PHENOTYPIC DETERMINANTS OF MURINE CHOLESTEROL GALLSTONES

胆石症，其中80%是胆固醇结石，是一种 是美国最常见和最昂贵的消化系统疾病之一。这个 人类疾病在一定程度上是家族遗传的，但遗传基础 是未知的。已经证明，在近交系小鼠中， 胆固醇结石的形成是由基因决定的，有两种 基因，Lith1和Lith2，解释了大多数差异 C57L和AKR菌株之间的敏感性。申请人建议： 近交系小鼠作为人类实验模型的研究 胆石症。老鼠的遗传背景提供了 强大的实验机会，以及对 表型对于克隆基因、鉴定蛋白质和 调节性分子，应作为合理药物的靶点 设计和预防胆结石。申请人建议(I) 近交系胆结石形成的胆汁表型特征 胆结石患病率高和低的小鼠；(Ii)确定 肝/肠胆固醇和胆盐代谢的改变 解释了胆固醇过饱和的胆汁；(Iii)定义 Lith1和Lith2相互遗传的肝胆管表型 确定单个基因的影响；(Iv)测试表型 Lith1基因座候选基因“megalin”的表达 可以控制小管胆固醇的转运；以及(V)确定 胆固醇的从头合成在胆结石形成和发展中的作用 预防。这些研究将与高- 同一小鼠品系、杂交组合和 由杰克逊实验室的贝弗利·佩根博士所作的基因工程 将遗传分析和功能分析结合起来理解 疾病的病理生理学。这项工作应该为 确定人类的主要Lith基因，这反过来应该导致 早期诊断特征的策略和合理的方法 为了预防。

Cholelithiasis, of which 80 percent are cholesterol gallstones, is one of the most common and expensive digestive diseases in the USA. The human disease is familial and heritable in part, but the genetic basis is unknown. It has been demonstrated that in inbred strains of mice, cholesterol gallstone formation is genetically determined, with two genes, Lith1 and Lith2, accounting for most of the difference in susceptibility between C57L and AKR strains. The applicant proposes to investigate the inbred mouse as an experimental model for human gallstone disease. The genetic background of the mouse provides powerful experimental opportunities, and a detailed knowledge of the phenotype is essential to clone the genes, identify the proteins and regulatory molecules, which should serve as targets for rational drug design and gallstone prevention. The applicant proposes to (i) characterize the biliary phenotypes of gallstone formation in inbred mice with high and low gallstone prevalence rates; (ii) determine alterations in hepatic/intestinal cholesterol and bile salt metabolism that account for cholesterol supersaturated bile; (iii) define the hepato-biliary phenotypes in reciprocal congenics of Lith1 and Lith2 to determine the effects of the individual genes; (iv) test the phenotype expression of "megalin", a candidate gene within the Lith1 locus that may control canalicular cholesterol transport; and (v) determine the role of de novo cholesterol synthesis in gallstone formation and prevention. These studies will be carried out in parallel with high- resolution genotype studies of the same mouse strains, crosses and congenics by Dr. Beverly Paigen at The Jackson Laboratory, thereby coupling genetic and functional analyses in understanding the pathophysiology of the disease. This work should pave the way for identifying the major Lith genes in humans, which, in turn, should lead to strategies for early diagnosis of the trait and rational approaches to prevention.