The epithelial lining of the intestine forms a protective barrier which separates the luminal contents from the rest of the intestine. The integrity of the intestinal barrier is dependant upon the maintenance of the epithelial cell interactions with apical junctional complexes and the underlying basement membrane. These interactions have been shown to be compromised in intestinal infections as well as in chronic inflammatory states, such as inflammatory bowel disease. Previous work by other laboratories demonstrate [sic] the intestinal barrier function can be altered by inflammatory cytokines, as shown by decreases in transepithelial resistance. The exact mechanism by which these inflammatory cytokines influence the intestinal barrier is unknown. Our preliminary data implicates matrix metalloproteinase-7 (matrilysin) in the pathogenesis of inflammatory cytokine-induced altered barrier resistance. Matrilysin gene transcription as well as protein production, secretion and activation are increased in response to inflammatory cytokines. Basolateral treatment with activated matrilysin results in increased barrier permeability in cultured colonic epithelial cell lines. Our hypothesis is that matrilysin influences colonic epithelial barrer [sic] function through cleaving basolaterally-located apical junction complex proteins and disrupting basement membrane adherence and its regulation by inflammatory cytokines plays a role in the onset of acute and chronic colitis.
Three specific aims will address the above hypothesis. First, we will elucidate the mechanism by which matrilysin regulates the shedding of extracellular components of apical junctional complex proteins and basement membrane adhesion proteins. Second, we will examine the inflammatory cytokine-induced regulation of matrilysin transcription. Third, we will determine whether matrilysin plays a key role in the onset of murine models of inflammatory bowel disease and infectious colitis. These studies will increase our understanding of the mechanism by which the intestinal epithelial cells maintain the barrier protecting the intestine from luminal contents both in tissue culture models and animal models of wound healing, infectious colitis and inflammatory bowel disease. These studies will also determine the mechanisms by which inflammatory cytokines regulate matrilysin gene expression.
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