Sex Hormones and Cardiac Arrhythmia in Transgenic LQT2 Rabbits

转基因 LQT2 兔的性激素和心律失常

• 批准号: 8242689
• 负责人: GIDEON KOREN
• 金额: $ 58.06万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242689
• 关键词: Action Potentials; Adrenergic Receptor; American; Arrhythmia; Biological Models; Calcium; Cardiac; Cardiomyopathies; Cell model; Code; Computer Simulation; Data; Disease; Electrocardiogram; Electrophysiology (science); Engineering; Environmental Risk Factor; Estrogens; Female; Fiber; Gender; Gene Expression; Genes; Genetic; Genetic Models; Genetic Predisposition to Disease; Goals; Gonadal Steroid Hormones; Health Benefit; Heart; Heart Diseases; Heart failure; Heterogeneity; Hormones; Human; In Vitro; Incidence; Investigation; Ion Channel; Knowledge; Lead; Left ventricular structure; Life; Light; Long QT Syndrome; Maps; Mechanics; Mediating; Modeling; Molecular; Molecular Models; Monitor; Muscle Cells; Mutation; Optics; Oryctolagus cuniculus; Pathogenesis; Patients; Pharmaceutical Preparations; Play; Population; Postpartum Period; Potassium; Preparation; Prevention strategy; Progesterone; Property; Proteins; Public Health; Refractory; Right ventricular structure; Risk; Role; Sex Characteristics; Sexual Maturation; Simulate; Stress; Substrate Interaction; Sudden Death; Surface; Sympathetic Nervous System; Syndrome; Tachyarrhythmias; Techniques; Theoretical model; Time; Tissue Model; Tissues; Transgenic Organisms; Ventricular; Withdrawal; base; comparative; drug market; high risk; in vivo; indexing; innovative technologies; insight; loss of function; mRNA Expression; molecular modeling; mutant; novel; novel strategies; patch clamp; prepuberty; protective effect; protein expression; public health relevance; receptor; sudden cardiac death

Sudden cardiac death (SCD) claims the lives of approximately 350,000 Americans each year. Emerging evidence indicates an important role for genetic predisposition to SCD; however, the molecular determinants have remained elusive. The overall goal of this proposal is to investigate new mechanisms that underlie SCD through the application of innovative technology and the novel use of new genetic models of long QT syndrome 2 (LQT2). This multi-pronged approach includes the investigation of hormone-treated prepubertal, ovariectomized LQT2 rabbits to explore new mechanistic paradigms that underlie the effects of sex hormones on cardiac arrhythmias using in vitro and in silico experimental approaches that will integrate novel molecular, cellular, tissue, and theoretical models. Because gender and the sympathetic nervous system plays a key role in triggering SCD in LQT2, the influence of sex hormones and the autonomic factors on SCD risk will be studied in detail. The proposal is composed of Four Specific Aims: Aim 1: To characterize of the sex hormone induced changes in cardiac repolarization (QT duration and cardiac refractory periods), incidence of spontaneous TdP and sudden cardiac death with the use of telemetric ECG monitoring and in vivo invasive electrophysiological studies; Aim 2: To analyze the action potential duration, dispersion of repolarization, conduction, triggered activity and the heterogeneities in electrical/mechanical restitution, and conduction block using optical mapping of action potential and calcium transients. Aim 3: To define (based on the optical studies) the molecular determinants of the gender differences in cardiac repolarization and excitation by analyzing the gender or sex hormone related differences in the expression of genes coding for the or subunits of the repolarizing potassium currents, calcium currents, and proteins that control Ca++ cycling, and the adrenergic receptors with the use of protein expression studies and quantitative real-time PCR, and cellular electrophysiological studies; and Aim 4: To perform a comparative analysis of action potential and calcium-handling properties in myocytes isolated from hormone-treated LQT2 rabbits under control conditions and during autonomic receptor stimulation, using patch-clamp and fluorescent-indicator techniques. b) To use computer modeling to examine how experimentally defined cellular/molecular alterations in these LQT2 models influence afterdepolarizations and arrhythmogenic substrate formation in simulated cardiac tissue. These studies will contribute to the understanding of the mechanisms that trigger and maintain arrhythmias in hormone-treated rabbits, and therefore lead to a better understanding of gender-related arrhythmias in long QT syndrome.

猝死（SCD）每年夺走大约35万美国人的生命。新兴 证据表明遗传易感性SCD的重要作用。但是，分子决定因素 仍然难以捉摸。该提案的总体目标是调查SCD基础的新机制 通过应用创新技术和长长QT的新遗传模型的新颖使用 综合征2（LQT2）。这种多管齐的方法包括调查激素处理的青春期前， 卵巢切除的LQT2兔子探索了性别影响的新机械范式 使用体外和计算机实验方法中的心律不齐的激素，这些方法将整合 新型分子，细胞，组织和理论模型。因为性别和交感神经 系统在触发LQT2，性激素和自主因素的影响的SCD方面起着关键作用 关于SCD风险，将详细研究。该提案由四个特定目的组成：目标1： 性激素诱导心脏复极化的特征（QT持续时间和心脏 耐火周期），自发性TDP的发生率和远程心脏死亡的发生率 监测和体内侵入性电生理研究；目标2：分析动作潜在持续时间， 复极化，传导，触发活性的分散以及电气/机械的异质性 使用动作电位和钙瞬变的光学映射进行恢复和传导块。目标3：到 定义（基于光学研究）心脏性别差异的分子决定因素 通过分析性别或性激素与表达的性别或性激素相关的差异，复制和激发 编码复制钾电流，钙电流和蛋白质的亚基的基因 通过使用蛋白质表达研究和 定量实时PCR和细胞电生理研究；目标4：进行比较 分析从激素治疗的肌细胞中的肌细胞中的动作电位和钙处理特性的分析 在控制条件下以及在自主受体刺激下，使用贴片钳和 荧光指导技术。 b）使用计算机建模来检查如何实验定义 这些LQT2模型中的细胞/分子改变会影响过极化和心律失常 模拟心脏组织中的底物形成。这些研究将有助于理解 触发和维持激素处理兔中心律不齐的机制，因此导致更好 理解长QT综合征中与性别相关的心律失常。