Intestinal Mucosal Growth in Health & Surgical Diseases

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Inhibition of intestinal mucosal growth occurs commonly in various critical surgical disorders. Since the mechanisms involved in regulation of mucosal growth are still obscure, effective therapies to maintain the mucosal epithelial integrity in patients with critical surgical illnesses are limited, leading to mucosal atrophy, delayed healing, impaired barrier function, and bacterial translocation. During previous funding period, we have established that a supply of polyamines to the dividing cells in the crypts of the intestinal mucosa is absolutely required for normal mucosal growth and that decreased polyamines inhibit cell proliferation by stabilizing p53 and other growth-inhibiting proteins in critical surgical conditions. However, the exact mechanisms by which polyamines modulate p53 stability at the molecular level remain unclear and are the focus of this competitive renewal application. Our preliminary results indicate that d) polyamine depletion induces nucleophosmin (NPM) protein and V) inhibition of NPM by siRNA strategy destabilizes p53 and decreases p53-dependent transcriptional activity in polyamine-deficient cells. Based on these observations, we HYPOTHESIZE that polyamine depletion-induced NPM interacts with and stabilizes p53, thus mediating inhibition of intestinal mucosal growth in critical surgical conditions. Three specific aims are proposed to test the hypothesis. 1) To define the molecular mechanisms by which cellular polyamines modulate NPM activity. 2) To characterize functional and physical interactions of NPM with p53 following polyamine depletion. 3) To determine the roles and mechanisms of NPM/p53 interaction in regulation of intestinal mucosal growth and apoptosis during surgical disorders in the presence or absence of cellular polyamines. Completion of these specific aims will provide novel information regarding control of intestinal mucosal growth under surgical conditions. It is hoped that these studies will identify potential therapeutic targets and agents which could be used in the future to maintain intestinal mucosal integrity in patients with critical surgical illnesses.