PEROXYNITRITE IN ENTEROCYTE APOPTOSIS & CELL SIGNALLING

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Gut barrier failure and bacterial translocation are important factors leading to nosocomial infections in critically ill patients. Previous work from Dr. Ford's lab has shown that sustained upregulation of inducible nitric oxide synthase (iNOS), enterocyte apoptosis, and immunoreactivity to 3-nitrotyrosine, afoot-print' of peroxynitrite (PN), co-localize in the intestinal mucosa in animal models of endotoxemia and in human necrotizing enterocolitis. This suggests that the sustained over-expression of iNOS occurring in these inflammatory conditions leads to enterocyte apoptosis through nitric oxide (NO) and PN formation. In addition to inducing apoptosis, PN may also inhibit enterocyte proliferative cell signaling pathways that are dependent on tyrosine phosphorylation, such as the Src family of tyrosine kinases. PN is able to nitrate tyrosine residues in proteins and thus prevent tyrosine phosphorylation. Several recent reports have shown that NO and PN are able to prevent tyrosine phosphorylation of various proteins involved in cell signaling pathways. It is hypothesized, therefore, that PN causes an imbalance between increased enterocyte apoptosis and decreased or static enterocyte proliferation which leads to mucosal denudation and bacterial translocation. The first goal of this proposal is to study the molecular mechanisms of PN-induced enterocyte apoptosis in vitro. The second goal is to study enterocyte cell signaling pathways, in particular Src tyrosine kinase pathways and signaling via the epidermal growth factor receptor, and to determine how these pathways are affected on a molecular level by PN.