The Metalloproteinases (MMP) are a family of Zn-dependent endopeptidases involved in a variety of physiological and pathological processes that require extracellular matrix degradation or protelytic activation such as wound healing, differentiation and inflammatory cell infiltration. MMP-9 is a secreted MMP considered to be a vital member of this protease family. MMP-9 is absent from normal adult intestine and colon but is highly upregulated during experimental colitis and human inflammatory bowel disease (IBD). Remarkably, up to this point, the regulation and function of MMP-9 in the intestine has not been studied. We demonstrated that epithelial cell-derived MMP-9 mediates tissue damage during intestinal inflammation. In addition to its role in inflammation, our data demonstrate that MMP-9 plays an important role in intestinal epithelial cell differentiation. This proposal is based upon an exciting hypothesis that will predict the physiological function of MMP-9 and provide insight into the pathophysiological and potentially clinically relevant consequence of MMP-9 expression. We hypthesize that i) the regulated expression of MMP-9 during intestinal cell differentiation plays a role in cell fate determination ii) the aberrant expression of MMP-9 during disease state mediates tissue injury by impairing cell-cell and cell-ECM interaction. Thus the objectives of this proposal are to examine the regulation and function of MMP-9 expression in intestinal epithelial cell differentiation (specific aim 1) and during colitis (specific aim 2 and 3). Taken together, our studies will not only elucidate the function, regulation and mechanism of action of MMP-9, but also provide a basis for MMP-9 targeted therapies that could be used in the clinical setting to prevent consequences of intestinal inflammation. Inflammatory diseases of the bowel are a cause of significant morbidity and mortality in U.S. The pathogenesis of inflammatory bowel disease is not known and current therapeutic strategies are sub-optimal and associated with significant side effects. This proposal will elucidate the function, regulation and mechanism of action of metalloproteinase-9, a protease that is highly upregulated during colitis. Importantly, information gained from this project will be instrumental for the generation of new strategies aimed at preventing and/or treating intestinal inflammation.
