matrix provides cells pro-invasive signals upregulating MT1-MMP expression and function. Pannus formation is initiated by infiltration of inflammatory cells into synovial membrane, and our recent data using the MT1-MMP selective inhibitor in animal models of arthritis suggest that MT1-MMP may be an enzyme that promotes infiltration of inflammatory cells into joint synovium. Therefore in this programme, we aim to investigate (i) cartilage-driven MT1-MMP upregulation through discoidin domain receptor 2; and (ii) the role of MT1-MMP and other related MMPs in inflammatory cell infiltration into arthritic joints. Understanding the mechanism of MT1-MMP regulation in these invading cells is a key to understanding RA pathogenesis, and to identify novel therapeutic targets for future RA therapy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Regulation of the Th17 pathway in rheumatoid arthritis and psoriatic arthritis
Funder: Arthritis Research UK

Abstract: Although cytokine blockade has been a fundamental therapeutic advance for patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA), it does not provide a cure nor is long lasting immunological tolerance restored. Regulatory T cells (Treg) have the potential to both curtail inflammatory responses and restore tolerance. However, the highly inflammatory cytokine Il-17, implicated in the pathogenesis of RA and PsA, is resistant to Treg suppression. Our pilot data have identified a potent Treg subset, isolated from RA patients treated with anti-TNF antibodies, which can suppress both IL-17 producing T cells (Th17) and Th1, in contrast to Treg from healthy controls or RA patients responding to etanercept. This finding provides a unique opportunity to dissect the molecular basis for this novel Treg population, their potential to be induced in PsA, and identify the mechanisms which endow these Treg with the ability to control Th17. We will investigate whether these Treg impact upon the immune response to tuberculosis, a particular complication of anti-TNF antibodies. Our aim is to develop novel and safe therapeutic strategies applicable to both RA and PsA, based on a full understanding of these powerful Treg in order to restrain both Th1 and Th17 associated inflammatory arthritis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Mechanisms underlying inflammation associated muscle loss
Funder: Arthritis Research UK

Abstract: Muscle weakness is a common and disabling feature of systemic inflammatory diseases and rheumatoid arthritis in particular. Increased systemic levels of pro-inflammatory cytokines appear to mediate this effect. Muscle weakness is also seen during glucocorticoid treatment but glucocorticoid signalling in muscle cells also appears essential for muscle loss in many pathological conditions. We have recently identified that pro-inflammatory cytokines dramatically increase the expression and activity of the glucocorticoid activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in muscle. The hypothesis to be explored in this Project Grant is that inflammation induced expression of 11β-HSD1, and the consequent increased tissue level of glucocorticoids, is the basis for inflammation associated myopathy and muscle loss. We will explore the regulation and functional consequences of 11β-HSD1 expression within muscle during inflammation. In a range of in vitro, in vivo and clinical studies we will determine the relationship between inflammation and 11β-HSD1 expression in muscle; examine the molecular mechanisms involved in induction of activity, and examine the functional impact of inflammation induced glucocorticoid activation on muscle mass, composition and strength.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Phosphoinositide 3-kinase isoforms as potential new therapeutic modalities in MSU crystal-mediated inflammasome activation and gout
Funder: Arthritis Research UK

Abstract: Gout is a debilitating auto-inflammatory condition, provoked by the deposition of monosodium urate (MSU) crystals. Phagocytes are implicated in gout pathology by taking up crystal deposits, which lead to activation of their inflammasome pathway and establish a state of chronic inflammation._x000D_ _x000D_ We propose to investigate the role of phosphoinositide 3-kinase (PI3K) signalling enzymes in inflammasome activation leading to gout. Using newly generated PI3K null mice, we have found that the p110β and Vps34 family members of PI3K are involved in crystal-mediated inflammasome activation._x000D_ _x000D_ Our key hypothesis is that these PI3Ks control the probing, capture and uptake of crystals by phagocytes leading to inflammasome activation. Interference with these early stages of uptake mechanisms could be a new therapeutic mode of interference with crystal-mediated auto-inflammatory disease, and identify these PI3K isoforms as novel therapeutic targets in gout._x000D_ _x000D_ Our key goals are:_x000D_ _x000D_ _x000D_ To determine the contribution and mechanism of action of p110β and Vps34 in MSU crystal-uptake and inflammasome activation by phagocytes in cell-based assays._x000D_ To uncover the role of p110β and Vps34 in MSU crystal-mediated inflammation leading to gout in vivo._x000D_ To explore the therapeutic outcomes of blocking the activity of these PI3K isoforms in animal models of advanced gout.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Monocyte function in enthesitis related arthritis- towards identification of targets for therapy
Funder: Arthritis Research UK

