PROTEIN LIPID INTERACTIONS IN GALLSTONE PATHOGENESIS

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Cholesterol gallstone disease is one of the commonest digestive diseases in the United States and results in 700,000 cholecystectomies annually with a direct health care cost in excess of $3 billion. Gallbladder mucin plays a central role in gallstone formation and this proposal will examine the mechanism by which mucin interacts with biliary lipids to promote gallstones. The specific Aims are to 1) Characterize the interaction of specific sites of the mucin molecule with lipid vesicles to improve our understanding of how mucin promotes crystallization of cholesterol monohydrate; 2) Characterize how mucin effects the morphology and rate of crystal growth in solution and in gels so that growth inhibitors can eventually be developed; 3) Examine the central role of mucin as the matrix protein in the biomineralization of both calcium and cholesterol. These Aim's will be achieved by utilizing multiple biophysical techniques to examine model systems where mucin and its modified structural forms will interact with biliary lipids similar to those seen in gallstone bile. Fluorescent assays, dynamic light scattering and magic angle spinning magnetic resonance will examine how mucin promotes vesicle fusion and sub- microscopic nucleation. Light and electron microscopy will examine the way in which mucin can promote both the pattern and rate of crystal growth. These studies may lead to strategies for the prevention and non-surgical therapy of this very common disease.