Calcineurin-Dependent Electrical Remodeling in Cardiac Hypertrophy and Failure

心脏肥大和衰竭中钙调神经磷酸酶依赖性电重塑

• 批准号: 7275642
• 负责人: JEFF M BERRY
• 金额: $ 5.48万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7275642
• 关键词: Adult; Adverse event; American; Arrhythmia; Berry; Calcineurin; Calcineurin inhibitor; Cardiac; Cardiac Death; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Characteristics; Chest; Cytoplasmic Protein; Data; Development; Disease; Echocardiography; Electrophysiology (science); Engineering; Event; Failure; Growth; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Hypertension; Hypertrophy; Investigation; Lead; Left ventricular structure; Measures; Mediator of activation protein; Modeling; Mus; Myocardial Infarction; Myocardium; Pathogenesis; Patients; Phenotype; Predisposition; Prevention; Process; Property; Protein Overexpression; Protein phosphatase; Proteins; Research; Risk; Role; Signal Transduction; Standards of Weights and Measures; Stratification; Sudden Death; Surgical Models; Technology; Testing; Time; Transgenes; Transgenic Mice; Transgenic Model; Transgenic Organisms; Ventricular; Ventricular Arrhythmia; Ventricular Remodeling; Work; clinically relevant; experience; in vivo; insight; molecular imaging; novel; parallel processing; pressure; prevent; research study; sudden cardiac death; ventricular hypertrophy

DESCRIPTION (provided by applicant): Cardiac hypertrophy is associated with adverse cardiovascular events, including an increased risk of arrhythmias and sudden death. Calcineurin, a cytoplasmic protein phosphatase, has been shown to be a major contributor to the pathogenesis of hypertrophic heart disease. Very little is known regarding the role of calcineurin in disease-related electrical remodeling of the heart. The long-term objective of this proposal is to elucidate mechanisms of arrhythmias associated with cardiac hypertrophy and the role of calcineurin therein. The hypothesis is that calcineurin activation triggers electrical remodeling of the adult heart independently and in association with pressure-overload hypertrophy. The specific aims are Aiml: To test the effect of calcineurin activation on the electrophysiological properties of the fully developed adult heart. Transgenic mice that express a regulated, cardiac-specific, constitutively active calcineurin transgene will be studied. In vivo electrophysiology (EP) studies will be performed to measure the electrical characteristics of each murine heart. Susceptibility to inducible ventricular arrhythmias will be tested. Aim2: To define the development of calcineurin-dependent electrical remodeling in relation to the development of cardiac hypertrophy and failure. A time course of the events occurring with calcineurin activation will determine whether electrical remodeling develops independently of hypertrophic growth. Data will be collected using in vivo EP studies, echocardiograms, histological imaging, and molecular analyses. Aim3: To test the role of calcineurin activation in the electrical remodeling that occurs in asssociation with pressure overload hypertrophy. A surgical model of pressure-overload cardiac hypertrophy in mice will be used. Transgenic mice that overexpress modulatory calcineurin-interacting protein 1 (MCIP1), an endogenous inhibitor of calcineurin, will be studied. The results of these experiments will provide much needed insight into the mechanisms of rhythm disturbances associated with cardiac hypertrophy. Investigations such as these are critical to the development of new treatments for arrhythmias and the prevention of sudden cardiac death. Relevance: Over 300,000 Americans per year experience sudden death, in which the heart stops beating with few if any warning signs. Research proposed here will investigate how sudden death occurs in patients with hypertrophic heart disease. The results of this work may lead to more effective strategies for preventing these catastrophic events.

描述（由申请人提供）：心脏肥大与不良心血管事件相关，包括心律失常和猝死的风险增加。钙调神经磷酸酶是一种细胞质蛋白磷酸酶，已被证明是肥厚性心脏病发病机制的主要贡献者。关于钙调磷酸酶在与疾病相关的心脏电重塑中的作用知之甚少。该提案的长期目标是阐明与心脏肥大相关的心律失常的机制以及钙调神经磷酸酶在其中的作用。假设是钙调神经磷酸酶激活独立地触发成人心脏的电重塑，并与压力超负荷肥大相关。具体目标是：测试钙调神经磷酸酶激活对发育完全的成人心脏的电生理特性的影响。将研究表达受调节的、心脏特异性的、组成型活性钙调神经磷酸酶转基因的转基因小鼠。将进行体内电生理学（EP）研究来测量每只小鼠心脏的电特性。将测试对诱发性室性心律失常的敏感性。目标 2：定义与心脏肥大和衰竭的发展相关的钙调神经磷酸酶依赖性电重构的发展。钙调神经磷酸酶激活事件的时间进程将决定电重塑是否独立于肥大性生长而发展。将使用体内 EP 研究、超声心动图、组织学成像和分子分析来收集数据。目标 3：测试钙调神经磷酸酶激活在与压力超负荷肥大相关的电重塑中的作用。将使用小鼠压力超负荷心脏肥大的手术模型。将研究过度表达调节性钙调神经磷酸酶相互作用蛋白 1 (MCIP1)（一种钙调神经磷酸酶的内源性抑制剂）的转基因小鼠。这些实验的结果将为了解与心脏肥大相关的节律紊乱机制提供急需的见解。诸如此类的研究对于开发心律失常新疗法和预防心源性猝死至关重要。相关性：每年有超过 300,000 名美国人经历猝死，即心脏停止跳动，几乎没有任何警告信号。这里提出的研究将调查肥厚性心脏病患者如何发生猝死。这项工作的结果可能会带来更有效的策略来预防这些灾难性事件。