Abstract: Enthesitis related arthritis (ERA) is a form of childhood arthritis causing peripheral arthritis and axial inflammation. There is a dearth of clinical and basic science research into this important condition despite the difference in clinical phenotype from other forms of juvenile idiopathic arthritis and also adult ankylosing spondylitis. At University College London Hospital, we have a large cohort of well-characterised patients with ERA and noticed two distinct clinical phenotypes within this group: those with axial disease - who were mostly HLA B27 positive and often had hip arthritis and those without axial disease - who had predominantly peripheral arthritis, enthesitis and a lower proportion of HLA B27 positivity. These differences in clinical phenotype suggest differences in the underlying pathological mechanism of disease; in particular we hypothesise that the function of key immune mediators, such as monocytes may differ between the two groups. _x000D_ _x000D_ The purpose of this Fellowship is to identify the cytokines and molecular pathways through which monocyte/macrophage activation occurs in ERA, with the aim of defining differences in the underlying pathological mechanisms between the two clinical phenotypes of ERA. This, potentially, will allow us to identify new therapeutic targets and appropriate treatments for this important childhood disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Exploring the role of synovial fibroblasts in regulating leukocyte accumulation during the development of persistent arthritis.
Funder: Arthritis Research UK

Abstract: Fibroblasts actively regulate the accumulation of leukocytes, and act in a pro- or anti-inflammatory manner depending on their site of origin. Therefore, the phenotype of the fibroblast, which becomes corrupted in chronic disease, may be a critical determinant of whether leukocyte recruitment and therefore inflammation resolves or persists. In this proposal we will test the hypothesis that reprogramming of fibroblasts during the development of rheumatoid arthritis is responsible for the accumulation and retention of lymphocytes in the joint. To test this, we will combine novel multi-cellular in vitro models developed in Birmingham with in vivo imaging, to track the capture of flowing lymphocytes and determine their subsequent fate within artificial synovial organ cultures. A key aim is to dissect how synovial fibroblasts from different stages of arthritis influence the recruitment and migration patterns of lymphocytes. Based on variations in these parameters, we will elucidate the molecular pathways responsible for the differential responses; identifying key fibroblast derived mediators responsible for the switch from resolving to persistent lymphocyte recruitment. Targeting fibroblasts to restore normal patterns of lymphocyte entry and exit is a novel and potentially powerful approach to treating rheumatoid arthritis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Neutrophil Migration through Lymphatic Vessels and their Role in Acquired Immunity in Rheumatoid Arthritis
Funder: Arthritis Research UK

Abstract: Neutrophils are key effectors of the innate immune response but can also contribute to the development of many acute inflammatory diseases. In addition there is evidence for neutrophil involvement in acquired immunity and pathogenesis of numerous chronic inflammatory conditions such as rheumatoid arthritis. The precise role of neutrophils in this autoimmune disorder is unclear but recent data from the applicant provides direct evidence for the ability of neutrophils to migrate into lymphatic vessels and lymph nodes following antigen-induced arthritis. It is thus hypothesized that neutrophil entry into lymphatic vessels plays an important role in the initiation of autoimmune diseases. This may be facilitated through altered phenotype of tissue recruited neutrophils during arthritis, as compared to blood neutrophils, a phenotype change that may promote both the entry of neutrophils into lymphatic vessels and in supporting the associated acquired immune response. The present project thus aims to characterize the mechanisms of neutrophil/lymphatic vessel interactions in vivo as analyzed by intravital confocal microscopy and the implications of this response to the development of arthritis. Collectively, the project will address a previously unexplored aspect of leukocyte biology and chronic disorders thus making a significant and novel contribution to the field of inflammation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The role of the cytokine TSLP in human inflammatory arthritis: factors influencing its secretion and effects.
Funder: Arthritis Research UK

