SURGICAL STUDIES OF GI PEPTIDES--MECHANISMS OF ACTION

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Gastrin is a trophic hormone for the normal mucosa of the gastrointestinal tract (GI). We have found that gastrin stimulates the growth of rodent and human GI cancers in vivo and in vitro. However, the mechanisms by which gastrin regulates cell proliferation have not been identified. Our long-term goal is to understand the mechanism of signal transduction from the cell surface to the nucleus that allows gastrin to regulate GI cell proliferation. The hypotheses to be tested include: gastrin regulates growth of GI cells by cell type-specific gastrin receptors; gastrin receptors that mediate the trophic action of gastrin are linked to cell type-specific intracellular signal-transduction pathways; gastrin regulates in vivo growth of some tumors through gastrin receptors, while in others gastrin interacts with other peptides and growth factors to regulate in vivo growth. In the studies in this proposal, we plan to characterize gastrin receptors through which gastrin regulates cell proliferation. The preliminary data suggest that there are multiple receptors capable of binding gastrin; our studies will define which receptors mediate the trophic actions of gastrin on GI epithelial cells. We will characterize the receptor-linked intracellular signal-transduction pathways through which gastrin regulates cell proliferation. Preliminary studies have shown that cell type-specific intracellular signal-transduction pathways, including cyclic AMP, phosphatidylinositol hydrolysis, and mobilization of intracellular Ca2+ are activated by gastrin in a cell type-specific manner to regulate cell proliferation. We will define cellular and molecular events involved in signal transduction stimulated by gastrin. We will examine the effects of gastrin on growth of human cells that naturally express gastrin receptors and that grow both in tissue culture and as xenografts in athymic nude mice or nude rats. We will determine whether the results of in vitro studies accurately predict the effects of exogenous and endogenous gastrin on cell proliferation in vivo. We will also examine analogs of gastrin as well as other members of the gastrin family (cholecystokinin) and structurally unrelated peptides (vasoactive intestinal polypeptide [VIP]), alone and combined with gastrin. The long-term goal of these studies is to precisely identify the steps in signal transduction after gastrin interacts with its specific transcriptional activity and gene expression in GI epithelial cells. Our studies could, in the future, provide the basis for development for new therapeutic strategies based upon manipulation of gastrin's action to restore gut mucosal mass and to regulate the growth of cancers of the gut in a manner similar to current strategies employed for endocrine treatment of breast and prostate cancers.