The objectives of this application are to use biophysical and pathophysiologic rationale and physical- chemical, biochemical and molecular biologic techniques to advance fundamental understanding of bile and its two major dysfunctions, namely cholestasis and gallstones of both pigment and cholesterol types, i) The first aim will determine whether enterohepatic infection with Heficobacter rodentium and hepaticus, both common human and murine enterobiliary pathogens, is the final common trigger in cholesterol gallstone pathogenesis via nucleation of cholesterol supersaturated bile. Studies will be carried out on genetically gallstone-susceptible mice coupled with in vitro analysis of cholesterol nucleation from model and native biles as well as quantifying evidence of Heficobacter infection in human biliary tissues, ii) Aim two will quantify the activity of the pathway responsible for trimethylation of phosphatidylethanolamine to phosphatidylcholine on the canalicular membrane in the lithogenic state, which may be coupled with biliary cholesterol hypersecretion. Elevation of plasma and bile homocysteine, a by-product of this reaction, may serve as a lithogenic marker and shed light on vicinal and distal organ dysfunction, iii) The third aim will investigate, and unambiguously prove, enterohepatic cycling of bilirubin and 'black'pigment gallstones in the setting of severe bile salt malabsorption in the SlclOa2 null mouse and determine its prevention by non- absorbed hydrogels containing covalently linked cholic acid, a strong bilirubin binder, or 13-glucaro,l-4 lactone, a potent inhibitor of bacterial 6-glucuronidase. iv) Aim four will work out, both experimentally and by molecular dynamic simulations, the physical states of conjugated and unconjugated bilirubins in native biles and define the thermodynamic conditions required for "black" pigment gallstone formation in human biles, v) The fifth aim will explore cholestasis and pigment "sludge" and gallstone formation associated with total parenteral nutrition, focusing on the lack of CCK and secretin from enteral starvation. The hormonal deficits cause enterohepatic cycling of unconjugated bilirubin which engenders hyperbilirubinbilia and also results in less alkaline hepatic bile, where endogenous 13-glucuronidase hydrolysis of bilirubin glucuronides and calcium bilirubinate precipitation occurs. The results of these hypothesis-driven basic research aims will provide insights that correlate native and model systems and should be readily translatable to prevent and treat these common heDatobiliarv diseases in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK036588-28
Application #
8490349
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Serrano, Jose
Project Start
1985-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
28
Fiscal Year
2013
Total Cost
$824,846
Indirect Cost
$353,307
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Wang, David Q-H; Carey, Martin C (2014) Therapeutic uses of animal biles in traditional Chinese medicine: an ethnopharmacological, biophysical chemical and medicinal review. World J Gastroenterol 20:9952-75
Fremont-Rahl, Jacqueline J; Ge, Zhongming; Umana, Carlos et al. (2013) An analysis of the role of the indigenous microbiota in cholesterol gallstone pathogenesis. PLoS One 8:e70657
Behar, J; Mawe, G M; Mawe, G et al. (2013) Roles of cholesterol and bile salts in the pathogenesis of gallbladder hypomotility and inflammation: cholecystitis is not caused by cystic duct obstruction. Neurogastroenterol Motil 25:283-90
Vitek, Libor; Carey, Martin C (2012) New pathophysiological concepts underlying pathogenesis of pigment gallstones. Clin Res Hepatol Gastroenterol 36:122-9
Zhang, Ji; Handy, Diane E; Wang, Yufang et al. (2011) Hyperhomocysteinemia from trimethylation of hepatic phosphatidylethanolamine during cholesterol cholelithogenesis in inbred mice. Hepatology 54:697-706
Freudenberg, Folke; Leonard, Monika R; Liu, Shou-An et al. (2010) Pathophysiological preconditions promoting mixed "black" pigment plus cholesterol gallstones in a DeltaF508 mouse model of cystic fibrosis. Am J Physiol Gastrointest Liver Physiol 299:G205-14
Wang, David Q-H; Cohen, David E; Carey, Martin C (2009) Biliary lipids and cholesterol gallstone disease. J Lipid Res 50 Suppl:S406-11
Maurer, Kirk J; Carey, Martin C; Fox, James G (2009) Roles of infection, inflammation, and the immune system in cholesterol gallstone formation. Gastroenterology 136:425-40
Biddinger, Sudha B; Haas, Joel T; Yu, Bian B et al. (2008) Hepatic insulin resistance directly promotes formation of cholesterol gallstones. Nat Med 14:778-82
Freudenberg, Folke; Broderick, Annemarie L; Yu, Bian B et al. (2008) Pathophysiological basis of liver disease in cystic fibrosis employing a DeltaF508 mouse model. Am J Physiol Gastrointest Liver Physiol 294:G1411-20

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