ROLES OF STAR IN REGULATED STEROIDOGENESIS

调节类固醇生成的一个关键事件是急性反应 类固醇生成细胞转化为营养激素。这一尖锐的反应 主要反映了胆固醇底物供应的增加 内部线粒体基质，胆固醇侧链断裂的地方 酶(P450scc)催化All生物合成的第一步。 生理类固醇。近年来先天性心脏病患者的临床分析 类脂性肾上腺增生症(LCAH)，一种遗传性疾病 由于类固醇合成的全球性缺陷，已经确定了 类固醇合成急性调节蛋白(STAR)对此至关重要 将胆固醇输送到P450scc。因此，它变得非常重要 了解STAR在体内扮演的确切角色，并描绘出 调节明星表达的机制。我们已经使用了靶向基因 破坏发展恒星基因敲除小鼠，提供一种系统，在其中 可以在受控设置中定义STAR的角色 完整的内分泌环境。利用这些星形基因敲除小鼠，细胞系 将通过转基因表达从类固醇生成器官中获得 使癌蛋白永生。这些细胞系将为研究提供便利 在STAR功能中，可以表达野生型或突变型 在类固醇生成细胞的最佳背景下的星状蛋白。结果 关键的恒星突变为其结构提供了新的见解- 将通过STAR基因敲除的转基因重组来验证功能 老鼠。最后，调节STAR表达的机制将是 在类固醇生成和非类固醇生成细胞系中进行评估，重点 关于STAR基因5‘侧翼区调控元件的研究 确定细胞选择性和激素诱导的表达。 总而言之，这些研究将提供对 被监管机构的这一重要组成部分的监管和职能 类固醇激素的生物合成。

A critical event in regulated steroidogenesis is the acute response of steroidogenic cells to trophic hormones. This acute response predominantly reflects increased supply of cholesterol substrate to the inner mitochondrial matrix, where the cholesterol side-chain cleavage enzyme (P450scc) catalyzes the initial step in the biosynthesis of all physiological steroids. Recent analyses of patients with congenital lipoid adrenal hyperplasia (LCAH), an inherited disorder characterized by global defects in steroidogenesis, have established that the Steroidogenic Acute Regulatory protein (StAR) is essential for this delivery of cholesterol to P450scc. It thus becomes very important to understand the precise role that StAR plays in vivo and to delineate the mechanisms that regulate StAR expression. We have used targeted gene disruption to develop StAR knockout mice, providing a system in which the roles of StAR can be defined in a controlled setting within an intact endocrine milieu. Using these StAR knockout mice, cell lines will be derived from steroidogenic organs by transgenic expression of immortalizing oncoproteins. These cell lines will facilitate the study of StAR function, making is possible to express wild-type or mutated StAR protein within the optimal context of steroidogenic cells. Results with key StAR mutations that provide novel insights into its structure- function will be validated by transgenic reconstitution of StAR knockout mice. Finally, the mechanisms that regulate StAR expression will be evaluated in steroidogenic and non-steroidogenic cell lines, focusing on regulatory elements in the 5'-flanking region of the StAR gene that determine cell-selective and hormonally induced expression. Collectively, these studies will provide novel insights into the regulation and function of this essential component of the regulated biosynthesis of steroid hormones.