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• infectious disease and the immune system

• Medicine

• Rheumatology

Our research focuses on understanding the underlying mechanisms that drive disease pathogenesis in Rheumatic diseases. Using a multidisciplinary approach we aim to (a) identify predictors of progression and response to therapy, (b) elucidate cellular/molecular mechanisms of disease pathogenesis; and (c) develop new therapeutic strategies. We have established a number in-situ, in-vitro and ex-vivo models of arthritis using human tissue from patient with inflammatory arthritis, these models closely reflect the in-vivo joint environment thus allowing us to have a translational bench-to-bedside approach. Our specific research themes include the following; (i) The role of hypoxia and cellular metabolism in regulating synovial inflammation; (ii) Molecular mechanisms of synovial angiogenesis, invasion and articular cartilage damage; (iii) To identify predictors of disease progression/response, and identify new therapeutic targets using high-throughput omic analysis along with a systems biology computational approach; (iv) Identification of novel immune cell subtypes in the inflamed joint using advanced molecular and cellular techniques and developing mechanisms by which we can induce an anti-inflammatory phenotype; (v) Pre-clinical proof of concept studies utilizing the ex-vivo whole tissue synovial explant model to establish pre-clinical drug development studies of novel biotherapeutics and small molecular weight candidates with industry partners.

Psoriatic Arthritis (PsA) is a chronic inflammatory disease, characterised by synovitis and bony destruction, associated with psoriasis. Targeted biologic therapies, including TNF inhibitors, have improved the outcome of PsA patients, however a significant proportion do not respond or respond sub-optimally, while others experience adverse events. The PsA joint is profoundly hypoxic as a result of inflammation and highly dysregulated blood vessels, which appear elongated, dilated and tortuous. Exposure to this adverse hypoxic environment drives cells to adapt and generate energy by switching from aerobic oxidative phosphorylation to anaerobic glycolysis. This provides sufficient energy and biosynthetic precursors for the rapidly dividing immune and inflammatory cells resulting in transcriptional activation of a many pro-inflammatory genes. We hypothesise that dysregulated metabolic pathways drive immune cell responses in the PsA joint, an effect inextricably linked to dysfunctional blood vessel formation and an hypoxic microenvironment. Therefore the aim of this study is to define the role of metabolism in driving pro-inflammatory responses in the PsA joint. Specifically we will (i) determine the metabolic profile of specific immune cell subtypes isolated from PsA synovial tissue from patients at different stages of disease and in responder vs non responders, (ii) examine the influence of altering metabolic and hypoxic pathways on pro-inflammatory mechanisms using primary synovial cell cultures/co-cultures, and (iii) test the effect of existing metabolic compounds in ?pre-clinical proof of concept studies? using ex-vivo whole tissue synovial tissue explant models.