Cholesterol gallstone disease is a common major health problem. It is now accepted that although the excretion of cholesterol supersaturated bile is often observed, the ability of the bile to nucleate cholesterol crystals is not necessarily parallel to the degree of cholesterol supersaturation. The ease with which cholesterol crystals can be nucleated from bile accurately predicts the propensity of developing gallstones. Current evidence indicates that the very first step in the formation of cholesterol gallstones is nucleation of the cholesterol from an aqueous phase (bile) into a solid crystalline phase (cholesterol monohydrate crystals). The crystals then grow in a number and size and agglomerate to form gallstones. We will carry out physical chemical characterization of the processes leading to cholesterol crystal formation. We will: 1) Examine each of what we believe to be the distinct and separate steps of: Vesicle Aggregation, Vesicle Fusion, Phase Separation, Crystal Growth (Stone Formation). Finally, growth of crystals will be monitored by spectrophometric methods established in the literature. Our chief tool will be fluorescence probe allowing separate determination of aggregation and fusion rates. 2) Determine the effect of pro and anti-nucleators on the steps in 1). Candidate pronucleators are mucin, aminopeptidase N, and Ca++, among others. Possible anti-nucleators are apolipoproteins and certain glycoproteins. Clues to the mechanism of action of these material will come from examination of their effect on each of the steps in 1). 3) Characterize the physical chemical packaging of biliary lipids, primarily using small angle neutron scattering. The results of this research should allow a clearer understanding of the nucleating process as well as the logical role of a number of pro and anti-nucleators. This, in turn will add insight into the pathogenesis and prevention of gallstones.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK041678-07
Application #
2654500
Study Section
Nutrition Study Section (NTN)
Project Start
1990-08-10
Project End
1999-01-31
Budget Start
1998-03-01
Budget End
1999-01-31
Support Year
7
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Ko, Cynthia W; Schulte, Scott J; Lee, Sum P (2005) Biliary sludge is formed by modification of hepatic bile by the gallbladder mucosa. Clin Gastroenterol Hepatol 3:672-8
Haigh, W G; Lee, S P (2001) Identification of oxysterols in human bile and pigment gallstones. Gastroenterology 121:118-23
Wrenn, S P; Gudheti, M; Veleva, A N et al. (2001) Characterization of model bile using fluorescence energy transfer from dehydroergosterol to dansylated lecithin. J Lipid Res 42:923-34
Ko, C W; Sekijima, J H; Lee, S P (1999) Biliary sludge. Ann Intern Med 130:301-11
Wrenn, S P; Kaler, E W; Lee, S P (1999) A fluorescence energy transfer study of lecithin-cholesterol vesicles in the presence of phospholipase C. J Lipid Res 40:1483-94
Ko, C W; Lee, S P (1999) Gallstone formation. Local factors. Gastroenterol Clin North Am 28:99-115
Ko, C W; Kowdley, K V; Haigh, W G et al. (1998) Biliary lipid composition after liver transplantation: effect of allograft function and cyclosporine. Liver Transpl Surg 4:258-64
Klinkspoor, J H; Yoshida, T; Lee, S P (1998) Bile salts stimulate mucin secretion by cultured dog gallbladder epithelial cells independent of their detergent effect. Biochem J 332 ( Pt 1):257-62
Luk, A S; Kaler, E W; Lee, S P (1998) Protein lipid interaction in bile: effects of biliary proteins on the stability of cholesterol-lecithin vesicles. Biochim Biophys Acta 1390:282-92
Luk, A S; Kaler, E W; Lee, S P (1997) Structural mechanisms of bile salt-induced growth of small unilamellar cholesterol-lecithin vesicles. Biochemistry 36:5633-44

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