The long-term objectives of this proposal are to examine the relevance of chromogranin-A-related peptides in the regulation of gut function. The central hypothesis of the proposed research is that chromogranin A (CGA) is a precursor of regulatory peptides with specific biological activities in the gastrointestinal (GI) tract and pancreas.
The specific aims of this proposal are: 1) to characterize the concentration and distribution of CGA-related peptides in the GI tract and pancreas. By means of immunochemical and protein characterization techniques, we will characterize the localization of CGA and of CGA-derived peptides in the normal gut and in selected endocrine tumors of the gut. ***We intend to focus primarily on pancreastatin, N-terminal fragments of CGA (i.e., beta- granin-like) and on CGA-31 residues (359-389)***; 2) to characterize the secretion of CGA, and of CGA-related peptides by the GI endocrine pancreas and pancreatic gut tumors. Whether CGA-related peptides occur intracellularly or systemically will be explored. We will investigate the generation of CGA-related peptides by endocrine gut tumors in vivo and in vitro. ***We intend to focus primarily on pancreastatin, N-terminal fragments of CGA (i.e., beta-granin-like) and on CGA-31 residues (359- 389)***; 3) to characterize the action of CGA and CGA-derived peptides on pancreatic insulin secretion. The effects of these peptides on neural, nutrient and hormone-stimulated insulin secretion will be examined. Possible mechanisms of action of these peptides on insulin secretion will be explored. Whether receptors for pancreastatin or CGA-related peptides exist on beta-cells will be explored. ***Because we have shown that CGA-31 residues (359-389) inhibits pancreatic endocrine tumor growth, we will explore further the actions of this CGA fragment on cell growth***; 4) to study the pathways of CGA proteolysis in the GI tract, pancreas, and selected endocrine gut tumors. Whether the quality and quantity of CGA- related peptides in tumors and normal tissues are influenced by nutrients or the endocrine environment will be explored. The possibility that the appearance of CGA-related peptides is auto-regulated will be examined. We will explore whether a tissue-specific processing of CGA occurs. Whether the secretion of CGA and the tissue-resident peptides (e.g., stomach- gastrin) are controlled by the same second messenger system will be examined. Appearance of mRNA for CGA in response to pharmacologic manipulation of second messenger systems will be examined. It is anticipated that these studies will lead to a better understanding of the relevance of chromogranin-A in the regulation of enteric physiology.
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