Molecular Mechanisms In Corin Activation

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 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.