Abstract: This project will investigate the role of the cytokine TSLP in inflammatory arthritis. TSLP is mainly produced by non-immune cells, particularly epithelial cell, but also synovial fibroblasts (FLS) Building on observations that TSLP plays a role in animal models of arthritis, and our findings that production of TSLP is strongly influenced by cellular stress, we will investigate the stimuli which elicit TSLP from FLS, and also dendritic cells (DC) [which we recently showed also to produce TSLP], and whether they differ. We will also examine the effects of different forms of cellular stress on TSLP production by the two kinds of cells, including stress caused by mechanical stretching, and the molecular basis of this effect, i.e. the transcription factors and signalling pathways involved, using shRNA knockdown and experiments in gene-targeted murine cells. Lastly, we will investigate the effects of TSLP from FLS, or through autocrine production, on DC. Specifically, we will determine the effects of TSLP-exposed DC on cytokine production of T cells, particularly IL-17. Lastly, we will test whether exposure to TSLP accounts for our previous observations of the emergence of CD8+ T cells secreting "Tc2" cytokines from co-cultures of DC and CD8+ T cells from AS patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Exploring risk and protective haplotypes of the MHC class III gene, MSH5, in systemic lupus erythematosus
Funder: Arthritis Research UK

Abstract: Genetic variants within the major histocompatibility complex (MHC), located on the short arm of chromosome 6, confer the greatest genetic risk for SLE in all populations studied thus far. Hence, delineating causal MHC variants will provide significant insights into the molecular pathways involved in disease pathogenesis. However, the basis of such association has remained elusive due to extended linkage disequilibrium, copy number variation and high polymorphism at loci within the region._x000D_ _x000D_ Recent data implicate polymorphism within the MHC class III gene, MSH5, in SLE risk. However, this locus is in linkage disequilibrium with the MHC class II gene, HLA-drB1. This study aims to fine-map MSH5 risk and protective haplotypes using high-density SNP sets and exome sequencing data from SLE cohorts of differing ancestry. Following these analyses, correlation and association will be sought between SNPs and HLA alleles and variant HLA allele amino acids in order to unravel these complex signals. The latter analyses are novel to SLE and a similar study has recently proven to be successful in refining MHC associations in HIV-1 infection. SNPs that are independent of HLA allele/amino acid association will be taken forward for downstream functional investigation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The role of the extracellular matrix in chronic inflammation and rheumatoid arthritis
Funder: Arthritis Research UK

Abstract: Rheumatoid arthritis (RA) is a debilitating disease affecting 1% of the population worldwide. Current biological drugs, such as anti-TNF, successfully treat some RA patients in the short-term. However, repeated treatments are required, rendering this an expensive therapeutic approach, and long-term remission is rare. Total suppression of cytokine function also carries inherent problems such as increased infectious risk. One major obstacle to developing better treatments for RA is that the factors that drive persistent joint inflammation are not well defined. Tenascin-C is an extracellular matrix protein that is specifically induced upon tissue injury and found at high levels in the RA joint. We demonstrated that tenascin-C induces pro-inflammatory cytokine synthesis, via activation of Toll-like receptor 4, and Th17 cell polarization causing prolonged inflammation and tissue destruction in human and murine models of joint disease. However, the precise mode of tenascin-C action is unknown. This study aims to identify the mechanism by which tenascin-C interacts with and signals to cells to mediate inflammation and to define how a pro-inflammatory extracellular niche within the RA synovium supports a sustained immune response. These data will advance our understanding of the molecular pathogenesis of RA and provide a number of new strategies for treating disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Mechanisms of pain in inflammatory arthritis: contribution of sensory neurons, dorsal horn neurons and microglia
Funder: Arthritis Research UK

Abstract: The ultimate aim of our research is to develop new and better treatments for patients with arthritis and related illnesses. In order to achieve this we will develop and test our own treatments but we will also test drugs that are already being used or studied in other conditions, such as cancer â this will be quicker than having to start from the beginning.When testing new drugs we will use a so-called âexperimental medicineâ approach. Rather than testing a new treatment on lots of patients, we will offer the treatment to just a few. To understand as much as we can about the drug and whether it may provide a good treatment, we will perform tests on their blood and possibly on other specimens, eg taken from the joint before and after treatment. We may also develop new scans for the same reason.When patients become involved with research they generally benefit, regardless of the actual drug under test. There are a number of reasons why this might be but we therefore feel it is really important for everyone to understand about research. Experimental medicine research in particular can seem quite daunting for the patient, and sometimes even for their nurse and doctor: the treatments are new and therefore may not work, and the patients may also need to undergo special tests to provide the specimens needed. Consequently we will also develop a programme of activities and materials that provide information to patients and their relatives/carers, doctors and nurses. This will help them to understand the research better and to decide whether or not to become involved


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Psychometric testing of the Valued Life Activities Questionnaire and Measure of Activity Performance-Hand in people with rheumatoid arthritis.
Funder: Arthritis Research UK

