PATHOGENESIS OF CALCIUM-CONTAINING GALLSTONES

这项资助的目的是为了确定钙的发病机制- 并开发安全、有效的治疗方法 他们的预防和治疗。钙在胆汁中沉淀， 由一种或多种“钙敏感”阴离子(胆红素， 碳酸盐、磷酸盐、棕榈酸酯)是所有 色素胆结石。因此，胆汁中的钙沉淀是一种清晰的 所有色素的启动和生长过程中的必要事件 胆结石。此外，由于所有的胆固醇结石 在它们的中心(病灶)区域被发现含有钙，我们有 推测胆汁中的钙沉淀可能是一种 从过饱和的胆固醇中沉淀胆固醇的核心 州政府。根据这一观点，钙在人体健康中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, 胆固醇结石上钙的表面沉淀 防止成功的化学胆结石溶解。进一步 因此，要阐明胆结石的形成需要定义 这些力量导致胆汁中的钙沉淀。 在赠款的有效期内，已经取得了巨大的进展 定义：(1)钙离子与单体和胶束胆盐结合； (2)高亲和力单体的构效关系 结合；(3)钙离子进入胆汁的机制和部位；(4) 胆汁中钙的物理化学状态；(5) Gibbs-Donnan力调节游离胆汁(Ca++)；(6)CaCO3 胆汁中的溶解性和致石性；(7)胆汁的作用 钙溶解的粘膜功能(H+分泌)；(8)胆红素 电离和溶解度；(9)生成胆汁时的溶质渗透性 流动；和(10)胆盐和NaHCO3的生理方面 分泌物进入胆汁。胆汁流动的定量模型已经被提出 建立了胆汁钙的热力学模型。 在拟议的资助期内，这些研究将大大 在两个重要的领域开展了更多的新研究 领域：(1)治疗性(钙结合)新型胆汁的开发 酸(Hofmann)和(2)成核研究(Ostrow)。基金是 请求5名关键调查人员：摩尔、奥斯特罗、霍夫曼、雷格 希夫曼。该提案分为9个部分：第一至第六部分 (Moore，Rege，Shiffman)描述了广泛的物理化学和 胆汁钙、胆盐、胆汁形成的生理学研究 第七节(胆红素)和 八(成核)是奥斯特罗提议的研究，第九节是 霍夫曼的建议。

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.