NIHRDataInsights/HRCSData huggingface dataset:
Title: Sustained and Controllable Local Delivery of Anti-inflammatory Therapeutics with Nanoengineered Microcapsules
Funder: Versus Arthritis

Abstract: Intra-articularly delivered drugs have the potential to have local anti-inflammatory effects without causing systemic side effects and if they are retained within the injected joint there is the opportunity for long-term effects at the desired site. At present the best formulations for this route of administration gradually and freely diffuse from the injection site. Through the optimal design of nano-engineered microcapsules we will exploit the fact that their size (3-5 µm) should result in their physical retention within joints so that drugs incorporated in their structure are actively retained at the injection site. The inclusion of magnetic nanoparticles within the microcapsule structure can further enhance retention through the use of an external magnet and also permits the use of clinically viable physical stimuli including an alternating magnetic field and ultrasound to control the release kinetics of drugs from microcapsules. ‘On-demand’ drug release would enable anti-inflammatory activity to be enhanced during disease flare without the need for repeated intra-articular injects. In this study we will focus on the delivery of a glucocorticoid and a peptide inhibitor of NF-?B, however this delivery approach could be relevant for other drugs and be applied in other joint conditions such as pain relief in osteoarthritis.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Harnessing glycan-dependent pathways in synovial fibroblasts to control chronic joint inflammation?
Funder: Versus Arthritis

Abstract: In Rheumatoid Arthritis (RA), synovial fibroblasts (SFs) adopt an aggressive phenotype that results in cytokine secretion and cartilage invasion, perpetuating inflammatory responses. I have recently shown that in addition to contributing to the initiation of pathogenesis, IL-22 can desensitise such pathogenic SFs to effect resolution of inflammation. My new data suggest that such protection is associated with modulation of the altered SF glycome induced by proinflammatory mediators and thus, I aim to define the glycosylation circuits underpinning such immunomodulation. This should provide further insight into the mechanisms underlying SF-dependent inflammation and its resolution. In particular, the SF glycome associated with pathogenic and resolving phenotypes will be defined by molecular and structural analysis to ultimately identify glycome signatures that could potentially provide novel diagnostic and therapeutic targets for clinical intervention. Moreover, as glycan recognition governs the majority of cell-cell and cell-extracellular matrix interactions, the impact of modulation of the SF glycome on pathophysiological processes such as cytokine/chemokine production, T cell polarization and cell barrier stabilization will be also evaluated. This is important as targeting cytokines with multiple regulatory roles may lead to identification of specific aberrant glycosylation and a better understanding of the glycobiology of stromal cells in chronic inflammation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Unravelling the molecular mechanisms of autoantibody-mediated endothelial dysfunction in systemic lupus erythematosus and antiphospholipid syndrome
Funder: Versus Arthritis

Abstract: Circulating pathogenic IgG autoantibodies, found in patients with the antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE), may bind and activate the vascular endothelium, promoting endothelial dysfunction and predisposing to thrombosis, atherosclerosis and premature cardiovascular disease (CVD). In order to understand how CVD develops in APS and SLE, and to identify ways to improve vascular outcomes, we must establish how autoantibodies drive endothelial dysfunction. I propose that autoantibodies disrupt innate homeostatic and cytoprotective signalling pathways, while enhancing pathogenic responses. By employing novel biological models and resources, I will identify the molecular basis of the changes in intracellular signalling, determine the functional outcomes, and explore therapeutic reversibility, by pursuing the following aims:


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The Microbiome as a Therapeutic Target in Inflammatory Arthritis
Funder: Versus Arthritis

Abstract: The human intestine contains a large number and diverse array of bacteria that contribute to health but when dysregulated can also promote disease. Recent studies in inflammatory arthritis including spondyloarthritis and rheumatoid arthritis suggest alterations in the intestinal microbiota and its interaction with the immune system may underlie disease. However whether these changes are causal or correlative and their mechanism of action remain to be established. The Inflammatory Arthritis Microbiome Consortium (IAMC) brings together a multi-disciplinary team to apply state of the art microbial sequencing, metabolomics, computational biology, high throughput culturing of human intestinal bacteria and advanced cellular and molecular immunology approaches to characterise the microbiota in inflammatory arthritis patients and establish its function in disease development, progression and response to therapy. By combining rigorous clinical studies with cutting edge computational and integrated functional analyses, the IAMC will bridge the gap between microbiome description and function, providing new insights into host microbial interactions in inflammatory arthritis that will provide a platform to facilitate the development of novel diagnostic and predictive tests and therapeutic strategies directly impacting on patient care.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The role of the microbiome in rheumatoid arthritis
Funder: Versus Arthritis

