The central hypothesis of our proposal is that gonadal and adrenal steroids play an important role in gut and pancreatic functions, which is substantiated by our findings, so far. We plan to further examine the interrelationships between the effects of gut and gonadal hormones in the gastrointestinal (GI) tract as follows. The specific interaction of estradiol (E2) and progesterone (Pg) at the cellular and subcellular level will be localized in tissues found by us to be positive for specific binding sites for E2 (EBP) and Pg (PBP) (pancreas and stomach). The hormonal regulation of steroid binding sites will be defined. The high- and low-affinity EBP from the pancreas and stomach of dogs and rodents will be physicochemically characterized in relation to peptide and steroid hormone levels. Since significant effects of gonadal hormones were observed on gut peptide receptor populations and on exocrine pancreatic functions, studies will be designed to: 1) investigate the kinetics of peptide hormone receptor regulation by gonadal hormones in vitro and in vivo; 2) to measure tissue and serum levels of peptide hormones in relation to gonadal hormone status of the animals; and 3) to measure the effects of steroid manipulation on gene expression for various peptide hormones in GI tissues. The direct effect of steroid hormones on gut and pancreatic functions will be examined in recently established, in vitro experimental models of perfused pancreatic acini, cultured islet cells and isolated perfused rat stomachs, and intracellular mechanisms defined. As a part of the ongoing studies, steroid binding sites in gut and pancreatic cancers from humans will be measured, and the results correlated with clinical parameters including survival of the patients. A role of gonadal steroids on the growth of gut and pancreatic cancer cells (found to be positive for one or more steroid binding sites) will be investigated in vivo and in vitro; these findings will be correlated with any regulatory effects of gonadal steroids on the binding kinetics of the known trophic hormones (gastrin, cholecystokinin [CCK], bombesin [BBS] on GI and pancreatic cancer cells, as a means of understanding the mechanism of action of gonadal steroids. It is hoped that the above studies will further increase our understanding of interrelationships of steroid and peptide hormones in GI physiology under normal and diseased conditions.
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