Regulation of the late-pathway of aldosterone biosynthesis

醛固酮生物合成后期途径的调节

基本信息

批准号：
8254384
负责人：
Celso Enrique Gomez-Sanchez
金额：
$ 19.13万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-05 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8254384
关键词：
Accounting Address Adrenal Glands Adult Aldosterone Aldosterone Synthase Americas Anabolism Angiotensin II Benzodiazepine Receptor Blood Blood Pressure CYP11B2 gene Cardiovascular system Cessation of life Cholesterol Cholesterol Monooxygenase (Side-Chain-Cleaving)Cleaved cell Cytosol Data Deoxycorticosterone Development Diagnosis Disease Enzymes Etiology Gland Health Human Hyperaldosteronism Hypertension Incidence Kidney Lead Left Ventricular Hypertrophy Mitochondria Morbidity - disease rate Nature Outer Mitochondrial Membrane Pathogenesis Pathology Pathway interactions Patients Peripheral Physiological Potassium Pregnenolone Process Progesterone Proteins Regulation Research Role Secondary Hypertension Steroid 21-Monooxygenase Stroke Time Transcriptional Regulation adenoma cerebrovascular effective therapy interest mortality public health relevance steroidogenic acute regulatory protein

项目摘要

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.

描述（由申请人提供）：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主过量分泌醛固酮引起的，是5-10%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，其中一些发生在细胞质中，其他的，尤其是第一个和最后一个发生在线粒体中。已知醛固酮生物合成在该途径中的两个步骤受到调节，早期步骤需要通过 StAR 蛋白将胆固醇转移到线粒体中，胆固醇在线粒体中被羟基化并裂解产生孕烯醇酮，而在该途径的后期，当脱氧皮质酮 (DOC) 被线粒体内 CYP11B2 基因醛固酮合酶的产物相继羟基化为醛固酮。醛固酮合酶主要在转录水平上受到调节。 DOC 由孕酮通过胞质酶 21-羟化酶合成。我们提供的初步数据表明，醛固酮生物合成也受到 DOC 通过主动过程有效转移到线粒体中的调节。我们提出解决以下假设：“醛固酮生物合成后期途径的调节涉及 DOC 从细胞质转移到线粒体的调节”这是解决特定目标的探索性建议： 1. 表征调节机制CYP11B2 酶促进 DOC 转移至线粒体并转化为醛固酮的过程 2. 鉴定并克隆负责促进 DOC 转移至线粒体的因子。与人类健康的相关性：高血压是成人最常见的诊断之一，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高于血压相应升高的患者。有关醛固酮合成调节的信息将为这些患者带来更有效的治疗。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%。醛固酮生物合成的调节尚不完全清楚，但已知该调节发生在生物合成途径的早期和晚期。后期途径涉及醛固酮合酶对线粒体内 DOC 的作用。我们已经证明 DOC 向线粒体的转移受到调节，并建议分离相关因子。