Abstract: The autoimmune disease rheumatoid arthritis (RA) has a considerable heritable component but despite a decade of progress in identifying associated genetic variants much remains to be learnt about underlying pathogenic mechanisms. The microbiome – the collective microorganisms living in and on us - influences immune system development in the young and may provide critical exposures years before RA onset. The microbiome therefore represents a major target for Arthritis Research UK to fulfil their stated 10 year goals. In this programme of highly cost effective, clinically relevant microbiome research we will build on existing large-scale projects in RA in twin- and patient volunteers to:-


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: Phenomic characterization of Psoriatic Arthritis: defining the role of the microbiome
Funder: Versus Arthritis

Abstract: Inflammatory diseases appear to interact with the microbiome and its signalling properties across a wide range of situations, including autoimmune diseases. To further understand the multilevel cross-signalling connections across human biology at a supra-organism level we propose to investigate the role of the gut microbiome in driving immunological and metabolic functionality in the aetiology and development of inflammatory disease using Psoriatic arthritis (PsA) as a model. PsA is a painful form of inflammatory arthritis affecting over half a million people in the UK, and for which there is an unknown aetiology.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Norfolk Arthritis Register - Request for Interim Funding (NOAR)
Funder: Versus Arthritis

Abstract: This application makes the case for additional funding to support the Norfolk Arthritis Register (NOAR) to sustain current rates of recruitment and follow up until 2018. NOAR was established in 1989 and is the UK’s only long term prospective cohort study of adult inflammatory arthritis. With over 4,000 recruits it continues to provide key data on occurrence, risk factors for disease and health resource use that are of international significance. In 2013, the register was included as a work package in the newly established Arthritis Research UK Centre of Epidemiology (CfE). The CfE application planned to maintain full recruitment and follow up to NOAR. Additional financial support was to be provided by INBANK, a new national arthritis research cohort that was in development. The discontinuation of INBANK in its originally proposed form placed the register’s immediate future at risk. In this proposal we request funding support to address this shortfall and keep the register intact for the duration the CfE award. This will allow research outputs to be maximised, and place us in a strong position to apply for further competitive funding to sustain the register beyond 2018.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: SALivary electro-stimulation for the treatment of dry mouth in patients with Sjogren's syndrome: a multicentRe randomISEd sham-controlled double-blind study (SALRISE)
Funder: Versus Arthritis

Abstract: Background: Dry mouth is a common feature of Sjogren's syndrome (SS), which significantly compromises speech, swallowing, oral health, and quality of life. Both patients and physicians have indicated that keeping the mouth moist and lubricated is a key therapeutic goal in the management of SS. However, the treatment of dry mouth of SS has proven challenging and there remains currently no widely adopted evidence-based effective therapy. Preliminary studies have suggested that neuro-electrostimulation of the salivary glands is a promising and adverse-effect free therapy for dry mouth. However, the effects of salivary electrostimulation in SS patients are unknown.


Research activity codes: 6.3 MEDICAL DEVICES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Stromal cells and tertiary lymphoid structures; new mechanisms in the pathogenesis of Sjogren's syndrome
Funder: Versus Arthritis

Abstract: Detection of germinal center-like structures within tertiary lymphoid organs (TLOs) in the salivary glands of patients with Sjogren’s syndrome (SS) is associated with increased risk of lymphoma. Moreover histological analysis of salivary glands is currently used as a prognostic tool in clinical practice and disaggregation of TLOs in post-treatment biopsies is considered a valid measure of positive outcome in ongoing clinical trials. Nonetheless, the biological role of TLOs in inflammation remains unclear. While a large body of evidence suggests that TLOs contribute to disease persistence, recent findings demonstrate a potential immunosuppressive function for TLOs in certain circumstances. I have identified a series of events that occur during TLO establishment and which profoundly change the resident stroma in target organs. Using a combination of functional in vivo studies in mice and observational studies on human samples from patients with SS, I will test the hypothesis that changes in the resident stroma contributes to the acquisition of a chronically activated, pathogenic microenvironment that supports disease progression. This approach, which has already revealed an unexpected pathogenic role for IL-22 in TLO formation during SS, will provide us with a better understanding of the relevance of TLO and stromal cells in disease progression.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigating the role of heparan sulfate proteoglycans in macrophage-driven inflammation and rheumatoid arthritis.
Funder: Versus Arthritis

