Molecular Mechanisms In Corin Activation

Corin 激活的分子机制

基本信息

批准号：
8857770
负责人：
Qingyu Wu
金额：
$ 39.63万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-08 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8857770
关键词：
Adult American Anabolism Atrial Natriuretic Factor Biochemical Blood Blood Pressure Blood Vessels Blood Volume C-terminal Cardiac Cardiac Myocytes Cardiovascular Diseases Cell membrane Cell model Cell surface Cells Chronic Kidney Failure Coronary artery Data Defect Diagnosis Digestion Disease Elements Enzyme Precursors Enzymes Equilibrium Excretory function Frizzled Domain Gene Mutation Genes Genetic study Goals Health Heart Heart Diseases Heart Hypertrophy Heart failure Hormones Human Human Genetics Hypertension Kidney Knockout Mice Label Link Low Density Lipoprotein Receptor Mediating Membrane Molecular Mus Mutation Myocardial Infarction N-terminal Natriuretic Peptides Organelles Pathway interactions Patients Peptide Hydrolases Peripheral Phenotype Plasma Play Pre-Eclampsia Process Proprotein Convertases Protease Domain Proteins Reporting Research Risk Factors Role Serine Protease Site Sodium Sodium Chloride Spiral Artery of the Endometrium Stroke Subtilisins System Transgenic Mice Transmembrane Domain Travel Trypsin Uterus Variant Water atrial natriuretic factor receptor A biochemical model genetic variant hypertensive heart disease in vivo insight kexin mouse model mutant novel public health relevance receptor salt sensitive salt sensitive hypertension scavenger receptor urinary

项目摘要

DESCRIPTION (provided by applicant): Hypertension is the most common cardiovascular disease, afflicting nearly one in every three American adults. The underlying disease mechanism in hypertension is not well understood. Atrial natriuretic peptide (ANP) is a cardiac hormone, which promotes sodium and water excretion and decreases peripheral vascular tension, thereby lowering blood volume and pressure. In cardiac myocytes, ANP is synthesized as a precursor, pro-ANP, which is activated to ANP by the cell membrane serine protease, corin, which we discovered in the heart. In mice, lack of corin abolishes pro-ANP activation. Corin knockout mice develop salt-sensitive hypertension and cardiac hypertrophy. In humans, corin variants and mutations have been identified in patients with hypertension and cardiac hypertrophy. We showed that the corin variants and mutants had impaired pro-ANP processing activity. Transgenic mice expressing corin variants developed salt-sensitive hypertension and cardiac hypertrophy. As a serine protease, corin is made as an inactive zymogen, which is activated by proteolytic cleavage. To date, the corin activator remains elusive. Recent studies indicate that impaired corin zymogen activation plays a critical role in hypertension and heart disease, highlighting the importance of studying corin activation. In this proposal, we plan to study the mechanism underlying corin activation. In Aim 1, we will determine cellular mechanism underlying corin activation. In Aim 2, we will identify structural elements important for corin biosynthesis and zymogen activation. In Aim 3, we will examine corin activation, pro-ANP processing and blood pressure in knockout mouse models. Our studies should provide new insights into the mechanism controlling corin activity and potential implication of impaired corin activation in hypertensive disease.

描述（由适用提供）：高血压是最常见的心血管疾病，每三个美国成年人中几乎都会折磨一个。高血压中的潜在疾病机制尚不清楚。心房尿液肽（ANP）是心脏马酮，可促进钠和水排泄并降低外周血管张力，从而降低血液体积和压力。在心肌细胞中，ANP合成为前体Pro-ANP，它被我们在心脏中发现的细胞膜丝网蛋白Corin激活为ANP。在小鼠中，缺乏科林消除了促进性激活。科林敲除小鼠会产生盐敏感的高血压和心脏肥大。在人类中，在高血压和心脏肥大的患者中已经鉴定出Corin变体和突变。我们表明，Corin变体和突变体损害了AR-ANP处理活性。表达科林变种的转基因小鼠会产生盐敏感性高血压和心脏肥大。作为丝氨酸蛋白，Corin是一种非活性Zymogen，它被蛋白水解裂解激活。迄今为止，科林激活剂仍然难以捉摸。最近的研究表明，Corin酶原激活受损在高血压和心脏病中起着至关重要的作用，强调了研究Corin激活的重要性。在此提案中，我们计划研究科林激活的基本机制。在AIM 1中，我们将确定Corin激活的基础细胞机制。在AIM 2中，我们将确定对Corin生物合成和酶原激活重要的结构元素。在AIM 3中，我们将检查敲除小鼠模型中的Corin激活，促进ANP加工和血压。我们的研究应提供有关控制科林活性的机制的新见解，以及在高血压疾病中Corin激活受损的潜在影响。