Phenotypic Determinants of Murine Cholelithiasis
Principal Investigator: Martin Carey
Abstract: 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.
Funding Period: 1998-09-01 - 2006-06-30
more information: NIH RePORT
- Interfacial properties of most monofluorinated bile acids deviate markedly from the natural congeners: studies with the Langmuir-Pockels surface balanceJohn M Kauffman
Department of Medicine, Harvard Medical School, Harvard Digestive Diseases Center, Brigham and Women s Hospital, Boston, MA, USA
J Lipid Res 46:571-81. 2005..These results provide a framework for designing F-modified bile acids to mimic or diverge from the natural compounds in vivo...
- Identification of cholelithogenic enterohepatic helicobacter species and their role in murine cholesterol gallstone formationKirk J Maurer
Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Gastroenterology 128:1023-33. 2005..To test this, we prospectively investigated the effects of Helicobacter spp infection in cholesterol gallstone pathogenesis in the highly susceptible C57L/J mouse model...
- Single and interacting QTLs for cholesterol gallstones revealed in an intercross between mouse strains NZB and SMMalcolm A Lyons
The Jackson Laboratory, Bar Harbor, Maine 04609, USA
Mamm Genome 16:152-63. 2005..The QTLs identified herein largely contributed to gallstone formation rather than gallstone severity. Cloning the genes underlying these murine QTLs should facilitate prediction and cloning of the orthologous human genes...
- Helicobacter pylori and cholesterol gallstone formation in C57L/J mice: a prospective studyKirk J Maurer
Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Ave, Cambridge, MA 02139, USA
Am J Physiol Gastrointest Liver Physiol 290:G175-82. 2006..Nonetheless, the C57L mouse develops severe lesions of both the glandular and nonglandular stomach in response to H. pylori infection and the lithogenic diet, respectively...
- Association of a lithogenic Abcg5/Abcg8 allele on Chromosome 17 (Lith9) with cholesterol gallstone formation in PERA/EiJ miceHenning Wittenburg
The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA
Mamm Genome 16:495-504. 2005..Significantly higher mRNA expression of Abcg5 and Abcg8 in strain PERA compared with strains I/Ln and DBA/2 further substantiated that the PERA allele of Abcg5/Abcg8 was responsible for lithogenicity underlying Lith9...
- Nongenomic effects of progesterone on the contraction of muscle cells from the guinea pig colonZuo Liang Xiao
Division of Gastroenterology, APC 406, Rhode Island Hospital Brown University Medical School, 593 Eddy St, Providence, RI 02903, USA
Am J Physiol Gastrointest Liver Physiol 290:G1008-15. 2006..This effect does not appear to be specific to PG because other steroid hormones such as aldosterone and testosterone can also induce it...
- QTL mapping for genetic determinants of lipoprotein cholesterol levels in combined crosses of inbred mouse strainsHenning Wittenburg
The Jackson Laboratory, Bar Harbor, ME, USA
J Lipid Res 47:1780-90. 2006....
- Pathophysiological basis of liver disease in cystic fibrosis employing a DeltaF508 mouse modelFolke Freudenberg
Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
Am J Physiol Gastrointest Liver Physiol 294:G1411-20. 2008..This study of the earliest stages of CF liver disease provides a framework for investigating the molecular pathophysiology of more advanced disease in murine models and in humans with CF...
- Cholangiocyte bile salt transporters in cholesterol gallstone-susceptible and resistant inbred mouse strainsJulia J Liu
Division of Gastroenterology, Department of Medicine, University of Alberta Hospital, Edmonton, Alberta, Canada
J Gastroenterol Hepatol 23:1596-602. 2008..We investigated the dietary and gender influences on the expression and functionality of cholangiocyte bile salt transporters and development of biliary hyperplasia in cholesterol gallstone-susceptible C57L/J and resistant AKR/J mice...