CHOLESTEROL HOMEOSTASIS IN THE INBRED MOUSE.

在所有被研究的人群中，胆固醇结石在女性中比男性更常见。这 女性和男性之间的差异从青春期开始，一直持续到生育阶段， 将注意力集中在女性性激素的影响上。患胆固醇结石的风险增加 女性与男性的差异与肝脏代谢胆固醇对雌激素的反应方式不同有关。我们 利用自交系AKR/J与A/J杂交的数量性状座位(QTL)分析 确定这些菌株所拥有的胆结石易感基因的子集。值得注意的是，一个新的QTL是 检测到并命名了定位于小鼠10号染色体的Lith5。我们的分子和遗传数据支持 编码雌激素受体O_2的ER_z基因作为LITH5的主要基因的候选，以及 在17[3-雌二醇(E2)诱导的胆结石中，肝脏ERA而不是ER[3]起着关键作用。然而， 鉴定Lith5的致石作用仍然是一个巨大的挑战。这份续期申请是 重点通过系统研究Lith5的病理生理学和生物学特性来确定其致石作用。 某些“制造”小鼠品系的生化功能，如ERO_(-/-)、ATP结合盒 转运蛋白GS/G8(ABCG5/G8)(-/-)和CCK-1R(-/-)小鼠。申请人 建议(I)研究靶向破坏小鼠Lith5/era基因是否会降低易感性 胆固醇结石形成；(Ii)检验E2-Lith5/ERO_-ABCG5/G8途径是 胆汁胆固醇高分泌；(Iii)测定Lith5_RC_in引起的改变 导致胆汁胆固醇过饱和的肝脏胆固醇和胆盐代谢；以及(Iv)探索 E_2-Lith5/ERA-CCK-1R通路是否诱导胆固醇结石时的胆囊动力减退 队形。这项工作应该为识别人类的主要Lith基因铺平道路，进而， 应导致早期诊断该特征的战略和合理的预防方法。

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_z gene, encoding estrogen receptor o_, as a major gene underlying Lith5, as well as the hepatic ERa, but not ER[3, plays a critical role in 17[3-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 ERo_ (-/-), 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/ERo_-ABCG5/G8 pathway is responsible for biliary cholesterol hypersecretion; (iii) determine the alterations induced by Lith5_Rc_ 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.