Corin in Cardiomyopathy and Heart Failure

描述（由申请人提供）：心力衰竭（HF）是美国和世界范围内一个巨大的、日益严重的公共卫生问题。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。尽管在治疗方面有所改进，但HF仍然是一种无法治愈的疾病过程，近一半的HF患者在5年内死亡。HF给社会带来巨大的成本; 2010年美国的年度成本为345亿美元，预计2030年的成本将超过1000亿美元。迫切需要对调节HF的发展和进展的机制有新的见解，以创造新的治疗和预防策略，减少这种疾病的痛苦，残疾和成本。 Corin是最近描述的心脏选择性膜蛋白，具有丝氨酸蛋白酶结构域，其将前心房利钠肽（pro-ANP）转化为活性ANP，此外还有卷曲和LRP结构域，其可以与配体相互作用以介导细胞内信号传导。我们在人类和小鼠中的研究表明corin是HF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水平可以防止心脏功能恶化，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HF进展和死亡。我们实验室和其他研究表明，性别和年龄是心肌病患者结局的重要决定因素，因此在具体目标1中，我们试图确定性别、年龄和心肌病如何影响corin-利钠肽系统的表达和活性。然后使用扩张型心肌病和缺血性心肌病的良好表征的实验模型和独特的遗传修饰小鼠，我们将在具体目标2中研究corin表达，特别是corin蛋白酶活性如何影响心肌病和HF的进展以及生存。在具体目标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中对HF进展至关重要的病理过程，然后在细胞水平上检查corin可能介导这些作用的潜在信号传导机制。鉴于在心肌病中，corin可防止HF的进展，保护收缩功能和心脏寿命，这些研究的结果有可能创建一个新的病理生理学范式，可以改善HF治疗和生存。 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%。我们和其他人已经发现corin，一种在心脏细胞上发现的分子，是人类心力衰竭的标志物。在这个项目中，我们试图扩展我们有希望的发现，在实验模型中，corin可以防止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.