Ornithine decarboxylase (ODC), the initial, rate-limiting enzyme in polyamine biosynthesis, is essential for cell proliferation and for the differentiation of certain cell types. Elevated levels of ODC can be the result of transcriptional, translational, and posttranslational mechanisms. The goal of this project is to elucidate the specific cell types in which ODC is expressed and the molecular mechanisms which govern its expression in two normal and two pathophysiological models of GI tract adaptation, relevant to human disease. The four experimental models are: 1) The postnatal development of the small intestine, in which a 15-fold spike of ODC activity occurs on the 20th postnatal day which is essential for intestinal maturation. 2) Poststarvation refeeding-induced recovery of the GI tract mucosa, which stimulates an increase in mucosal ODC activity; inhibition of ODC inhibits repair of starvation-induced mucosal atrophy. 3) Stress-induced ulceration of the stomach, which causes an increase in ODC activity during both the restitution and proliferative repair processes; inhibition of ODC blocks both repair events. 4) Parasite- induced anaphylaxis in the small intestine, which causes epithelial damage followed by hyperplastic repair. Acute parasite infection stimulates an increase in intestinal mucosal ODC during the repair process; inhibition of ODC blocks mucosal repair. Currently, it is not known in which cell types the essential increase in ODC occurs or what molecular mechanisms regulate ODC expression in GI tract adaptation. This information will be elucidated by two complementary experimental designs. One is a quantitative analysis of the mechanisms regulating ODC expression at the transcriptional, translational, and posttranslational level employing biochemical, immunobiochemical, and molecular biology techniques. The other is a cytological analysis to identify the specific cell types of ODC expression and the molecular mechanisms responsible for employing immunolocalization and in situ hybridization techniques. The results obtained will reveal whether the molecular regulatory events governing ODC expression and the cell types involved are the same or different in physiological versus pathophysiological states of GI tract adaptation. This new information regarding the fundamental events required for polyamine biosynthesis in GI tract maturation and repair will also provide a foundation for the development of therapeutic interventions which may protect against damage or promote adaptation in GI tract disease states.
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