ELECTROPHYSIOLOGY OF TRANSGENIC CARDIOMYOPATHIC MICE

转基因心肌病小鼠的电生理学

• 批准号: 2724177
• 负责人: CHARLES I BERUL
• 金额: $ 10.98万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 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 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2724177
• 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 （根据申请人的摘要改编）该提案的目的是 研究心脏传导的分子机制 肥厚性心肌病的障碍。 为了直接评估 特定基因产物在使用体内心脏传导中的作用 转基因模型，申请人最近开发了一个小鼠模型 基于人类临床的完整心脏电生理学（EP）研究 方案，包括对程序刺激和药理的响应 代理商。 该提案中的研究旨在将此鼠标EP模型应用于 表征导致心脏传导异常的分子缺陷 肥厚性心肌病（HCM）中的心律不齐。 两条HCM小鼠 并将评估他们的窝窝控制。 第一个要点 鼠A肌球蛋白重链（ARG4O3GLN）中的突变，导致 HCM的组织学和血液动力学异常特征和A 突然死亡的倾向。 第二个鼠标线将在 编码心脏肌钙蛋白T蛋白的基因，该蛋白在人类中产生 HCM以最小肥大为特征，但突然的频率很高 死亡。 在我们进行的初步EP研究中，杂合子 ARG4O3GLN HCM小鼠具有诱导的心室心动过速，一个明显的 在正常小鼠中尚未观察到的异常发现。 使用ARG4O3GLN HCM小鼠的初步数据表明， 性别之间的疾病进展率，也表明 发育（与年龄相关的）在这些猝死风险中增加 小鼠，最初15周没有死亡。 因此，都是男性 和雌性小鼠，以及几个不同年龄的小鼠 详细调查了几种的电生理特征 不同的控制和HCM小鼠种群。 来自完整的EP研究的数据， 包括异丙肾上腺素输注，将从每只动物中收集 与表面6铅ECG数据相关，包括分散 通过无线监测，复制以及长期的心电图监测 基础心肌的微端测定和组织学评估 组织。 综上所述，这些研究将允许对 由两个不同的特异性产生的电生理异常 引起HCM的突变，从而有助于我们对 心脏传导的分子机制和常见的 心血管疾病。