Regulation of the late-pathway of aldosterone biosynthesis

说明（申请人提供）：醛固酮在高血压和心血管损伤的发生中具有重要作用。原发性醛固酮增多症是由肾上腺自发性分泌过多的醛固酮引起的，是5-10%高血压患者的高血压病因。醛固酮的合成需要几个酶促步骤，一些发生在细胞质中，其他的，特别是第一个和最后一个，在线粒体中。已知醛固酮生物合成在该途径中的两个步骤中调节，早期步骤需要通过星星蛋白将胆固醇转移到线粒体中，在线粒体中胆固醇被羟基化并裂解以产生双烯醇酮，并且在该途径的后期，当脱氧皮质酮（DOC）在线粒体内通过CYP 11B 2基因的产物醛固酮合酶连续羟基化为醛固酮时。醛固酮合酶主要在转录水平上调节。DOC由孕酮通过胞质酶21-羟化酶合成。我们目前的初步数据表明，醛固酮的生物合成也受到调节的有效转移DOC到线粒体的一个积极的过程。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从胞质溶胶转移到线粒体”这是一个探索性的建议，以解决具体的目标：1。表征DOC通过CYP 11B 2酶2转移到线粒体转化为醛固酮的调节机制。鉴定和克隆负责促进DOC转移到线粒体的因子。与人类健康的相关性：高血压是成年人最常见的诊断之一，并导致心血管疾病的发病率和死亡率，以及中风，这是美国发病率和死亡的主要原因。醛固酮增多症患者的心血管、肾脏和脑血管病变明显大于血压同等升高的患者。有关醛固酮合成调节的信息将为这些患者提供更有效的治疗。 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，约占高血压患者的7-10%。醛固酮生物合成的调节还不完全清楚，但已知调节发生在生物合成途径的早期和晚期。晚期途径涉及醛固酮合酶对线粒体内DOC的作用。我们已经表明，DOC到线粒体的转移受到调节，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.