Regulation of the Steroidogenic Acute Regulatory Protein

描述：（由申请方提供）肾上腺和性腺中的类固醇生成 是由热带激素通过调节合成的 类固醇生成急性调节（星星）蛋白。星星合成对于 胆固醇通过线粒体外膜转运到线粒体内膜 胆固醇膜，类固醇生成的第一个酶促步骤发生于此;胆固醇 通过胆固醇侧链裂解酶转化为双烯醇酮。 星星基因突变导致产生非功能性 蛋白质是先天性肾上腺脂质紊乱的遗传基础 增生（LCAH）。LCAH患者的肾上腺和性腺功能明显受损， 由于不能将胆固醇转运到 线粒体因此，了解控制星星表达的机制 和功能是至关重要的。多种信号通路已经被 显示在转录和转录后调节星星 以细胞特异性的方式。星星转录和蛋白表达， 然而，似乎是由cAMP-蛋白激酶a 通路本研究的总体目标是阐明 cAMP依赖性调节星星表达的机制， 小鼠中的转录和翻译以及翻译后水平 睾丸间质细胞和肾上腺细胞。本提案中概述的研究将确定 I）星星基因激活的cAMP依赖性增加是否涉及 抑制因子的丧失和激活因子的获得，功能，2） cAMP依赖性蛋白激酶A活性区分星星（急性）和CYP 1 IA（慢性）基因表达，3）蛋白激酶A在 转录后水平控制星星蛋白表达，和4）星星是 在与线粒体相关的多核糖体上翻译。来限定特定 在一种细胞类型内cAMP依赖性星星调节的机制是重要的 在定义促激素作用的相似性和差异方面， 肾上腺、卵巢和睾丸产生类固醇。这将最终 从而更好地了解潜在的发育或疾病状态 这是由于星星在细胞特异性 方式

DESCRIPTION: (provided by applicant) Steroidogenesis in the adrenal and gonads is acutely controlled by tropic hormones via regulating the synthesis of the steroidogenic acute regulatory (StAR) protein. StAR synthesis is critical for cholesterol translocation across the mitochondrial outer membrane to the inner membrane where the first enzymatic step in steroidogenesis occurs; cholesterol conversion to pregnenolone by the cholesterol side-chain cleavage enzyme. Mutation(s) in the StAR gene that lead to the production of a non-functional protein is the genetic basis for the disorder lipoid congenital adrenal hyperplasia (LCAH). LCAH patients have markedly impaired adrenal and gonadal steroidogenesis due to the inability to transport cholesterol into mitochondria. Thus, understanding the mechanisms that control StAR expression and function is fundamentally important. Multiple signaling pathways have been shown to regulate StAR at both the transcriptional and post-transcriptional level in a cell-specific manner. StAR transcription and protein expression, however, appear to be independently regulated by the cAMP-protein kinase a pathway. The overall objective for this research is to elucidate the molecular mechanisms for the cAMP-dependent regulation of StAR expression at the transcriptional and translational, and post-translational levels in mouse Leydig and adrenal cells. The studies outlined in this proposal will determine whether I) the cAMP-dependent increase in StAR gene activation involves both loss of repressor and gain of activator, functions, 2) the level of cAMP-dependent protein kinase A activity distinguishes StAR (acute) from CYP1 IA (chronic) gene expression, 3) protein kinase A functions at the post-transcriptional level to control StAR protein expression, and 4) StAR is translated on polysomes associated with mitochondria. Defining the specific mechanisms for cAMP-dependent StAR regulation within one cell type is important in defining the similarities and differences in tropic hormone action on adrenal, ovarin, and testicular production of steroids. This will ultimately lead to a better understanding of potential developmental or disease states that result from aberrant over- or under-expression of StAR in a cell-specific manner.