The objective of this proposal is to study the mechanisms of secretion and action of secretin (S) and cholecystokinin (CCK). Four major hypotheses will be tested: l) The releases of S and CCK are mediated by lumenally active S- and CCK-releasing peptides (S-RP and CCK-RP) in the upper small intestine and by a pancreatic S-RP found in canine pancreatic juice; 2) The releases and actions of S and CCK are neurally mediated; 3) Secretin- containing endocrine cells in gastric mucosa are controlled by neuropeptides and participate in the regulatory mechanism of gastric acid secretion; 4) The release of CCK from pancreatic islets is neurally regulated and participates in regulation of pancreatic exocrine secretion. The existence of S-RP and/or CCK-RP will be proved by purification and structure determination of these peptides from rat intestinal extract or canine pancreatic juice. Synthetic peptide corresponding to these peptides will be synthesized to confirm their bioactivity and to raise polyclonal antibodies for establishing specific radioimmunoassays and histochemical localization of these peptides in the gastrointestinal tract. The physiological actions of S-RP and CCK-RP will be studied in various animal models. The involvement of neuronal factors in the releases and actions of S and CCK will be tested by studying the effects of chemical ablation of the sensory afferent neurons, immunoneutralization of various candidate neuropeptides, antagonists of neurotrasmitters or neuropeptides, and determination of specific receptors for S or CCK in the synaptosomal membranes of the submucous, myenteric and vagal nerves. Existence of mRNA of S in gastric mucosa will be shown by in situ hybridization with a specific cDNA probe and by reverse transcription-polymerase chain reaction. The function of gastric S will be tested in isolated and perfused rat stomach by studying the effects of a specific anti-S serum on secretion of gastric acid, gastrin, somatostatin and prostaglandins and by demonstrating release of S from the mucosal explants of the antrum and fundus. The existence of CCK in pancreatic islet will be confirmed by in situ hybridization with a CCK-specific cDNA probe and by studying CCK release from isolated islets. The function(s) of islet CCK will be tested by studying the effect of the specific CCK receptor antagonist, loxiglumide, on exocrine secretion from isolated and perfused rat pancreas or isolated islets. The results of these studies may lead to better understanding of the release and action mechanisms of S and CCK, of the involvement of S in defense mechanism of gastric mucosa, and the physiological and pathophysiological mechanism of pancreatic exocrine secretion, thereby leading to better treatment of pancreatic insufficiency.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK025962-19
Application #
2608366
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
May, Michael K
Project Start
1979-07-01
Project End
1999-11-30
Budget Start
1997-12-01
Budget End
1998-11-30
Support Year
19
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Rochester
Department
Internal Medicine/Medicine
Type
Schools of Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
Chey, William Y; Chang, Ta-Min (2014) Secretin: historical perspective and current status. Pancreas 43:162-82
Chey, William Y; Chang, Cecilia H; Pan, Huei-Ju et al. (2003) Evidence on the presence of secretin cells in the gastric antral and oxyntic mucosa. Regul Pept 111:183-90
Li, J P; Chang, T M; Chey, W Y (2001) Roles of 5-HT receptors in the release and action of secretin on pancreatic secretion in rats. Am J Physiol Gastrointest Liver Physiol 280:G595-602
Li, J P; Lee, K Y; Chang, T M et al. (2001) MEK inhibits secretin release and pancreatic secretion: roles of secretin-releasing peptide and somatostatin. Am J Physiol Gastrointest Liver Physiol 280:G890-6
Li, J P; Chang, T M; Wagner, D et al. (2001) Pancreatic phospholipase A2 from the small intestine is a secretin-releasing factor in rats. Am J Physiol Gastrointest Liver Physiol 281:G526-32
Li, P; Song, Y; Lee, K Y et al. (2000) A secretin releasing peptide exists in dog pancreatic juice. Life Sci 66:1307-16
Chang, T M; Thagesen, H; Lee, K Y et al. (2000) Canine vagus nerve stores cholecystokinin-58 and -8 but releases only cholecystokinin-8 upon electrical vagal stimulation. Regul Pept 87:7-Jan
Li, P; Chang, T M; Coy, D et al. (2000) Inhibition of gastric acid secretion in rat stomach by PACAP is mediated by secretin, somatostatin, and PGE(2). Am J Physiol Gastrointest Liver Physiol 278:G121-7
Jyotheeswaran, S; Li, P; Chang, T M et al. (2000) Endogenous nitric oxide mediates pancreatic exocrine secretion stimulated by secretin and cholecystokinin in rats. Pancreas 20:401-7
Song, Y; Li, P; Lee, K Y et al. (1999) Canine pancreatic juice stimulates the release of secretin and pancreatic secretion in the dog. Am J Physiol 277:G731-5

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