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:
- 金额:$ 48.23万
- 依托单位:
- 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:
- 关键词:AffectAgeAmericanApoptosisAtrial Natriuretic FactorBiological MarkersCardiacCardiac MyocytesCardiomyopathiesCaringCessation of lifeCleaved cellCongenic MiceDataDefectDeteriorationDevelopmentDiagnosisDiagnosticDilated CardiomyopathyDiseaseDisease ProgressionElderlyEquilibriumExperimental ModelsFibrosisFunctional disorderGene ExpressionHeartHeart failureHumanIndiumLDL-Receptor Related ProteinsLaboratoriesLifeLigandsMediatingMembrane ProteinsModelingMorbidity - disease rateMusMyocardialMyosin ATPaseNatriuretic PeptidesOutcomePathologic ProcessesPatientsPeptide HydrolasesPlasmaPlayPreventionPrevention strategyProcessProtease DomainProtein IsoformsPublic HealthRoleSerine ProteaseSignal TransductionSocietiesSodium ChlorideSystemTissuesTransgenesWatercostdisabilityheart cellheart functionimprovedinsightmiddle agemortalitynovel therapeutic interventionpreventprognosticrestorationsextreatment 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) 是美国和全世界一个巨大且日益严重的公共卫生问题。心力衰竭最常由心肌病(一种心脏疾病或功能障碍)引起。尽管治疗方法有所改进,心力衰竭仍然是一种无法治愈的疾病,近一半的心力衰竭患者会在 5 年内死亡。 HF 给社会带来巨大成本; 2010 年美国的年度费用为 345 亿美元,预计到 2030 年费用将超过 1000 亿美元。迫切需要对调节心力衰竭发生和进展的机制有新的见解,以便制定新的治疗和预防策略减少这种情况的痛苦、残疾和费用。 Corin 是最近描述的一种心脏选择性膜蛋白,具有丝氨酸蛋白酶结构域,可将心房钠尿肽原 (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,corin 是心力衰竭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表明,增加corin水平可以防止心脏功能恶化、减少心力衰竭的发生、减少心肌纤维化并延长寿命。 该项目旨在研究影响心脏中corin表达的因素,并阐明corin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中的心力衰竭进展和死亡。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-利尿钠肽系统的表达和活性。然后,使用特征明确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,我们将在特定目标 2 中研究 corin 表达(特别是 corin 蛋白酶活性)如何影响心肌病和心力衰竭的进展以及生存。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,然后在细胞水平检查corin 可能通过潜在的信号机制介导这些作用。鉴于在心肌病中,corin 可以防止心力衰竭的进展,保留收缩功能并延长寿命,这些研究的结果有可能创建一种新的病理生理学范式,从而改善心力衰竭的治疗和生存。
公共卫生相关性:心力衰竭仍然是一种无法治愈的疾病,5 年内死亡率高达 50%。我们和其他人发现,心脏细胞上发现的一种分子 Corin 是人类心力衰竭的标志。在这个项目中,我们寻求扩展我们有希望的发现,即在实验模型中,corin 可以防止心力衰竭的进展并降低死亡率。
项目成果
期刊论文数量(0)
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Inna P Gladysheva其他文献
Inna P Gladysheva的其他文献
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{{ truncateString('Inna P Gladysheva', 18)}}的其他基金
Corin in Cardiomyopathy and Heart Failure
Corin 在心肌病和心力衰竭中的应用
- 批准号:
8534811 - 财政年份:2012
- 资助金额:
$ 48.23万 - 项目类别:
Corin in Cardiomyopathy and Heart Failure
Corin 在心肌病和心力衰竭中的应用
- 批准号:
8714036 - 财政年份:2012
- 资助金额:
$ 48.23万 - 项目类别:
Corin in Cardiomyopathy and Heart Failure
Corin 在心肌病和心力衰竭中的应用
- 批准号:
8877623 - 财政年份:2012
- 资助金额:
$ 48.23万 - 项目类别:
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