Phenotypic Determinants of Murine Cholelithiasis

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DESCRIPTION (provided by applicant): Progress in understanding cholesterol gallstone formation in inbred mice has led to new and continuing specific aims, which are mostly extensions of the previous grant. The principal experimental goals are to identify, characterize and quantify the molecular pathophysiologies and phenotypes involved in murine gallstone formation, particularly those caused by cholesterol gallstone (Lith) genes. Aim I proposes to determine the critical pathophysiological changes that are induced by genetic susceptibility within newly-identified quantitative trait loci (QTL) in genetically-diverse inbred mouse strains. This information will be crucial for identifying positional candidate genes for selected QTL's. Aim 2 will determine whether the proximal biliary tree plays a decisive role in bile lithogenicity and cholesterol gallstone susceptibility induced by the Lith1 locus and establish whether blocking cholehepatic shunting of bile salts prevents cholelithogenesis. Aim 3 will examine efflux transporters and their regulation at the enterocyte level as causes of the augmented cholesterol absorption from the intestine of gallstone-susceptible inbred mice. Aim 4 will investigate the pathogenesis of cholesterol cholelithogenesis in mice with targeted disruption of the cholecystokinin (CCK)-A receptor and carboxypeptidase E, the latter intracellular enzyme processing pro-CCK to CCK; it is anticipated that in addition to biliary dysmotility, there will be small intestinal hypomotility leading to augmented lumenal cholesterol absorption. Aim 5 will elucidate the pathogenesis of pigment gallstones in murine models of cystic fibrosis. The hypothesis predicts a less alkaline bile within the intrahepatic biliary tree and gallbladder with enterohepatic cycling of unconjugated bilirubin from bile salt malabsorption, the latter speculated to be secondary to apical sodium-bile salt co-transporter (ASBT) dysfunction. As a result of a more acidic bile, there will be increased endogenous ?-glucuronidase activity intrahepatically, as well as in the gallbladder, with augmented hydrolysis of bilirubin conjugates resulting in calcium bilirubinate precipitation, thereby leading to "black" pigment gallstones, as well as intrahepatic microprecipitates causing mechanical bile duct obstruction. Because of the close genetic correspondence between mammalian genomes, these pathophysiological studies should lead to more fundamental understanding of these common, as well as economically-significant digestive diseases in human beings.