Abstract: Stratified healthcare programme: Maximising therapeutic use of biologic drugs using diseased tissue biomarkers (specific markers in diseased tissue) – Modelling its impact on patient care and validation in prospective clinical trials.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Development of novel recombinant biotherapeutics for the treatment of Rheumatoid Arthritis.
Funder: Arthritis Research UK

Abstract: Despite the obvious impact of current biological agents for the treatment of Rheumatoid Arthritis, development of novel agents that offer a greater frequency of remission induction and improved safety profiles remains an important goal in RA therapy (1). Developing rationally designed, molecularly targeted therapy to the joint for the treatment of disease offers the promise of greater specificity coupled with reduced systemic toxicity. In this context, we have successfully generated a panel of human framework recombinant antibodies with specificity for human synovium microvasculature. In characterising these, we have found one antibody, scFv-A7, exhibits strong reactivity to synovial microvasculature in vitro and can efficiently and preferentially target microvasculature of human arthritic synovial xenografts in SCID mice. Further, scFv-A7 does not exhibit reactivity with microvasculature of normal human tissues. The specific reactivity of scFv-A7 indicates this antibody represents a unique, powerful and versatile tool with great potential for the development of ligand-based vascular targeting biopharmaceuticals, capable of selective accumulation at arthritic neo-vascular site. The aim of this proposal is to identify the target molecule for scFv-A7 and establish the application of scFv-A7 as an innovative therapeutic for the treatment of RA.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Stromal markers in early arthritis: the role of fibroblast markers in determining progression to and outcome in rheumatoid arthritis.
Funder: Arthritis Research UK

Abstract: In order to address these aims we will carry out a programme of work that will focus on a series of more specific questions. These will include:


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Trial of Rituximab in Refractory Extra-Renal Systemic Lupus Erythematosus (TREES)
Funder: Arthritis Research UK

Abstract: What is the relationship between ankle injury and chronic ankle osteoarthritis (OA)? Can we improve treatment of ankle injuries to prevent development of OA?


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Developing an educational framework to facilitate optimal care delivery for juvenile idiopathic arthritis within clinical networks
Funder: Arthritis Research UK

Abstract: Clinical networks have the potential to address inequities in clinical care within paediatric rheumatology. This is acknowledged in the consensus derived British Society for Paediatric and Adolescent Rheumatology (BSPAR) and Arthritis and Musculoskeletal Alliance (ARMA) Standards of Care (SOC) for Juvenile Idiopathic Arthritis (JIA). These SOC set out minimum requirements for a quality clinical service to include “access to specialist multidisciplinary teams working within identifiable clinical networks, and with appropriate skills and experience for managing children and young people with arthritis”. The number of paediatric rheumatology clinical networks is increasing and involve clinicians with variable expertise and training. Pilot data demonstrates a self-perceived unmet need for postgraduate training amongst clinicians working in such networks. Using existing literature, qualitative methodologies and opinion from stakeholders within different healthcare settings we will identify educational needs of doctors working in clinical networks. We will also describe barriers and challenges to addressing these needs and identify strategies to deliver these needs within educational programmes. Our goals are intrinsically linked to improving access to optimal care and improved outcomes for children and young people with JIA.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Differential effects of anti-TNF therapies for inflammatory arthritides on immune responses to Mycobacterium tuberculosis.
Funder: Arthritis Research UK

Abstract: Tumour necrosis factor (TNF) antagonists have revolutionised the therapy for rheumatoid arthritis and other inflammatory arthropathies. This success is partly tempered by the substantially increased risk of granulomatous infectious diseases, particularly tuberculosis (TB). My aim is to elucidate how TNF blockade leads to an increased incidence of tuberculosis. In those patients with inflammatory arthritis and known immunological memory for Mycobacterium tuberculosis (Mtb), a novel in vivo approach based on genome-wide transcription profiling of skin biopsy samples after intradermal injection of TB antigens will be used, to assess the effects of anti-TNF therapies at molecular and systems levels. Additional ex vivo and in vitro experiments, will be used to test the hypothesis that regulatory T cells, previously identified to be induced by anti-TNF antibodies, modulate innate (mononocyte, macrophage and dendritic cell) or adaptive (T cell) immune responses to Mtb. These results will inform the development of rational approaches to prevention/treatment of TB in patients receiving anti-TNF therapy and may allow more targeted therapeutic immunomodulation for the treatment of inflammatory arthritis. Biomarkers or assays could be identified to assess the potential of novel biologic agents to cause clinically significant immunodeficiency.


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