The purpose of this grant is to define the pathogenesis of calcium- containing gallstones and to develop safe, effective methods for their prevention and treatment. Calcium precipitates in bile, composed of one or more """"""""calcium-sensitive"""""""" anions (bilirubinate, carbonate, phosphate, palmitate') are major constituents of all pigment gallstones. Calcium precipitation in bile is thus a clear requisite event in the initiation and growth of all pigment gallstones. In addition, since all cholesterol stones have been found to contain calcium in their central (nidus) regions, we have postulated that calcium precipitates in bile may serve as a nucleus for precipitation of cholestereol from its supersaturated state. According to this view, calcium plays a crucial role in the formation of both pigment and cholesterol gallstones. In addition, surface precipitation of calcium on cholesterol stones usually prevents succesful chemical gallstone dissolution. Further elucidation of gallstone formation therefore requires definition of those forces which lead to calcium precipitation in bile. Enormous progress has been made during tenure of the grant in defining: (1) Ca++ binding to monomeric and micellar bile salts; (2) the structure-activity relations for high-affinity monomeric binding; (3) the mechanisms and sites of Ca++ entry into bile; (4) the physicochemical states of calcium in bile; (5) the influence of Gibbs-Donnan forces in modulating free biliary (Ca++); (6) CaCO3 solubility and lithogenicity in bile; (7) the role of gallbladder mucosal function (H+ secretion) in calcium solubility; (8) bilirubin ionization and solubility; (9) solute osmosity in generating bile flow; and (10) physiological aspects of bile salt and NaHCO3 secretion into bile. A quantitative model of bile flow has been developed, as well as a thermodynamic model of biliary calcium. In the proposed grant period, these studies would be greatly extended, and additional new studies undertaken in two important areas: (1) Development of therapeutic (Ca++-binding) novel bile acids (Hofmann) and (2) Studies of nucleation (Ostrow). Funds are requested for 5 key investigators: Moore, Ostrow, Hofmann, Rege Shiffman. The proposal is divided into 9 Sections: Sections I-VI (Moore, Rege, Shiffman) described extensive physicochemical and physiological studies of biliary calcium, bile salts, bile formation, and ductular and gallbladder function; Sections VII (bilirubin) and VIII (nucleation) are Ostrow's proposed studies, and Section IX is Hofmann's proposal.
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