NIHRDataInsights/HRCSData huggingface dataset:
Title: Reducing the persistent pain of juvenile arthritis: a targeted translational approach
Funder: Versus Arthritis

Abstract: Young people with juvenile idiopathic arthritis (JIA) often have persistent pain, even without active arthritis, which negatively impacts on their quality of life. We have shown in rodent models that inflammatory pain sensitivity peaks in pre-adolescence and that spinal pain pathways are uniquely vulnerable to ‘priming’ by early life inflammation leading to increased pain sensitivity in later life. Understanding the mechanisms underlying this pattern of pain in young individuals will lead to better treatments for JIA pain. Behavioural, electrophysiological, pharmacological and molecular biological methods will be used in juvenile and adult rodent arthritic models to test three hypotheses 1: Joint pain and central sensitization in young patients is driven by a unique pro-nociceptive spinal cytokine profile not observed in adults 2: Nociceptive inputs from young inflamed joints alter spinal neuroimmune maturation, enhancing the pro-nociceptive cytokine response to future inflammation, 3: Current treatments do not target central pain generating cytokines and a state of central sensitization remains. The experiments will identify novel targets to reduce JIA pain. To facilitate translation into clinical practice, quantitative sensory testing will be used to map pain and central sensitization in adolescent JIA patients, thus paving the way for future clinical studies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Interleukin-37 isoform A (IL-37a): a novel immunosuppressive cytokine in autoimmune arthritis
Funder: Versus Arthritis

Abstract: Despite advances in biologic therapies, there remains significant unmet clinical need in psoriatic arthritis (PsA) and rheumatoid arthritis (RA). Dysregulation of T cells, in particular Th17 cell activation and self-tolerance, plays a role in the pathogenesis of both disorders. There is a need to identify factors which can correct immunotolerance and inhibit major pathogenic pathways. IL-37a, a unique member of the IL-37 family, may represent a novel immunosuppressive cytokine. To date, only the function of the IL-37b isoform has been studied. Our preliminary results suggest that IL-37a differs from IL-37b in induction, maturation and nuclear translocation, and is more effective in the suppression of inflammatory response in vitro and in vivo. Furthermore, IL-37 expression is higher in RA synovial tissue than PsA, suggesting possible disease-specific differences. We propose here to define the novel anti-arthrogenic effects of IL-37a in PsA and RA patient-derived cells, and to define the underlying mechanisms by which IL-37 isoforms inhibit the key arthrogenic pathways in animal models and human subjects. Potential findings from this study are expected not only to identify previously unrecognised anti-arthrogenic pathways in RA and PsA but also offer potential therapeutic options for inflammatory arthritic diseases.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Targeting endothelial activation to suppress pain in a model of inflammatory arthritis
Funder: Versus Arthritis

Abstract: Systemic inflammatory diseases, e.g. rheumatoid arthritis are associated with systemic endothelial dysfunction/activation and increased risk of cardiovascular disease. In experimental inflammatory arthritis, we found that activation of endothelial cells in the spinal cord correlates with the development of pain. Targeting vascular endothelial growth factor receptor 2 (VEGFR2) reduced both the pain and the number of activated dorsal horn blood vessels. We hypothesise that spinal endothelial activation contributes to the pain in inflammatory arthritis by facilitating migration of immune cells into the central nervous system, which then differentiate into activated microglia and enhance pain signaling.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Translating findings from genome wide association studies into novel therapeutic targets for rheumatoid arthritis
Funder: Versus Arthritis

Abstract: Genetics provides the largest component for predisposition to rheumatoid arthritis (RA). Association studies have been successful in determining over 100 genetic regions containing variants associated with RA risk. However, since the vast majority of these variants lie in non-coding regions of the genome, there has been limited success in finding disease-causing genes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Development, Validation and Clinical Implementation of Novel MRI Biomarkers of Inflammation in Enthesitis-Related Arthritis
Funder: Versus Arthritis

Abstract: Aim: To develop and validate novel quantitative magnetic resonance imaging (MRI) biomarkers of sacroiliac joint (SIJ) inflammation in enthesitis-related arthritis (ERA).


