Mucosal protease and their inhibitors in inflammat.. (IBDase)
Mucosal protease and their inhibitors in inflammatory bowel disease: From etiopathogenetic insight to innovative therapy
Start date: Mar 1, 2008,
End date: May 31, 2011
IBDase addresses the etiology and pathogenesis of inflammatory bowel disease (IBD) with a multidisciplinary plan for innovative diagnosis and therapy focused on mucosal proteases and their inhibitors (P/PIs). The incidence of IBD, a multifactorial disease influenced by environmental factors in a background of complex genetic susceptibility, is rising, particularly among European children. Current therapies lack efficacy and specificity. The gut microflora plays a crucial role in IBD but the cause for this is still poorly understood. Research implicating P/PIs in gut mucosal inflammation requires further mechanistic insight and the P/PIs relevant in human IBD need to be identified. To this end we will identify human mucosal P/PI polymorphisms affecting expression levels and/or activity of P/PIs and analyse their genotype/phenotype associations in IBD patient cohorts across Europe. IBD-associated P/PIs will be characterised by biochemical properties, expression in human clinical samples and manipulation of experimental models. Their interaction with microflora will be examined in animal models with controlled colonisation of the gut and in vitro co-culture models of intestinal mucosa and bacteria. In vivo studies will use targeted, well-established and new mouse models and evaluate zebrafish as an IBD model. Molecular mechanisms for involvement of IBD specific P/PI gene variants in the inflammatory response will be proposed. Therapeutics development will focus on specific inhibition or promotion of proteolysis in the intestinal mucosa, and select at least three validated P/PI of the intestinal mucosa for follow-up in clinical trials. Embracing the concept of tailoring treatment to individual patient characteristics to increase efficacy and reduce side-effects, IBDase strengthens international visibility of IBD related research, policies and industry and fosters IBD related research to the benefit of European society in both patient care and economic interest.
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