ELECTROPHYSIOLOGY OF TRANSGENIC CARDIOMYOPATHIC MICE

转基因心肌病小鼠的电生理学

• 批准号: 2027125
• 负责人: CHARLES I BERUL
• 金额: $ 7.54万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-15 至 1997-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2027125
• 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)本提案的目的是 探讨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 转基因模型，申请者最近开发了一种小鼠模型 基于人类临床的完整心脏电生理(EP)研究 方案，包括对程序化刺激和药理学的反应 探员们。本方案中的研究试图将该小鼠EP模型应用于 描述导致心脏传导异常的分子缺陷 和肥厚型心肌病(HCM)的心律失常。两种HCM小鼠品系 并将对它们的产仔控制进行评估。第一个是有道理的 小鼠α-肌球蛋白重链(Arg4O3Gln)突变，导致 肥厚性心肌病的组织学和血流动力学特征异常，以及 猝死的倾向。第二个鼠标生产线将在 编码心肌肌钙蛋白T蛋白的基因，它在人类中产生 肥厚性心肌病以轻度肥大为特征，但突然发作的频率较高。 死亡。在我们进行的初步EP研究中，杂合子 Arg4O3Gln HCM小鼠有诱导性室性心动过速，明显 在任何时候都没有在正常小鼠身上观察到的异常发现。 Arg4O3Gln HCM小鼠的初步数据表明， 两性之间的疾病进展速度，也表明 这些人的发育(与年龄相关)猝死风险增加 小鼠，在出生后15周内没有死亡。因此，无论是男性还是 和雌性小鼠，以及几个不同年龄的小鼠将被检查 详细研究了几种生物材料的电生理特性 不同种群的对照组和HCM小鼠。来自完整的EP研究的数据， 包括异丙肾上腺素输注，将从每只动物和 与体表6导联心电数据相关，包括离散度 复极化，以及通过无线进行长期心电监测 基础心肌的显微遥测和组织学评价 组织。综上所述，这些研究将允许对 两种截然不同且特异的电生理异常 导致肥厚型心肌病的突变，从而有助于我们理解 心脏传导的分子机制和共同的 心血管疾病。