The long-term objectives of this proposal are to characterize the structure and properties of gallbladder mucin in experimental animals and man, and to elucidate the contribution of this glycoprotein to the pathophysiology of cholesterol and pigment gallstones. To accomplish these objectives we will employ biochemical and biophysical techniques to further define the structure of mucin, and will study nucleation and stone formation in vitro and in vivo.
Our specific aims are as follows: 1. To determine the subunit structure of gallbladder mucin, particularly the contribution of disulfide bridges and hydrophobic interactions to polymer formation and gelation. Viscometric and quasielastic light scattering spectroscopy will be used to study gel formation of native mucin in solution. 2. To compare the ability of native and modified mucins from animals and human gallbladders to nucleate cholesterol monohydrate in bile. These studies will help to elucidate one mechanism of gallstone nucleation. 3. To test the ability of mucolytic agents to enhance gallstone dissolution in cholesterol solvents such as mono-octanoin and bile salts. These agents will be tested in vitro first, then in vivo on human gallstones implanted in gallbladders of experimental animals receiving a lithogenic diet. We also will study the formation and composition of biliary sludge in experimental animals and man, as this material, a precipitate of bilirubin and mucin, is thought to be a precursor of gallstones. These studies have direct relevance to human gallstone disease, and may lead to improved stone dissolution therapy.
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