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Towards personalised therapy in stricturing Chrohn’s disease – exploring and exploiting the role of NADPH oxidase in intestinal fibrosis

Crohn’s disease (CD), an inflammatory bowel disease characterized by transmural inflammation throughout the digestive tract, is commonly complicated by the development of fibrosis and stricture formation. Although several effective therapies targeting intestinal inflammation exist, there is still a dearth of anti-fibrotic therapies and surgery remains the only treatment option for end-stage fibrosis. Transforming growth factor beta (TGFβ1) is an important driver of tissue fibrosis in multiple organ systems including the small intestine. A key mediator of the effect of TGFβ1 in lung and liver fibrosis is the H2O2-generating NADPH oxidase NOX4. Similar to observations in lung tissues derived from patients with idiopathic pulmonary fibrosis, we have shown that NOX4 expression in ileal stricture tissues is significantly increased, thus supporting the connection between NOX4 and CD-associated fibrosis. Intriguingly, additional pilot data revealed elevated NOX4 levels (although to a lesser degree) in disease-free caecal biopsies of patients with a stricturing versus non stricturing CD phenotype, suggesting that NOX4 may be a useful biomarker for this phenotype. We aim to explore the role of NOX4 in the development and progression of fibrosis, determine the potential for NOX4 as a biomarker for stricturing disease and explore the therapeutic potential of NOX4 inhibitors in the prevention and treatment of intestinal fibrosis. We have access to large, well characterized patient cohorts which will permit analysis of surgical stricture specimens from paediatric and adult patients, and biopsy specimens from paediatric patients. Additionally, we will use a validated mouse model of disease to perform pre-clinical NOX4 inhibitor testing. This project will be of significant benefit to patients with stricturing CD as it will enhance our understanding of the pathophysiology of fibrosis and bring closer the possibility of personalised medicine through the development of new diagnostic tools and drug therapies.