PHENOTYPIC DETERMINANTS OF MURINE CHOLESTEROL GALLSTONES

鼠胆固醇胆结石的表型决定因素

• 批准号: 6177969
• 负责人: MARTIN CONRAD CAREY
• 金额: $ 18.81万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6177969
• 关键词: RNase protection assay; cholanate compound; cholelithiasis; cholesterol; gene expression; genetic strain; genetic susceptibility; immunofluorescence technique; laboratory mouse; liver metabolism; low density lipoprotein receptor; molecular pathology; northern blottings; nutrition related tag; pathogenic diet; phenotype; steroid metabolism; western blottings

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.

胆石症是其中的一种，其中 80% 是胆固醇结石 美国最常见和最昂贵的消化系统疾病。 这 人类疾病具有家族性和部分遗传性，但遗传基础 未知。 研究表明，在近交系小鼠中， 胆固醇胆结石的形成是由基因决定的，有两个 基因 Lith1 和 Lith2 解释了大部分差异 C57L 和 AKR 菌株之间的易感性。 申请人提议 研究近交小鼠作为人类实验模型 胆结石疾病。 小鼠的遗传背景提供了 强大的实验机会和详细的知识 表型对于克隆基因、鉴定蛋白质和 调节分子，应作为合理药物的靶标 设计和胆结石预防。 申请人提议 (i) 表征近交系胆结石形成的胆道表型 胆结石患病率高和低的小鼠； (二) 确定 肝脏/肠道胆固醇和胆汁盐代谢的改变 胆汁中胆固醇过饱和的原因； (iii) 定义 Lith1 和 Lith2 的肝胆表型互为同源 确定单个基因的影响； (iv) 测试表型 Lith1 基因座内的候选基因“megalin”的表达 可以控制小管胆固醇转运； (v) 确定 胆固醇从头合成在胆结石形成中的作用和 预防。 这些研究将与高 相同小鼠品系、杂交和杂交的分辨率基因型研究 杰克逊实验室的 Beverly Paigen 博士提出了 congenics，从而 将遗传和功能分析结合起来以了解 该疾病的病理生理学。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 来预防。