Corin in Cardiomyopathy and Heart Failure

描述（由申请人提供）：心力衰竭（HF）在美国和全世界都是一个巨大的、日益严重的公共卫生问题。心衰最常由心肌病引起，心肌病是一种心脏疾病或功能障碍。尽管治疗方法有所改善，但心衰仍是一种无法治愈的疾病，近一半的心衰患者在5年内死亡。HF给社会带来了巨大的成本；2010年，美国的年度成本为345亿美元，预计到2030年将达到1000亿美元。目前迫切需要对心衰发展和进展的调控机制有新的认识，以便制定新的治疗和预防策略，以减少这种疾病的痛苦、残疾和成本。Corin是最近发现的一种心脏选择性膜蛋白，其丝氨酸蛋白酶结构域可将前心房钠素肽（pro-ANP）转化为活性ANP，此外还有卷曲结构域和LRP结构域可与配体相互作用以介导细胞内信号传导。我们对人类和小鼠的研究表明，科林是心衰和心肌病的重要生物标志物。此外，我们有令人兴奋的新数据表明，增加corin水平可以防止心功能恶化，减少HF的发展，减少心肌纤维化并延长寿命。本项目旨在研究影响心脏中corin表达的因素，并阐明在扩张型心肌病和缺血性心肌病小鼠模型中，corin表达及其蛋白酶活性如何影响心衰进展和死亡。我们实验室和其他实验室的研究表明，性别和年龄是心肌病患者预后的重要决定因素，因此在Specific Aim 1中，我们试图确定性别、年龄和心肌病如何影响科林-利钠肽系统的表达和活性。然后，我们将使用具有良好特征的扩张型心肌病和缺血性心肌病实验模型，以及独特的转基因小鼠，在Specific Aim 2中研究corin表达，特别是corin蛋白酶活性如何影响心肌病和心衰的进展以及生存。在特定目标3中，根据目标1和目标2的见解，我们将在组织和细胞水平上确定corin如何改变扩张型心肌病和缺血性心肌病的病理过程，这对HF的进展很重要，然后在细胞水平上检查corin可能介导这些作用的潜在信号机制。鉴于在心肌病中，科林可以防止心衰的进展，保持收缩功能并延长寿命，这些研究的发现有可能创造一种新的病理生理学范式，可以改善心衰的治疗和生存率。

DESCRIPTION (provided by applicant): Heart failure (HF) is an enormous, growing public health problem in the U.S. and worldwide. HF is most frequently caused by cardiomyopathy, a disease or dysfunction of the heart. Despite improvements in treatment, HF remains an incurable disease process, and nearly half of patients with HF die within 5 years. HF has an enormous cost to society; annual costs were $34.5 billion in the U.S. in 2010 and costs are estimated to be >$100 billion in 2030. There is a critical need for new insights into the mechanisms that regulate the development and progression of HF in order to create new treatment and prevention strategies for reducing the suffering, disability and cost of this condition. Corin is a recently described cardiac-selective membrane protein, with a serine protease domain that converts the pro-atrial natriuretic peptide (pro-ANP) to active ANP, in addition to frizzled and LRP domains that may interact with ligands to mediate intracellular signaling. Our studies in humans and mice show that corin is an important biomarker of HF and cardiomyopathy. In addition, we have exciting new data that increasing corin levels prevents deterioration of heart function, reduces the development of HF, diminishes myocardial fibrosis and extends life. This project is directed to examining the factors that affect corin expression i the heart and, to elucidating how corin expression and, its protease activity affect HF progression and death in murine models of dilated cardiomyopathy and ischemic cardiomyopathy. Studies from our laboratory and others have indicated that sex and age are important determinants of outcomes in patients with cardiomyopathy, consequently in Specific Aim 1 we seek to determine how sex, age and cardiomyopathy affect the expression and activity of the corin-natriuretic peptides system. Then using well characterized experimental models of dilated cardiomyopathy and ischemic cardiomyopathy and, unique, genetically modified mice, we will examine in Specific Aim 2 how corin expression and, specifically corin protease activity, affect the progression of cardiomyopathy and HF, as well as survival. In Specific Aim 3, informed by the insights of Aims 1 and 2, we will determine at the tissue and cellular level how corin alters pathologic processes in dilated cardiomyopathy and ischemic cardiomyopathy important for the progression of HF and, then examine at the cellular level the potential signaling mechanisms through which corin may mediate these effects. Given that in cardiomyopathy, corin protects against the progression of HF, preserves systolic function and prolongs life, findings from these studies have the potential to create a new pathophysiologic paradigm that could improve HF treatment and survival.