FEEDBACK REGULATION OF PANCREATIC SECRETION

University Of Texas Hlth Sci Ctr San Ant, San Antonio TX

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Abstract

A cholecystokinin-releasing peptide, termed Luminal CCK-Releasing Factor (LCRF), has been purified from rat intestinal secretions. It has a molecular weight of 8136 daltons, and the sequences has been determined for the N-terminal 41 amino acids. All preliminary studies indicate that LCRF is the important, but elusive factor governing intestinal CCK release. The long term objective of this proposal is to determine the role of this newly discovered peptide in gastrointestinal function. We hypothesize that LCRF is a critical component in the regulation of intestinal cholecystokinin release in the rat. The regulation of LCRF secretion will be investigated in conscious rats with isolated Thiry-Vella Fistulas of jejunum by measuring the effects of nutrients, bile acids and neural blockade on the secretion of immunoreactive LCRF into jejunal loop, and the effect of the luminal environment of the in-continuity proximal intestine (e.g., fed versus fasted state) on LCRF secretion into the jejunal loop. The role of LCRF in pancreatic secretion and CCK release stimulated by dietary protein, trypsin inhibitors, and diversion of bile- pancreatic juice will be investigated using immunoneutralization with anti-sera raised to the biologically active portion of LCRF. The tissue and cellular distribution of LCRF will be investigated using immunohistochemistry and radioimmunoassay (RIA) with antisera raised to selected fragments of the known amino acid sequence of LCRF. All of the major organs associated with regulating gastrointestinal and pancreatic function will be investigated, including the duodenum and ileum, the stomach, the pancreas. Additional studies will test whether LCRF has secretin-releasing activity, based on LCRF-stimulation of a higher/fluid protein ratio of pancreatic secretion compared to CCK-8. These studies are considered critical to the understanding of the tissue distribution of LCRF, to phenotypic identification of the cells producing LCRF, and to understanding the physiology and pathophysiology of LCRF regulation and release. Improved understanding of the mechanisms controlling CCK release is important in diagnosis and treatment of digestive diseases such a pancreatitis, gallbladder disease, gastric emptying abnormalities, colonic dismotility and in food intake regulation.