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（由申请人提供）：高血压是最常见的心血管疾病，近三分之一的美国成年人患有高血压。心房钠尿肽 (ANP) 是一种促进钠和钠离子升高的心脏激素。水排泄并降低外周血管张力，从而降低血容量和压力。在心肌细胞中，ANP 被合成为前体 ANP，它被细胞膜激活为 ANP。我们在小鼠心脏中发现了丝氨酸蛋白酶 Corin，Corin 基因敲除小鼠会出现盐敏感性高血压和心脏肥大。在高血压患者中，已发现 Corin 变异和突变。我们发现表达corin变体的转基因小鼠出现了盐敏感性高血压和心脏肥大。一种通过蛋白水解裂解激活的非活性酶原，迄今为止，corin 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发挥着关键作用，这凸显了研究 corin 激活的重要性。我们计划研究 corin 激活的机制。在目标 1 中，我们将确定 corin 激活的细胞机制。在目标 2 中，我们将确定对 corin 生物合成重要的结构元件。在目标 3 中，我们将在基因敲除小鼠模型中检查 corin 激活、pro-ANP 加工和血压，我们的研究将为控制 corin 活性的机制以及高血压疾病中 corin 激活受损的潜在影响提供新的见解。