Despite recent advances in understanding the pathogenesis of Inflammatory Bowel Disease (IBD) there remains a significant clinically unmet need in terms of appropriate strategies aimed at therapeutic intervention. As current insights into mechanisms of disease are overwhelmingly derived from investigations in adult patients, there is a considerable lack of knowledge into how IBD develops during childhood and adolescence. This is of particular importance as data identified from adult patient cohorts may be obscured by established chronicity, co-morbidities, existing therapeutic interventions and exposure to confounding lifestyle factors. As such, it will likely prove beneficial to identify faithful biomarkers of disease and new avenues for therapeutic intervention during the earliest stages of disease progression. We have established a translational research programme aimed at identifying important mediators in the development and progression of early stage IBD. During our investigations into mucosal inflammation in these patients, we have identified novel cytokines of the IL-36 family as playing an important role in disease pathogenesis. We have carried out extensive validation of this pathway as a novel potential target in IBD through patient cohort as well as human and animal studies. This proposal aims to extend the preclinical progression of this potential new target pathway through an analysis of its significance in defining patient outcomes and the development of a novel strategy to specifically target its signalling in established preclinical models of IBD.
