Molecular Mechanisms In Corin Activation

 描述(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还不是很清楚。心钠素(ANP)是一种心脏激素，能促进钠和水的排泄，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被合成为前体Pro-ANP，它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，缺乏Corin会取消前ANP的激活。Corin基因敲除小鼠出现盐敏感型高血压和心肌肥厚。在人类中，已经在高血压和心肌肥厚患者中发现了Corin变异和突变。我们发现Corin突变体和突变体削弱了前ANP的加工活性。表达Corin变异体的转基因小鼠出现盐敏感型高血压和心肌肥厚。作为一种丝氨酸蛋白酶，Corin是一种失活的酶原，通过蛋白水解酶的切割而被激活。到目前为止，Corin的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，这突显了研究Corin激活的重要性。在这项提案中，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，我们将确定对Corin生物合成和酶原激活至关重要的结构元件。在目标3中，我们将在基因敲除的小鼠模型中检测Corin的激活、心钠素前体的处理和血压。我们的研究将为控制Corin活性的机制以及高血压疾病中Corin活性受损的潜在意义提供新的见解。

 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.