The inhibition of gastrointestinal mucosal growth occurs commonly in critical illness including a variety of surgical conditions. Data from the Investigator's laboratory and others indicate that the supply of polyamines to the dividing cells is an important step in the regulation of normal intestinal mucosal growth and that decreasing cellular polyamines inhibits cell renewal. The goal of this project is to elucidate the fundamental mechanisms by which the intestinal mucosal renewal process is impaired following polyamine depletion. The hypothesis is that inhibition of polyamine synthesis suppresses intestinal mucosal growth by altering expression of the p53 gene.
Four specific aims are proposed: 1) to identify the relationship between expression of the p53 gene and growth inhibition in small intestinal mucosa in vivo, 2) to determine the role of cellular polyamines in p53 gene expression in intestinal crypt cells in vitro. The Investigators will first define the level where the effect of polyamines on p53 gene expression occurs and then concentrate on understanding the mechanism by which polyamines modulate post-transcription of the p53 gene, 3) to determine the role of increased p53 gene expression in growth inhibition following polyamine depletion. The Investigators will determine whether decreasing p53 levels by antisense oligonucleotides or increasing p53 levels by transfecting a conditional p53 expression vector alters intestinal epithelial cell growth in the presence or absence of polyamines, 4) to identify the basic mechanism by which p53 results in the growth inhibition following polyamine depletion. The Investigators will elucidate the role of p21cip1/waf1 in p53-mediated inhibition of intestinal epithelial cell proliferation in polyamine-deficient cells. The Investigators propose that these studies will enhance understanding of the biology of intestinal mucosal growth and have broader implications for the pathophysiology of mucosal growth inhibition in critical illness.
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