PATHOGENESIS OF CALCIUM CONTAINING GALLSTONES

这项资助的目的是确定钙的发病机制- 含有胆结石，并开发安全，有效的方法， 他们的预防和治疗。 钙在胆汁中沉淀， 由一种或多种“钙敏感性”阴离子（碳酸盐， 碳酸盐，磷酸盐，棕榈酸盐“）是所有的主要成分 胆色素结石 因此，胆汁中的钙沉淀是一种明确的 在所有色素的起始和生长中的必要事件 胆结石。 此外，由于所有胆固醇结石都是 发现含有钙在其中央（病灶）地区，我们有 假设胆汁中的钙沉淀物可能作为 用于从过饱和的对苯二酚中沉淀对苯二酚的核 状态 根据这一观点，钙在人体内起着至关重要的作用。 胆色素结石和胆固醇结石的形成。 此外，本发明还提供了一种方法， 胆固醇结石上钙的表面沉淀通常 防止成功的化学溶解胆结石。 进一步 因此，要阐明胆结石的形成， 导致胆汁中钙沉淀的那些力。 在赠款的任期内， 定义：（1）Ca++与单体胆汁盐和胶束胆汁盐的结合; (2)高亲和力单体构效关系 结合;（3）Ca++进入胆汁的机制和部位;（4） 胆汁中钙的理化状态;（5） Gibbs-Donnan力调节胆汁游离Ca ~（++）;（6）CaCO_3 胆汁溶解性和成石性;（7）胆囊的作用 粘膜功能（H+分泌）在钙溶解度;（8）胆红素 游离度和溶解度：（9）胆汁生成过程中的溶质浓度 流动;和（10）生理方面的胆盐和碳酸氢钠 分泌到胆汁中。 胆汁流动的定量模型已被 开发，以及胆汁钙的热力学模型。 在拟议的赠款期间，这些研究将大大 在两个重要的领域进行了扩展和额外的新研究 研究领域：（1）开发治疗性（Ca++结合）新型胆汁 酸（Hofmann）和（2）成核研究（Ostrow）。 资金 要求5名关键调查员：摩尔、奥斯特罗、霍夫曼、雷杰 希夫曼 该提案分为9个部分：第一至第六部分 （摩尔，Rege，Shiffman）描述了广泛的物理化学和 胆汁钙，胆汁盐，胆汁形成， 以及胆管和胆囊功能;第VII节（胆红素）和 VIII（成核）是奥斯特罗提出的研究，第IX节是 霍夫曼的提议

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.