Corin in Cardiomyopathy and Heart Failure

Corin 在心肌病和心力衰竭中的应用

基本信息

批准号：
8345021
负责人：
Inna P Gladysheva
金额：
$ 48.23万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-22 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8345021
关键词：
Affect Age American Apoptosis Atrial Natriuretic Factor Biological Markers Cardiac Cardiac Myocytes Cardiomyopathies Caring Cessation of life Cleaved cell Congenic Mice Data Defect Deterioration Development Diagnosis Diagnostic Dilated Cardiomyopathy Disease Disease Progression Elderly Equilibrium Experimental Models Fibrosis Functional disorder Gene Expression Heart Heart failure Human Indium LDL-Receptor Related Proteins Laboratories Life Ligands Mediating Membrane Proteins Modeling Morbidity - disease rate Mus Myocardial Myosin ATPase Natriuretic Peptides Outcome Pathologic Processes Patients Peptide Hydrolases Plasma Play Prevention Prevention strategy Process Protease Domain Protein Isoforms Public Health Role Serine Protease Signal Transduction Societies Sodium Chloride System Tissues Transgenes Water cost disability heart cell heart function improved insight middle age mortality novel therapeutic intervention prevent prognostic restoration sex treatment strategy

项目摘要

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.

描述（由申请人提供）：心力衰竭（HF）是美国和全球范围内越来越多的公共卫生问题。 HF最常见的是心肌病，心脏疾病或功能障碍。尽管治疗有所改善，但HF仍然是无法治愈的疾病过程，而HF患者中有近一半在5年内死亡。 HF对社会有巨大的代价； 2010年，美国的年成本为345亿美元，估计成本在2030年为1000亿美元。对于规范HF的发展和进步的机制，至关重要的是，为了制定新的治疗和预防策略，以减少这种状况的痛苦，残障和成本。 Corin是一种最近描述的心脏选择性膜蛋白，其丝氨酸蛋白酶结构域可将前原始Natriuretic肽（pro-ANP）转换为活性ANP，此外还可以与毛躁和LRP结构域相互作用，这些结构域可能与卷曲和LRP结构域相互作用，这些结构域可能与配体相互作用以介导细胞内信号。我们对人类和小鼠的研究表明，科林是HF和心肌病的重要生物标志物。此外，我们还有令人兴奋的新数据，可以提高科林水平，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。该项目旨在研究影响康林表达I心脏的因素，并阐明Corin表达及其蛋白酶的活性如何影响HF的进展和死亡，这是在扩张的心肌病和缺血性心肌病的鼠模型中。我们实验室和其他人的研究表明，性别和年龄是心肌病患者结局的重要决定因素，因此在特定目的1中，我们寻求确定性别，年龄和心肌病如何影响科林 - 纳他尿素肽系统的表达和活性。然后，我们将使用良好的扩张心肌病和缺血性心肌病的实验模型，以及独特的，转基因的小鼠，我们将在特定的目标2中研究Corin表达和特异性Corin蛋白酶活性如何影响心肌病和HF的进展以及生存。在AIM 1和2的见解中，我们将在组织和细胞水平上确定Corin在扩张的心肌病和缺血性心肌病中如何改变对HF进展重要的病理过程，然后在细胞上检查细胞水平的潜在信号机制，从而通过哪些效果介绍这些作用。鉴于在心肌病中，科林可以预防HF的进展，可保留收缩功能并延长寿命，这些研究的发现可能会产生一种新的病理生理范式，从而改善HF治疗和生存。公共卫生相关性：心力衰竭仍然是无法治愈的疾病过程，死亡率在5年内高达50％。我们和其他人发现，在心脏细胞上发现的分子科林是人类心力衰竭的标志。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，科林可以防止心力衰竭进展并改善死亡率。