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Defining the role of TAM receptor signalling in lupus nephritis
Funder: Versus Arthritis

Abstract: Systemic lupus erythematosus (SLE) carries substantial morbidity and mortality due to severe nephritis. There is an urgent need to address deficiencies in current treatments, which are costly with unwanted side effects. The purpose of this study is to define the role of TAM receptor signalling in lupus nephritis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigating and exploiting the lactate/SLC5A12-induced metabolic signalling network in rheumatoid arthritis stratified medicine and therapy
Funder: Versus Arthritis

Abstract: Rheumatoid arthritis (RA) is characterised by a highly heterogeneous chronic inflammatory synovitis, with different histological phenotypes i.e. lymphoid-(L), myeloid-(M) and fibroid-(F). As a result of inflammation the RA synovial microenvironment is hypoxic and acidic partly due to the accumulation of lactate, the end product of anaerobic glycolysis. Exposure of CD4+ T-cells to lactate inhibits their migratory capabilities and induces their shift toward a Th17 phenotype. These effects are mediated by lactate interaction with its transporter SLC5A12 and provide the rationale to exploit the targeting of the lactate/SLC5A12 metabolic signalling pathway to modulate inflammatory responses in RA joints. In this application I propose to i) Investigate the lactate/SLC5A12-metabolic pathway in the RA synovium as a potential biomarker for patients stratification, disease progression and response to treatment; ii) test whether the modulation of the lactate/SLC5A12 signalling can be exploited to manipulate RA CD4+ T-cell functions in vitro and iii) evaluate the therapeutic effects of the blockade of SLC5A12 in animal models of arthritis in promoting the resolution of joint inflammation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Acquired immunodeficiency in ANCA associated vasculitis (AAV) (ACQUIVAS)
Funder: Versus Arthritis

Abstract: Immunosuppressive therapies, including rituximab, a B cell depleting agent, have transformed ANCA associated vasculitis (AAV) from a largely fatal to a chronic relapsing condition. However, all cause mortality and rates of infection remain increased in patients with AAV compared to the general population. The cumulative adverse effects of disease activity and treatments now dominate patient outcomes. These include an increased propensity for infection and acquired humoral immune deficiency as long term consequences of immunosuppression.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Improving delivery of care and self management for young people with arthritis
Funder: Versus Arthritis

Abstract: Background: Arthritis beginning in childhood or adolescence (juvenile idiopathic arthritis, JIA) causes pain, swelling and stiffness of the joints. JIA progresses into adulthood in the majority of patients with JIA, and if not treated effectively during the childhood and adolescent years, can lead to disability and problems related to educational, social and physical development in later life. Adolescence is a unique period during which young people (YP; ages 11-24 years) need to develop an executive suite of skills including autonomy, resilience and self-management. Disappointingly, gaps in the care of this patient group, particularly at transfer from paediatric to adult health-care provision, are still reported, despite the solid evidence base supporting the need for planned and individualized developmentally appropriate care. Health service provision which fails to meet the needs of YP at this time of significant change may thus result in deterioration in health or disengagement with services and consequent non-adherence to treatment which can have negative long-term consequences. Developmentally appropriate care is also re-assuring to parents who are at the same time trying to ‘let go’ of their child’s care, as they become self-sufficient. The overall focus of this project is to improve the care service provision for YP with JIA and ultimately their quality of life through driving service improvement and reducing unwarranted variation. The aim of this project is therefore to develop composite measures of optimal care in the form of a benchmarking toolkit that will allow comparative evaluation of clinical service performance in rheumatology YP friendly services across the country – applicable to both paediatric and adult rheumatology services delivering care to YP.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Role of Salt Inducible Kinases in Autoimmunity
Funder: Versus Arthritis

Abstract: Inflammatory arthritis remains difficult to treat despite recent therapeutic advances. The identification and validation of new drug targets therefore remains an important goal. We have recently identified members of the Salt Inducible Kinases (SIK) family as being important in regulating the balance between pro and anti-inflammatory cytokine production in ex vivo immune cells. Inhibition of SIK increased IL-10 production while repressing pro-inflammatory cytokines such as TNF and IL-12. The aim of this project will be to translate these findings into in vivo models and provide validation of SIKs as a drug target. To achieve this, we have generated knockin mice expressing catalytically inactive mutants of each SIK isoform. Due to a developmental phenotype in the SIK3 knockin, we have also obtained a conditional SIK3 knockout. These mice will be used to determine the effect of SIK inhibition on pathology in mouse models of arthritis and lung fibrosis (a common co-morbidity with inflammatory arthritis). In addition, we will explore the effect of pharmacological inhibition of SIK in vivo and look at potential molecular mechanisms of action downstream of SIKs. Together these studies will allow evaluation of the roles of SIK in autoimmunity and its suitability as a therapeutic target.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: RUNX3 regulation in ankylosing spondylitis
Funder: Versus Arthritis

