The purpose of this MERIT award renewal is to define the roles and mechanisms by which gastrin, somatostatin, and gastrin releasing peptide (GRP) regulate gastric acid secretion and mucosal proliferation. The primary hypothesis is that secretory and trophic functions of the histamine-secretin enterochromaffin-like (ECL) cell are stimulated by circulating gastrin acting on CCK-B/gastrin receptors and inhibited by oxyntic D cell somatostatin acting by local gastric paracrine/capillary delivery on type 2 somatostatin receptors. The secondary hypothesis is that secretion and growth of the antral gastrin (G) cell are stimulated by chemosensory stimulatory reflexes involving GRP acting directly upon the G cell and inhibited by chemosensory inhibitory reflexes involving VIP or CGRP acting upon antral D cells to stimulate somatostatin release. The ECL cell, D cell, and G cell therefore are responsible for endocrine and paracrine regulation of gastric acid secretion. We will define the actions of gastrin and somatostatin in regulation of ECL cells by a) determining how the ECL cell gastrin receptors that regulate histamine secretion and ECL cell proliferation differ from the parietal cell/brain CCK-B receptor, b) determining mechanisms for regulation of gastrin/CCK-B receptor signal transduction in ECL cells and in cells transfected with this receptor, and c) determining the mechanisms by which gastrin regulates proliferation of fibroblasts stably transfected with CCK-B receptors. We also will describe regulation of oxyntic and antral D cells and define their targets by a) determining how isolated oxyntic and antral D cells differ in their responses to neuropeptides and defining physiological reflexes in stimulation of somatostatin synthesis and release in oxyntic and antral glands and b) determining which of the five known somatostatin receptor subtypes are produced in the stomach and their cellular distribution. Finally, we will define the actions of somatostatin and GRP in regulation of G cells by a) characterizing the mechanisms by which somatostatin inhibits gastrin release and G cell proliferation, b) determining the distribution of GRP receptor subtypes and the role of local neural release of GRP in regulating of G cells, and c) defining pathways for desensitization, internalization, and resensitization of GRP receptors. These studies have important physiological implications for mechanisms for control of gastrointestinal mucosal secretion and growth by locally released peptides interacting with hormones and neurotransmitters.
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