Abstract: Heparan sulfate proteoglycans play an important role in regulating the immune response through their ability to bind to and regulate the bioavailability of numerous cytokines, chemokines, growth factors and other regulatory molecules. In a preliminary study in my laboratory, Laura Collins the named student on this application, found that several genes controlling biosynthesis of heparan sulfate are regulated by LPS-stimulation of primary human macrophages. Additionally, we found that several of these heparan sulfate biosynthesis genes show altered regulation in synovial membranes of rheumatoid arthritis patients compared with osteoarthritis patients. This suggests that these genes contribute to determining the inflammatory phenotype of macrophages, and that their dysregulation contributes to chronic inflammation. We propose that these findings form the basis of Laura’s PhD project, in which she will determine how these genes modulate macrophage phenotype and behaviour, and establish which genes are dysregulated at which stage of rheumatoid arthritis. This project will provide a strong training in molecular immunology, and additionally establish the role of heparan sulfate proteoglycan biosynthesis genes in regulating inflammation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Exome sequencing in paediatric lupus and functional studies on a novel de novo mutation in C1QTNF4
Funder: Versus Arthritis

Abstract: More than 50 disease susceptibility loci have been mapped in SLE. Using a family-based exome sequencing experiment, the Vyse group has recently identified missense de novo mutations that arise in affected adults with SLE. One of these mutations causes an H198Q change in C1QTNF4. Little is known about this protein’s function. Our preliminary data indicate that C1QTNF4 acts (with TNF) to cause both NF-?B activation and cell death. Two complementary approaches will be taken to examine the function of C1QTNF4 and its H198Q mutation. One approach will examine known components of TNF-related pathways and the second approach will be to look at changes in gene expression by RNA sequencing following exposure to C1QTNF4. The student will ask how the H198Q mutation affects the balance between the induction of NF-?B activation and in cell death. In a second sequencing project, the student will seek to identify de novo mutations that contribute to juvenile onset SLE using parent-affected-offspring family trios. Childhood disease will develop in the setting of a greater genetic burden than adult SLE. Thus, these sequencing experiments should yield a large number of highly informative genetic factors in what is a severe disease subtype.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Aryl hydrocarbon receptor: novel activator of regulatory B cells?
Funder: Versus Arthritis

Abstract: Regulatory B cells (Bregs) suppress inflammation and autoimmunity via the release of Interleukin-10 (IL-10). Nothing is known regarding which transcription factors regulate the transcription of IL-10 in Bregs. By utilising a genome-wide transcriptomics approach while comparing IL-10+B cells to IL-10-B cells in IL-10-GFP-reporter mice, we identified the transcription factor aryl hydrocarbon receptor (AhR) as amongst the most significantly upregulated transcripts in IL-10+B cells. We have now preliminary results supporting a pivotal role for AhR in the up-regulation of IL-10 in Bregs: 1) B cells derived from AhR-/- mice do not efficiently differentiate into IL-10+Bregs and fail to suppress Th1/Th17 differentiation in vitro; 2) Bregs isolated from AhR-/+ mice failed to suppress the development of arthritis upon adoptive transfer, suggesting that signals via AhR directly or indirectly contribute to the generation of Bregs. By taking advantage of a newly generated AhR conditional knock-out B cell strain crossed to an IL-10 reporter mouse, we propose to unravel the molecular mechanisms of AhR in the controlling Bregs differentiation and consequent progression of arthritis. Understanding how AHR signals regulate Breg differentiation could lead to a novel therapeutic target for treatment of rheumatoid-disorders, via the induction of Bregs.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Defining the cellular response to misfolded HLA-B27 molecules - revealing new targets for future interventions.
Funder: Versus Arthritis

