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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK062805-04
Application #
6984127
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2003-01-15
Project End
2007-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
4
Fiscal Year
2006
Total Cost
$125,010
Indirect Cost
Name
University of Iowa
Department
Surgery
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Samuel, Isaac; Tephly, Linda; Williard, Deborah E et al. (2008) Enteral exclusion increases MAP kinase activation and cytokine production in a model of gallstone pancreatitis. Pancreatology 8:6-14
Meyerholz, David K; Williard, Deborah E; Grittmann, Ana-Maria et al. (2008) Murine pancreatic duct ligation induces stress kinase activation, acute pancreatitis, and acute lung injury. Am J Surg 196:675-82
Samuel, Isaac (2008) Bile and pancreatic juice exclusion activates acinar stress kinases and exacerbates gallstone pancreatitis. Surgery 143:434-40
Meyerholz, David K; Samuel, Isaac (2007) Morphologic characterization of early ligation-induced acute pancreatitis in rats. Am J Surg 194:652-8
Samuel, Isaac; Yorek, Mark A; Zaheer, Asgar et al. (2006) Bile-pancreatic juice exclusion promotes Akt/NF-kappaB activation and chemokine production in ligation-induced acute pancreatitis. J Gastrointest Surg 10:950-9
Mattson, David L; Kunert, Mary Pat; Roman, Richard J et al. (2005) Substitution of chromosome 1 ameliorates L-NAME hypertension and renal disease in the fawn-hooded hypertensive rat. Am J Physiol Renal Physiol 288:F1015-22
Samuel, Isaac; Zaheer, Smita; Zaheer, Asgar (2005) Bile-pancreatic juice exclusion increases p38MAPK activation and TNF-alpha production in ligation-induced acute pancreatitis in rats. Pancreatology 5:20-6
Samuel, Isaac; Chaudhary, Ashok; Fisher, Rory A et al. (2005) Exacerbation of acute pancreatitis by combined cholinergic stimulation and duct obstruction. Am J Surg 190:721-4
Samuel, Isaac; Toriumi, Yasuo; Zaheer, Asgar et al. (2004) Mechanism of acute pancreatitis exacerbation by enteral bile-pancreatic juice exclusion. Pancreatology 4:527-32
Samuel, Isaac; Zaheer, Asgar; Zaheer, Smita et al. (2004) Bile-pancreatic juice exclusion increases cholinergic M3 and CCK-A receptor expression and interleukin-6 production in ligation-induced acute pancreatitis. Am J Surg 188:511-5

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