ELECTROPHYSIOLOGY OF TRANSGENIC CARDIOMYOPATHIC MICE

转基因心肌病小鼠的电生理学

• 批准号: 2635031
• 负责人: CHARLES I BERUL
• 金额: $ 7.74万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2635031
• 关键词: arrhythmia; cytoskeletal proteins; disease /disorder model; electrocardiography; electrophysiology; genetic disorder; genetically modified animals; heart conduction system; heart electrical activity; hypertrophic myocardiopathy; laboratory mouse; molecular pathology

DESCRIPTION (Adapted from the applicant's abstract) The purpose of this proposal is to investigate the molecular mechanisms underlying cardiac conduction disturbances in hypertrophic cardiomyopathy. In order to assess directly the role of specific gene products in cardiac conduction in vivo using transgenic models, the applicants recently developed a mouse model of a complete cardiac electrophysiology (EP) study based on human clinical protocols, including responses to programmed stimulation and pharmacologic agents. The studies in this proposal seek to apply this mouse EP model to characterize the molecular defects that lead to abnormal cardiac conduction and arrhythmias in hypertrophic cardiomyopathy (HCM). Two lines of HCM mice and their littermate controls will be evaluated. The first bears a point mutation in the murine a-myosin heavy chain (Arg4O3Gln), which leads to histological and hemodynamic abnormalities characteristic of HCM, and a propensity to sudden death. The second mouse line will have a disruption in the gene encoding the cardiac troponin T protein, which in humans produces HCM characterized by minimal hypertrophy but a high frequency of sudden death. In preliminary EP studies we have performed, the heterozygous Arg4O3Gln HCM mice have inducible ventricular tachycardia, a distinctly abnormal finding that has not been observed in normal mice at any time. Preliminary data with the Arg4O3Gln HCM mice suggest a difference in the rate of disease progression between the sexes, and also suggest a developmental (age-related) increase in the risk of sudden death in these mice, with no mortality in the first 15 weeks of age. Therefore, both male and female mice, and mice at several different ages will be examined to investigate in detail the electro-physiological characteristics of several different populations of control and HCM mice. Data from a full EP study, including isoproterenol infusion, will be collected from each animal and correlated with surface 6-lead ECG data, including dispersion of repolarization, as well as with longer-term ECG monitoring with wireless microtelemetry and histological evaluation of the underlying myocardial tissue. Taken together, these studies will allow a comparative analysis of electrophysiological abnormalities produced by two distinct and specific mutations that cause HCM, and thus will contribute to our understanding of the molecular mechanisms underlying cardiac conduction and a common cardiovascular disorder.

描述 （改编自申请人的摘要）本建议书的目的是 研究心脏传导的分子机制 肥厚型心肌病的紊乱。 为了直接评估 特异性基因产物在体内心脏传导中的作用 在转基因模型中，申请人最近开发了一种小鼠模型， 基于人体临床的完整心脏电生理学（EP）研究 方案，包括对程控刺激和药理学的反应 剂. 本提案中的研究旨在将这种小鼠EP模型应用于 表征导致异常心脏传导的分子缺陷 和肥厚型心肌病（HCM）中的心律失常。 两种HCM小鼠 并评价其同窝对照。 第一个观点有一点 鼠α-肌球蛋白重链（Arg 4 O3 Gln）突变，导致 HCM组织学和血流动力学异常特征， 猝死倾向 第二条鼠标线将中断， 编码心肌肌钙蛋白T蛋白的基因， HCM的特征是轻微的肥大，但突然的高频率 死亡 在我们进行的初步EP研究中， Arg 4 O3 Gln HCM小鼠具有可诱导的室性心动过速， 在任何时间在正常小鼠中未观察到的异常发现。 Arg 4 O3 Gln HCM小鼠的初步数据表明， 性别之间的疾病进展率，也表明 这些人猝死风险的发展（与年龄相关）增加 小鼠，在前15周龄内无死亡。 因此，无论是男性 和雌性小鼠，以及几个不同年龄的小鼠将被检查， 详细研究了几种电生理特性， 不同群体的对照和HCM小鼠。 来自完整EP研究的数据， 包括异丙肾上腺素输注， 与表面6导联ECG数据相关，包括 复极，以及长期心电图监测与无线 基础心肌的微遥测和组织学评价 组织. 综合起来，这些研究将使我们能够比较分析 由两种不同的和特异性的 导致HCM的突变，因此将有助于我们理解 心脏传导的分子机制和常见的 心血管疾病