Corin in Cardiomyopathy and Heart Failure

描述(由申请人提供)：心力衰竭(HF)在美国和世界范围内是一个巨大的、日益严重的公共健康问题。心力衰竭最常见的原因是心肌病，一种心脏疾病或功能障碍。尽管治疗方法有所改进，但心力衰竭仍然是一种不治之症，近一半的心力衰竭患者在5年内死亡。HF给社会带来了巨大的成本；2010年美国的年成本为345亿美元，2030年的成本估计为1000亿美元。迫切需要对控制心力衰竭的发展和进展的机制有新的见解，以便创造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是一种新近发现的心脏选择性膜蛋白，它含有一个丝氨酸蛋白酶结构域，可将心钠素前体(Pro-ANP)转化为活性ANP，此外还有卷曲结构域和LRP结构域，它们可能与配体相互作用，介导细胞内信号转导。我们在人类和小鼠身上的研究表明，Corin是心力衰竭和心肌病的重要生物标志物。此外，我们有令人振奋的新数据表明，增加Corin水平可以防止心功能恶化，减少心力衰竭的发生，减少心肌纤维化，延长生命。本项目旨在研究影响Corin在心脏中表达的因素，并阐明Corin的表达及其蛋白酶活性如何影响扩张型心肌病和缺血性心肌病小鼠模型的心衰进展和死亡。我们实验室和其他实验室的研究表明，性别和年龄是决定心肌病患者预后的重要因素，因此，在特定的目标1中，我们试图确定性别、年龄和心肌病如何影响Corin-Natriuretic多肽系统的表达和活性。然后，利用扩张型心肌病和缺血性心肌病的实验模型和独特的转基因小鼠，我们将在特定的目标2中研究Corin的表达，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。在具体的目标3中，根据目标1和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对心力衰竭进展至关重要的病理过程，然后在细胞水平上研究Corin可能介导这些作用的潜在信号机制。鉴于在心肌病中，Corin可防止心力衰竭的进展，保护收缩功能和延长生命，这些研究的发现有可能创造一种新的病理生理学范例，可以改善心力衰竭的治疗和存活率。 公共卫生相关性：心力衰竭仍然是一种不治之症，5年内死亡率高达50%。我们和其他人发现，心脏细胞上的一种分子Corin是人类心力衰竭的标志。在这个项目中，我们试图扩展我们的有希望的发现，在实验模型中，Corin预防心力衰竭的进展并提高死亡率。

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. PUBLIC HEALTH RELEVANCE: Heart failure remains an incurable disease process with a mortality of up to 50% within 5 years. We and others have found that corin, a molecule found on heart cells, is a marker of heart failure in humans. In this project we seek to extend our promising findings that, in experimental models, corin protects against progression of heart failure and improves mortality.