CHOLESTEROL HOMEOSTASIS IN THE INBRED MOUSE.

描述(由申请者提供)：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。女性和男性之间的这种差异从青春期开始，一直持续到育龄阶段，将注意力集中在女性性激素的影响上。女性患胆固醇结石的风险高于男性，这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AKR/J和A/J近交系的数量性状基因座(QTL)分析来确定这些自交系所具有的胆结石易感基因亚集。值得注意的是，我们检测到一个新的QTL，命名为Lith5，被定位在小鼠10号染色体上。我们的分子和遗传学数据支持ER(编码雌激素受体的基因)作为Lith5的主要基因，以及肝脏的ER(，而不是ER()，在17-雌二醇(E2)诱导的胆结石中起关键作用。然而，鉴定Lith5的致石作用仍然是一个巨大的挑战。这一新的应用重点是通过系统地研究Lith5在一些“制造”的小鼠品系中的病理生理和生化功能，如ER(-/-)、三磷酸腺苷结合盒转运体GS/G8(ABCG5/G8)(-/-)和CCK-1R(-/-)小鼠，来鉴定Lith5的致石作用。申请人建议：(I)研究靶向干扰小鼠Lith5/era基因是否会降低胆固醇结石形成的易感性；(Ii)检验E2-Lith5/ER(-ABCG5/G8途径)与胆汁胆固醇高分泌有关的假说；(Iii)确定Lith5/ER(-ABCG5/G8)途径诱导的肝脏胆固醇和胆盐代谢的变化；(V)研究导致胆固醇过饱和的胆汁中胆固醇过饱和的原因；以及(Iv)探索E2-Lith5/era-CCK-1R通路是否会在胆固醇结石形成过程中诱导胆囊动力减退。这项工作应该为确定人类主要的Lith基因铺平道路，这反过来又应该导致对该特征的早期诊断策略和合理的预防方法。

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.