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.
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