Molecular Mechanisms In Corin Activation

Corin 激活的分子机制

• 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
• 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

 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，几乎每三个美国成年人中就有一个患有高血压。高血压的潜在疾病机制尚不清楚。心房利钠肽（ANP）是一种心脏激素，可促进钠和水的排泄，降低外周血管张力，从而降低血容量和血压。在心肌细胞中，ANP作为前体合成，pro-ANP，其被我们在心脏中发现的细胞膜丝氨酸蛋白酶corin激活为ANP。在小鼠中，corin的缺乏消除了pro-ANP激活。Corin基因敲除小鼠发生盐敏感性高血压和心脏肥大。在人类中，corin变异体和突变已在高血压和心脏肥大患者中被鉴定。我们发现corin变体和突变体具有受损的pro-ANP加工活性。表达corin变异体的转基因小鼠出现盐敏感性高血压和心脏肥大。作为一种丝氨酸蛋白酶，corin被制成一种无活性的酶原，其通过蛋白水解裂解而被激活。到目前为止，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起着关键作用，突出了研究corin激活的重要性。在这个提议中，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corin生物合成和酶原激活的重要结构元件。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corin活性的调控机制以及corin活性受损在高血压疾病中的潜在意义提供新的见解。