Abstract: Most of the genetic associations of ankylosing spondylitis (AS) are unexplained but several (RUNX3, EOMES, TBX21, IL7 and IL7R) affect lymphocyte biology. The AS-associated single nucleotide polymorphism (SNP), rs4648889, located in a regulatory region (enhancer) 2kb upstream of RUNX3, may explain the disease association at this locus by its allele-specific effects on transcription factor (TF) recruitment in CD8+ T-cells. This enhancer shows functional effects and contains several SNPs associated with AS. I will identify the components of the local protein-DNA “interactome” that regulate transcription and define the epigenetic landscape of the 5’ RUNX3 region modulated by AS-associated SNPs. I will use biochemical/biomolecular approaches to establish functional causality of SNPs in the 5’ RUNX3 enhancer, including 1) DNA pull-down/mass spectrometry to characterise allele-specific TF binding, 2) ChIP-seq to demonstrate effects ex vivo, 3) chromosome conformation capture to analyse chromatin interaction(s), 4) serial editing (CRISPR-Cas9 technology) of the 5’ RUNX3 enhancer, and 5) in vitro knockdown of RUNX3 to investigate its downstream regulatory effects using gene expression arrays. By investigating the AS-associated mechanisms controlling RUNX3 transcription and the regulatory effects of RUNX3 itself on downstream gene expression I expect to identify pathways that include credible therapeutic targets for future drug development.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Computational modelling and functional investigation of neutrophil activation and plasticity in inflammatory disease
Funder: Versus Arthritis

Abstract: Neutrophils contribute to disease pathology in inflammatory diseases including rheumatoid arthritis (RA), lupus and vasculitis. Their activation induces rapid release of tissue-damaging proteases and ROS, secretion of inflammatory cytokines/chemokines, and exposure of auto-antigens on neutrophil extracellular traps (NETs). My research uses RNA-seq to understand the complex, heterogeneous phenotypes of neutrophils in inflammatory diseases. My work has (a) replicated the complex RA gene expression profiles observed in vivo by using combinations of agonists in vitro; (b) identified RA blood neutrophil gene biomarkers that stratify RA patients into responders and non-responders to TNFi therapy; (c) characterised a subset of neutrophils in RA (low-density granulocytes, LDGs), which may be novel disease regulators arising from developmental plasticity. This project will develop a computational model of neutrophil activation in inflammatory disease by combining data from RA neutrophils (clinically-characterised) and healthy neutrophils treated with inflammatory mediators. It will use advanced machine-learning to construct a model to predict regulators of inflammation in sub-groups of patients (disease responders/non-responders; early/severe disease), information that will be used to develop strategies for stratification of patients to therapy and development of new therapies. The model will be validated by functional analysis of new RA samples and samples from patients with vasculitis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Manipulating intracellular amino acid availability to selectively suppress pro-inflammatory Th17 cells in rheumatoid arthritis
Funder: Versus Arthritis

Abstract: Rheumatoid arthritis (RA) is an autoimmune disease of the joints that affects approximately 70 million people worldwide. T helper 17 (Th17) and Foxp3+ regulatory T-cells (Tregs) play opposing roles in driving RA. Th17 cells promote inflammation, and the severity of RA correlates with an increase in the number of these cells. Tregs on the other hand regulate deletrious immune responses, and limit the damage mediated by immue cells. Tregs are suppressed in RA, and restoring this imbalance in T-cell responses will be immensely beneficial in the management of RA. One way to achieve this is by manipulating CD4+ T-cell differentiation to favour Treg generation. Starving CD4+ T-cells of amino acids (AAs) favours Treg but not Th17 differentiation. These effects occur without affecting activation and proliferation of T cells. AA insufficiency can be achieved in vivo by inhibiting AA transporters. This makes AA transporters potential therapeutic targets that can be harnessed to control AA uptake and selectively inhibit Th17 differentiation. Thus, the objectives of this research are to identify AA transporters that can be targeted to inhibit Th17s and effect Treg skewing and assess the benefit of targeting AA transporters in the management of RA


Research activity codes: 5.1 PHARMACEUTICALS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Development and feasibility of an evidence-based DIGital self-management Intervention Tool for people with primary Sjögren's syndrome (DIGITS)
Funder: Versus Arthritis

Abstract: Primary Sjögren’s syndrome (PSS) patients experience symptoms of fatigue, pain, sleep disturbance, dryness and difficulty performing daily tasks including social and work activities.


