Acute pancreatitis is a common disease with significant morbidity and mortality but no specific treatment is available as the pathogenic mechanisms are not known. The purpose of this research proposal is to elucidate early events in pathogenesis of gallstone-induced acute pancreatitis. We use the rat model of bile-pancreatic duct ligation-induced acute pancreatitis as an experimental corollary. Bile-pancreatic juice exclusion from gut causes feedback exocrine pancreatic stimulation via cholecystokinin-A receptor (CCK-AR) mechanisms. The role of the CCK-AR in disease pathogenesis is not known. Our preliminary studies provide the first evidence that CCK-AR mediated pancreatic acinar cell hyperstimulation plays a contributory role in disease pathogenesis and that induction of CCK-AR occurs within one hour of duct ligation. We hypothesize that pathological amplification of CCK-AR mediated signal transduction exacerbates disease pathogenesis. We propose experiments to test this hypothesis and pursue these specific aims: 1) Characterize the role of the CCK-AR in duct occlusion-induced acute pancreatitis pathogenesis. 2) Characterize the expression and regulation of the CCK-AR in duct occlusion-induced acute pancreatitis. 3) Characterize the CCK-AR mediated signal transduction pathway in duct occlusion-induced acute pancreatitis. Competitive binding assays with radiolabeled ligand will be done to study receptor number, specificity, and affinity. Receptor sensitivity and activity will be determined by measuring downstream signals (cyclic AMP, inositol phosphate). Differences between the induced and native receptor will be determined both in terms of altered functional characteristics and perturbations in intracellular signal transduction pathways. The possibility that promiscuous G-protein coupling in acute pancreatitis could drastically increase CCK-AR affinity and also perpetuate a grossly amplified intracellular signal may have profound implications in mechanisms of disease pathogenesis. An innovative feature of this proposal is the use of an original surgical model, """"""""The Donor Rat Model"""""""", that provides a unique opportunity to investigate disease pathogenesis. The significance and health-relatedness of this research endeavor is its ultimate goal to elucidate mechanisms of disease pathogenesis that provide the rationale to base new treatment protocols intended to reduce the morbidity and mortality of acute pancreatitis.
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