Regulation of the late-pathway of aldosterone biosynthesis

描述(由申请人提供)：醛固酮在高血压和心血管损害的发展中具有重要作用。原发性醛固酮增多症是由肾上腺自主过度分泌醛固酮引起的，是5-10%的高血压患者高血压的病因。醛固酮的合成需要几个酶促步骤，其中一些发生在胞浆中，另一些则发生在线粒体中，特别是第一步和最后一步。已知的是，醛固酮的生物合成在该途径中分两个步骤进行调节，早期步骤需要由STAR蛋白将胆固醇转移到线粒体，在那里它被羟化并裂解以产生孕烯醇酮，以及在该途径的后期，脱氧皮质酮(DOC)通过线粒体内的CYP11B2基因的产物-醛固酮合成酶被相继羟化为醛固酮。醛固酮合成酶主要在转录水平上被调节。DOC是由黄体酮在胞浆酶21-羟基酶作用下合成的。我们提供的初步数据表明，醛固酮的生物合成也受到DOC通过活性过程有效地转移到线粒体的调节。我们提出了以下假设：“调节醛固酮生物合成的晚期途径涉及调节DOC从胞浆到线粒体的转移”这是一个探索性的建议，以解决特定的目的：1.表征促进DOC转移到线粒体的调节机制2.鉴定和克隆促进DOC转移到线粒体中的促进DOC进入线粒体的因子。与人类健康相关：高血压是成年人最常见的诊断之一，导致心血管疾病和死亡，以及中风，在美国，中风是导致发病率和死亡的主要原因。与血压同等升高的患者相比，醛固酮增多症患者的心血管、肾脏和脑血管病变明显更严重。有关醛固酮合成调节的信息将导致对这些患者进行更有效的治疗。 公共卫生相关性：原发性醛固酮增多症是继发性高血压最常见的形式，约占未经选择的高血压患者的7%-10%。对醛固酮生物合成的调控尚不完全清楚，但已知的是，这种调控发生在生物合成途径的早期和晚期。后一种途径涉及到线粒体中的醛固酮合成酶对DOC的作用。我们已经证明DOC到线粒体的转移是受调控的，并建议分离相关因子。

DESCRIPTION (provided by applicant): Aldosterone has a significant role in the development of hypertension and cardiovascular damage. Primary Aldosteronism, caused by the autonomous and excessive secretion of aldosterone by the adrenal, is the etiology of the high blood pressure in 5-10% of hypertensive patients. Synthesis of aldosterone requires several enzymatic steps, some occurring in the cytosol, others, notably the first and last, in mitochondria. Aldosterone biosynthesis is known to be regulated at two steps in the pathway, an early step requiring the transfer of cholesterol by the StAR protein into the mitochondria where it is hydroxylated and cleaved to produce pregnenolone, and late in the pathway when deoxycorticosterone (DOC) is successively hydroxylated to aldosterone by the product of the CYP11B2 gene, aldosterone synthase, within the mitochondria. Aldosterone synthase is regulated primarily at the transcriptional level. DOC is synthesized from progesterone by the cytosolic enzyme 21-hydroxylase. We present preliminary data indicating that aldosterone biosynthesis is also regulated by the efficient transfer of DOC into the mitochondria by an active process. We proposed to address the following hypotheses: "Regulation of the late pathway of aldosterone biosynthesis involves regulation of the transfer of DOC from the cytosol into the mitochondria" This is an exploratory proposal to address the specific aims: 1. Characterize the mechanism of the regulation of the facilitated transfer of DOC into the mitochondria for conversion into aldosterone by the CYP11B2 enzyme 2. Identify and clone of the factor responsible for facilitating the transfer of DOC into the mitochondria. Relevance to human health: Hypertension is one of the most common diagnoses in adults and contributes to cardiovascular morbidity and mortality, as well as stroke, the primary causes of morbidity and death in America. Patients with aldosteronism have significantly greater cardiovascular, renal and cerebrovascular pathology than those with equivalent increases in blood pressure. Information about the regulation of aldosterone synthesis will lead to more effective therapy for these patients. PUBLIC HEALTH RELEVANCE: Primary Aldosteronism is the most common form of secondary hypertension, accounting for about 7-10% of unselected patients with hypertension. The regulation of aldosterone biosynthesis is incompletely understood, but it is known that the regulation occurs both early and late in the biosynthetic pathway. The late pathway involves the action of the enzyme aldosterone synthase upon DOC within the mitochondria. We have shown that the transfer of DOC into the mitochondria is regulated and propose to isolate the factor involved.