Research activity codes: 7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: In vivo efficacy of human S2- selected Mesenchymal Stromal cells in preclinical models of rheumatoid arthritis
Funder: Versus Arthritis

Abstract: Rheumatoid Arthritis (RA) affects 1% of the UK population and remains a major cause of disability and reduced life expectancy, with annual NHS costs of £560 million, and social costs of £1.8 billion. Control of disease in RA continues to present challenging management issues with variable long-term responses to frequently toxic therapies. Although disease remission is possible for short periods of time a cure remains an elusive dream.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Omega–3 fatty acids for the prophylaxis of acute attacks of gout on initiating urate lowering treatment – feasibility study for a randomized controlled trial
Funder: Versus Arthritis

Abstract: Omega-3 fatty acids block several pathways through which monosodium urate crystals induce inflammation. Our preliminary finding demonstrate that low concentration of omega-3 fatty acids in the plasma associates with frequent gout attacks.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: TRPA1- inflammasome signalling in temporomandibular joint inflammatory pain
Funder: Versus Arthritis

Abstract: Temporomandibular joint disorders (TMDs) are the most common chronic pain condition in the orofacial region and constitute a significant public health problem affecting approximately 5-12% of the population. However the pathophysiology of TMDs remains unclear and there is no effective therapy to date. The aim of this project is to decipher the mechanisms underlying temporomandibular joint (TMJ) pain by studying interactions between novel pain receptors and inflammasomes (innate immunity proteins that are activated by danger signals to mediate inflammatory response) in order to identify novel pain relief targets in TMDs. We will specifically focus our attention on TRPA1, a member of transient receptor potential (TRP) family of ion channels that sense danger signals and determine its role in inflammasome activation. The objectives of the study are: (1) To investigate the effect of inflammation on the expression and localisation of TRPA1 and inflammasomes in TMJ and trigeminal nerves in vivo in an acute zymosan model of TMJ; (2) To determine the effect of TRPA1 on TMJ inflammation, inflammasome activation and mechanical hyperalgesia in mice in a chronic arthritis model induced by complete Freund’s adjuvant (CFA), and (3) To study the signalling pathway leading to TRPA1 dependent inflammasomes activation, IL-1ß release and maintenance of chronic inflammatory pain. By combing multidisciplinary expertise in inflammation and pain research our project will utilize cutting edge methods to achieve its aims. We will use validated in vivo and in vitro assays to study TRPA1 and inflammasome signalling in inflamed TMJ. These will include calcium imaging, qPCR, ELISA, Western Blotting and immunohistochemistry. The outcome of this proposal will be the identification, for the first time, of a role for inflammasomes in TMJ pain and inflammation and decipher how inflammasomes are activated via TRPA1 signalling. The novel data and findings of the study will improve our understanding of TMJ pain and will enable future identification of more effective drugs for pain relief in inflammatory pain conditions such as TMDs that are associated with arthritis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Novel mechanistic insights into the pathogenesis of juvenile dermatomyositis.
Funder: Versus Arthritis

Abstract: There is a major unmet need for new treatments for inflammatory myositis, including paediatric-onset juvenile dermatomyositis (JDM). The complement pathway, formerly thought to be serum-based, has now been shown to regulate Th cell homeostasis and differentiation intracellularly. Using the large UK-wide JDM cohort and biobank, we have generated novel transcriptome data from sorted blood CD4+ T cells, which suggest that complement homeostasis is dysregulated in T cells from JDM patients with active disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Stakeholder perspectives on preventive approaches to rheumatoid arthritis
Funder: Versus Arthritis

Abstract: There is considerable interest in the identification of individuals at risk of developing rheumatoid arthritis (RA), and trials are underway to evaluate the efficacy of preventive therapeutic interventions. It is therefore increasingly important to understand the perspectives of all stakeholders to inform the design and delivery of predictive/preventive strategies.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Where, when and what do tolerogenic dendritic cells do to T cells?
Funder: Versus Arthritis

Abstract: Currently, treatment of autoimmune diseases such as rheumatoid arthritis relies on broad immunosuppression. The ‘holy grail’ of the immunotherapy field is to develop a treatment that specifically targets and rectifies the pathological autoimmune response, whilst leaving protective immunity intact. Treatment with tolerising DC (tolDC) promises to achieve this goal, and data from early clinical trials (including our own) have been encouraging. However, these trials have highlighted critical unanswered questions, specifically:


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