The overall hypothesis of this research proposal is that gastrointestinal (GI) hormones are related in both cause and effect to the changes that occur in the GI tract with aging. These age-related alterations include 1) an increased proliferative activity of the GI mucosa, and 2) a decreased secretory function in the GI tract. The long-term objective of this project is to define at least some of the mechanisms involved in the pathophysiology of the age-related derangements in growth and secretion of the GI tract. To establish the progression of GI organismal aging, Fischer 344 rats of three age groups (4-mo, 12-mo, and 24-mo old) will be used. Associations of causality with GI hormones will be established by giving GI hormones either as an exogenous administration or as an increased endogenous release, with or without the administration of highly selective GI hormone receptor antagonists.
One specific aim will test the hypothesis that apoptosis in GI mucosa is regulated by GI hormones, and that loss of regulation of apoptosis by GI hormones is responsible for an exaggerated mucosal cell proliferation. Apoptosis in the stomach, duodenum, ileum and colon will be induced by causing mucosal atrophy, which will be accomplished either by fasting or by feeding an elemental diet. The ability of trophic GI hormones (eg, gastrin, cholecystokinin [CCK], neurotensin [NT], bombesin [BBS]) to inhibit apoptosis will be determined, and correlated with changes in GI mucosal cell proliferation. Apoptosis will be monitored histologically by in situ immunostaining of nuclear DNA fragmentation. Cell proliferation will be monitored by BrdU nuclear labelling. Patterns of gene expression associated with apoptosis in the GI tract will be established by measuring changes in mRNA and protein levels of GI hormones and their receptors, and of apoptosis-associated genes (eg, TGF-Beta1, p53 and bcl- 2). A second specific aim will test the hypothesis that the anti-aging actions of caloric restriction (CR) operate through the regulation of GI hormone metabolism which, in turn, determines the expression of cytoprotective mechanisms, namely antioxidant scavenging enzymes (catalase and superoxide dismutase [SOD]) and heat-shock proteins (hsp). CR will be accomplished by feeding CR-restricted rats 60% (wt/wt) the amount of food ingested by ad lib fed rats. CR-induced changes in GI hormone metabolism will be investigated at the levels GI hormone gene expression (tissue mRNA and peptide levels) and release, and at the responsiveness of the GI hormone targets (GI hormone receptor gene expression). The relationships between changes in GI hormone metabolism with changes in gastric acid secretion, pancreatic exocrine and endocrine secretions, and expression of catalase, SOD and hsp70 in GI hormone targets, will be established. Understanding of the mechanisms involved in dysregulation of growth and secretion of the GI tract in rats may help to devise strategies for the treatment of age-related diseases with similar derangements in humans.
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