Ingested nutrients stimulate secretion of gastrointestinal hormones that are necessary for the coordinated processes of digestion and absorption of food. One of the most important hormonal regulators of the digestive process is cholecystokinin (CCK)). This hormone is concentrated in the proximal small intestine and is secreted into the blood upon the ingestion of proteins and fats. The physiologic actions of CCK include stimulation of pancreatic secretion and gallbladder contraction, regulation of gastric emptying, and induction of satiety. Therefore, in a highly coordinated manner CCK regulates the ingestion, digestion, and absorption of nutrients. The manner by which foods affect enteric hormone secretion is largely unknown. However, it has recently become apparent two """"""""CCK releasing factors"""""""" are present in the lumen of the proximal small intestine. One of these factors, known as monitor peptide, has been chemically characterized. Monitor peptide is produced by pancreatic acinar cells and is secreted by way of the pancreatic duct into the duodenum. Upon reaching the small intestine monitor peptide interacts with CCK cells to induce hormone secretion. Studies in the PI's laboratory have demonstrated that monitor peptide directly stimulates CCK release from isolated intestinal mucosal cells and from an intestinal CCK-containing cell line. Moreover, monitor peptide has been used to enrich CCK-containing cells by calcium fluorescence-activated cell sorting. The observations that monitor peptide stimulates CCK release in a calcium- dependent manner and recent radioligand binding data have lead to the hypothesis that luminal releasing factors, such as monitor peptide, affect CCK secretion through a receptor-mediated mechanism. The objective of these studies is to evaluate the manner by which luminal releasing factors (with monitor peptide as the prototype) activate the intracellular signaling pathways that lead to CCK secretion. Preliminary studies have identified several heterotrimeric GTP-binding (g) proteins present in CCK cells which are proposed to participate in monitor peptide-stimulated CCK secretion. Therefore, the first Specific Aim of these studies is to: (1) characterize the heterotrimeric GTP binding proteins (G proteins) and t heir receptor coupling in CCK-producing cells. The second Specific Aim will be to (2) determine the second messenger pathways involved in monitor peptide-stimulated CCK release with particular emphasis on modulation of adenylyl cyclase, phospholipase C, and regulation of CCK release by protein phosphatases. The final Specific Aim will be to (3) clone the cDNA encoding the monitor peptide receptor in order to more fully understand the molecular interactions involved with receptor-stimulated signaling by luminal releasing factors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK038626-11
Application #
2444000
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1988-07-14
Project End
1999-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
11
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
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