Identification of the role of matrix metalloproteinases (MMP's) in the development and persistence of chronic bowel inflammation.

Crohn’s disease and ulcerative colitis are chronic disabling inflammatory bowel diseases (IBDs) with increasing prevalence throughout the world. The etiopathogenesis of IBD is poorly understood and is thought to be based on a combination of environmental factors, abnormal immunity and genetic factors. Recently published data indicate that matrix metalloproteinases (MMPs), a family of Zn2+-dependent extracellular matrix (ECM) endopeptidases, are the predominant proteases involved in the pathogenesis of IBD. The proteolytic activity of MMPs is tightly controlled by specific tissue inhibitors of metalloproteinases (TIMPs) and this critical balance has been shown to be dysregulated in IBD. With this project, we aim to investigate the role of MMPs in the disease  evelopment of IBD with the following three objectives. First, a systematic review will summarize the regulation of MMPs and TIMPs by innate immune receptors and additional experiments will complement the knowledge about which agonists induce which MMPs or TIMPs in specific cell types. Second, functional insights will be obtained by complementing expression analysis of patient and animal biopsies with data at the protein level using optimized techniques. Third, we aim to link innate and adaptive immune mechanisms in IBD by defining MMP substrates and remnant  pitopes that may contribute to the chronic bowel damage. This may lead to new therapeutic targets in IBD, especially for the prevention of fibrotic complications.