ROLES OF STAR IN REGULATED STEROIDOGENESIS

调节类固醇生成中的一个关键事件是 类固醇生成细胞转化为营养激素。 这种急性反应 主要反映了增加的胆固醇底物的供应， 内部线粒体基质，其中胆固醇侧链裂解 酶（P450 SCC）催化所有生物合成的初始步骤， 生理类固醇先天性心脏病患者的近期分析 类脂质肾上腺增生（LCAH），一种遗传性疾病， 类固醇合成的全球性缺陷，已经确定， 类固醇生成急性调节蛋白（星星）对此至关重要 将胆固醇递送至P450 SCC。 因此， 了解星星在体内发挥的确切作用， 调节星星表达的机制。我们使用靶向基因 中断开发星星敲除小鼠，提供了一个系统， 追回星星的作用可在一个受控的环境中加以界定， 完整内分泌环境。 使用这些星星敲除小鼠， 将通过转基因表达 永生化癌蛋白 这些细胞系将有助于研究 的星星功能，使得表达野生型或突变的 星星蛋白在类固醇生成细胞的最佳环境中。 结果 关键的星星突变提供了对其结构的新见解- 将通过星星敲除的转基因重建来验证功能 小鼠最后，调节星星表达的机制将是 在类固醇生成和非类固醇生成细胞系中进行评价， 在星星基因的5 '侧翼区的调控元件上， 确定细胞选择性和细胞诱导的表达。 总的来说，这些研究将提供新的见解， 这一重要组成部分的监管和功能 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.