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.
|Miles, Donald R B; Shen, Jun; Chuang, Alice Y et al. (2016) Alpha-Defensin 5 Expression is Regulated by microRNAs in the Caco-2 Intestinal Epithelial Cell Line. J Inflamm Bowel Dis Disord 1:|
|Wu, Feng; Dong, Fengshi; Arendovich, Nikolai et al. (2014) Divergent influence of microRNA-21 deletion on murine colitis phenotypes. Inflamm Bowel Dis 20:1972-85|
|Chuang, Alice Y; Chuang, Jim C; Zhai, Zili et al. (2014) NOD2 expression is regulated by microRNAs in colonic epithelial HCT116 cells. Inflamm Bowel Dis 20:126-35|
|Puthenedam, Manjula; Wu, Feng; Shetye, Alysha et al. (2011) Matrilysin-1 (MMP7) cleaves galectin-3 and inhibits wound healing in intestinal epithelial cells. Inflamm Bowel Dis 17:260-7|
|Mori, Yuriko; Olaru, Alexandru V; Cheng, Yulan et al. (2011) Novel candidate colorectal cancer biomarkers identified by methylation microarray-based scanning. Endocr Relat Cancer 18:465-78|
|Olaru, Alexandru V; Selaru, Florin M; Mori, Yuriko et al. (2011) Dynamic changes in the expression of MicroRNA-31 during inflammatory bowel disease-associated neoplastic transformation. Inflamm Bowel Dis 17:221-31|
|Li, Zhaoxia; Wu, Feng; Brant, Steven R et al. (2011) IL-23 receptor regulation by Let-7f in human CD4+ memory T cells. J Immunol 186:6182-90|
|Hu, Shien; Dong, Tien Sy; Dalal, Sushila R et al. (2011) The microbe-derived short chain fatty acid butyrate targets miRNA-dependent p21 gene expression in human colon cancer. PLoS One 6:e16221|
|Wu, Feng; Guo, Natalie Jia; Tian, Hongying et al. (2011) Peripheral blood microRNAs distinguish active ulcerative colitis and Crohn's disease. Inflamm Bowel Dis 17:241-50|
|Wu, Feng; Zhang, Simin; Dassopoulos, Themistocles et al. (2010) Identification of microRNAs associated with ileal and colonic Crohn's disease. Inflamm Bowel Dis 16:1729-38|
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