STRUCTURE AND FUNCTION OF INTESTINAL MUCIN

这项提案的长期目标是确定结构的特征 以及实验动物和人的胆囊黏蛋白的性质，以及 阐明该糖蛋白在糖尿病的病理生理机制中的作用 胆固醇和色素胆结石。为了实现这些目标，我们将 使用生化和生物物理技术进一步定义 粘蛋白的结构，并将在体外研究成核和结石形成 在活体内。我们的具体目标如下：1.确定 胆囊黏蛋白的亚基结构，尤其是对胆囊壁粘蛋白的作用 二硫键和疏水相互作用对聚合物的形成和 凝胶化。粘性和准弹性光散射光谱将 用于研究天然粘蛋白在溶液中的凝胶形成。2.比较 动物和人天然粘蛋白和修饰粘蛋白的能力 胆管使胆汁中的一水合胆固醇成核。这些研究 将有助于阐明胆结石成核的一种机制。3.测试 粘液溶解剂促进胆结石溶解的实验研究 胆固醇溶剂，如单辛酸和胆盐。这些特工 将首先在体外进行测试，然后在体内植入人体胆结石 在接受致石饮食的实验动物的胆囊中。我们 也将研究胆泥的形成和组成。 实验动物和人作为这种物质，是胆红素的沉淀物 和粘蛋白，被认为是胆结石的前驱。这些研究已经 与人类胆结石疾病直接相关，并可能导致结石改善 溶解疗法。

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.