Abstract: The misfolding of HLA-B27 molecules during assembly in the endoplasmic reticulum is proposed to be the cause for the initiating pathogenesis in ankylosing spondylitis (AS). However, details of how the misfolded HLA-B27 molecules are degraded and the impact of this process upon key immune cells such as dendritic cells remains relatively uncharacterised. We have recently discovered the role of EDEM1 and HRD1 in this pathway. We propose here to use unique non-folding mutants of HLA-B27 to globally define by proteomics and interactomics the detailed pathway of degradation and the cellular response in cells undergoing degradation of misfolded HLA-B27, and to extend our novel findings based on EDEM1 and HRD1. This will yield important insights towards novel therapeutic targets in this pathway that will allow the specific modification of HLA-B27 behaviour for future patient benefit, providing the first targeted therapy for AS.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Dissection of autoantigen specificity and pathogenicity of recombinant monoclonal antibodies generated from single lesional B-cells of Sjögren’s syndrome patients.
Funder: Versus Arthritis

Abstract: The development of ectopic lymphoid structure (ELS) in the salivary glands is one of the hallmarks of Sjögren’s syndrome (SS), a chronic autoimmune disorder affecting 1% of the general population leading to generalised exocrine glandular dysfunction. ELS support functional germinal centre responses promoting in situ B-cell activation and differentiation into autoantibodies producing plasmacells. Autoantibodies, such as those against muscarinic receptor M3, have been suggested to directly mediate exocrine dysfunction, but a formal proof of this phenomenon is missing. Furthermore, 5% of SS patients progress towards B-cell lymphoma, most commonly of the Mucosa Associated Lymphoid Tissue (MALT-L), whose appearance and evolution is the result of continuous antigen driven immune responses in ectopic germinal centres. The resulting accumulation of genetic instability leads to an oligo and then monoclonal proliferation with the subsequent escape of malignant clones. However, the nature of the antigen(s) driving the (auto)immune response within ELS is still unknown. In this PhD proposal we aim to characterise the autoantigen specificity and pathogenicity of lesional B-cells by i) generating recombinant monoclonal antibodies from single reactive or neoplastic B-cells isolated from ELS+ salivary glands and MALT-L; ii) define their fine immunoreactivity; iii) dissect their pathophysiological role in vitro and in vivo.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Cloning and Validation of an anti-arthritic ACTH species devoid of side effects
Funder: Versus Arthritis

Abstract: ACTH (adrenocorticotrophin hormone) has long been known to effectively treat joint disease including RA and gout. Its prolonged use is limited by the side effects due to sustained elevation in glucocorticoids. Hovewer, over the last decade a new mechanism of action for ACTH has emerged: activation of specific receptors on immune cells to promote anti-inflammatory and tissue-protective effects indicating that adrenal stimulation is no longer perceived as the main mechanism for ACTH anti-arthritic profile. How can we harness this knowledge? How would we develop ACTH for wider clinical use?


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Exploring the dynamic regulation of inflammation governed by DNA methylation in apopotic cells
Funder: Versus Arthritis

Abstract: Understanding how the immune system is controlled to avoid tissue destruction will yield insight into disease mechanisms and lead to more effective treatments. Efficient clearance of apoptotic cells (AC) has long been considered pivotal in preventing autoimmune diseases such as systemic lupus erythematosus (SLE). Moreover, we have shown that administration of AC can suppress inflammatory arthritis via TGFß. However, activation of cells prior to apoptosis abolishes their protective effects via IL-6 production highlighting the potential danger of clearing AC in an inflammatory environment. Our pilot data from mice and patients supports the hypothesis that this dynamic regulation of inflammation during AC clearance is regulated by the degree of DNA methylation within AC. We will test this hypothesis using animal models of arthritis and samples from patients with rheumatoid arthritis and SLE. Our aim is to identify the receptors and signalling mechanisms that sense changes in DNA methylation and mediate these opposing effects of resting and activated AC. Our ultimate goal is to reverse the pro-inflammatory consequences following removal of activated AC and to unravel the cellular pathways that are triggered by AC DNA to discover novel therapeutic targets that can restore tolerance in patients with autoimmune rheumatic disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Effectiveness and uptake of the seasonal trivalent influenza vaccine in autoimmune inflammatory rheumatic disease patients receiving disease modifying anti-rheumatic drugs
Funder: Versus Arthritis

Abstract: Objectives: To examine (1) whether vaccination with seasonal trivalent influenza vaccine (STIV) reduces the incidence of influenza like illness, lower respiratory tract infection, exacerbation of chronic obstructive airway disease, pneumonia, hospitalization and mortality in auto-immune rheumatic disease (AIRD) patients on disease modifying anti-rheumatic drugs (DMARDs), and (2) to investigate temporal trends and geographic variation in uptake of STIV in this patient group.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM