Gastrointestinal mucosal injury occurs commonly in critical surgical conditions such as trauma, thermal injury, shock, and sepsis and/or after exposure to non-steroidal anti- inflammatory compounds and other medication. The restoration of mucosal integrity - successful repair of wounds and ulcers - requires epithelial cell decisions that regulate signaling networks controlling gene expression, cell survival, migration and proliferation. Our previous studies and others have demonstrated that polyamines, including spermidine, spermine and their precursor putrescine, are required for normal repair of gastric and duodenal mucosal stress erosions and that polyamine's effects on cell renewal during healing are associated with their ability to regulate expression of the proto-oncogene c-Myc. However, the exact role of polyamine-induced c-Myc expression in gut mucosal healing is still unknown. Our preliminary studies indicate that inhibition of c-Myc expression by the antisense oligomers not only decreases normal intestinal epithelial cell renewal but also prevents restoration of cell proliferation by exogenous spermidine in polyamine-deficient cells. The immediate goal of this project is to test the hypothesis that polyamine- induced c-Myc expression following injury plays an important role in the stimulation of epithelial cell renewal during healing.
Three specific aims will be pursued by using both in vivo and in vitro model systems. 1) To delineate the signaling mechanisms involved in the regulation of the c-Myc gene transcription by polyamines in intestinal epithelial cells. 2) To determine whether polyamine-induced c-Myc is required for the stimulation of intestinal epithelial cell renewal following injury. 3) To investigate the mechanisms through which polyamine-induced c-Myc mediates the stimulation of epithelial cell renewal during healing. Completion of these specific aims will reveal novel mechanisms of gut mucosal repair in surgical disorders and other critical conditions. Considering the fact that gut mucosal injury is not uncommon under surgical conditions and disrupts epithelial barrier function, the subject matter of this proposal is timely, important, and has direct clinical application.
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