CHOLESTEROL HOMEOSTASIS IN THE INBRED MOUSE.

描述（由申请人提供）：在研究的每个人群中，胆固醇胆结石在女性中比男性更常见。男女之间的这种差异从青春期开始，一直持续到生育年龄，重点关注女性性激素的影响。女性与男性患胆固醇结石的风险增加与肝脏在雌激素作用下代谢胆固醇的方式不同有关。本研究利用AKR/J和A/J自交系的数量性状位点（QTL）分析，确定了这两个菌株所具有的胆结石易感基因亚群。值得注意的是，一个新的QTL被检测到并命名为Lith5，它被定位在小鼠的10号染色体上。我们的分子和遗传数据支持ER（编码雌激素受体）基因，作为Lith5的主要基因，以及肝脏ER(但不是ER()，在17？-雌二醇（E2）诱导的胆结石。然而，确定Lith5的成岩作用仍然是一个重大挑战。本次更新申请的重点是通过系统地研究Lith5在一些“人造”小鼠品系(如ER（(-/-)）、atp结合盒转运体GS/G8 (ABCG5/G8)（-/-）和胆囊收缩素-1受体（CCK-1R）（-/-）小鼠中的病理生理和生化功能，来确定Lith5的造石作用。申请人建议(i)研究靶向破坏小鼠Lith5/Era基因是否会降低胆固醇胆石形成的易感性；（ii）验证E2-Lith5/ER（-ABCG5/G8通路）导致胆道胆固醇高分泌的假说；（iii）确定Lith5/ER（）对肝脏胆固醇和胆盐代谢的改变，从而导致胆固醇过饱和胆汁；（iv）探索E2-Lith5/ERa-CCK-1R通路是否在胆固醇胆结石形成过程中诱导胆囊功能低下。这项工作将为识别人类主要的lithh基因铺平道路，从而为早期诊断该特征和合理的预防方法提供策略。

DESCRIPTION (provided by applicant): Cholesterol gallstones are more common in women than men in every population that has been studied. This difference between women and men begins during puberty and continues through the childbearing years, focusing attention upon the effects of female sex hormones. The increased risk of cholesterol gallstones in women vs. men is related to differences in how the liver metabolizes cholesterol in response to estrogen. We employed quantitative trait locus (QTL) analyses of an intercross between inbred strains AKR/J and A/J to determine the subset of gallstone susceptibility genes these strains possess. Significantly, a new QTL is detected and named Lith5 that is mapped to mouse chromosome 10. Our molecular and genetic data support the candidacy of the ER( gene, encoding estrogen receptor (, as a major gene underlying Lith5, as well as the hepatic ER(, but not ER(, plays a critical role in 17?-estradiol (E2)-induced gallstones. However, the identification of lithogenic effects of Lith5 remains a significant challenge. This renewal application is focused on identifying the lithogenic effects of Lith5 by systematically studying its pathophysiological and biochemical functions in some "manufactured" mouse strains such as ER( (-/-), ATP-binding cassette transporters GS/G8 (ABCG5/G8) (-/-), and cholecystokinin-1 receptor (CCK-1R) (-/-) mice. The applicant proposes to (i) investigate whether targeted disruption of the murine Lith5/Era gene decreases susceptibility to cholesterol gallstone formation; (ii) test the hypothesis that E2-Lith5/ER(-ABCG5/G8 pathway is responsible for biliary cholesterol hypersecretion; (iii) determine the alterations induced by Lith5/ER( in hepatic cholesterol and bile salt metabolism that account for cholesterol supersaturated bile; and (iv) explore whether E2-Lith5/ERa-CCK-1R pathway induces gallbladder hypomotility during cholesterol gallstone formation. 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.