Exploring Mechanisms of Atrial Fibrillation through use of Transgenic Mouse Models

通过使用转基因小鼠模型探索心房颤动的机制

基本信息

批准号：
9330912
负责人：
Jeffrey M Abrams
金额：
$ 4.9万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9330912
关键词：
Action Potentials Affect Age Age-Years American Antibodies Appearance Arrhythmia Atrial Fibrillation Binding Binding Sites Biochemical Cardiac Cardiac Myocytes Cessation of life Collagen Crossbreeding Data Development Dilated Cardiomyopathy Disease Doxycycline Electrocardiogram Electrophysiology (science)Female Fibrosis Frequencies Functional disorder Gender Genes Genetic Engineering Genetic Predisposition to Disease Goals Heart Heart Atrium Heart Diseases Histologic Hour Human Hypertrophy Immunohistochemistry In Vitro Ion Channel Laboratory Study Lead Left Left Ventricular Dysfunction Limb structure Local Anesthetics Long QT Syndrome Maintenance Methods Mission Molecular Mus Muscle Cells Mutation Myocardial Nature Operative Surgical Procedures Optics Patch-Clamp Techniques Pathogenesis Pathologic Pharmacologic Substance Phenocopy Phenotype Play Potassium Channel Public Health Pulmonary veins Radiofrequency Interstitial Ablation Recurrence Research Resistance Risk Role Ryanodine Receptors Staining method Stains Stroke Structure Techniques Telemetry Testing Time Torsades de Pointes Transgenic Mice Transgenic Organisms Trichrome stain United States National Institutes of Health Ventricular Ventricular Arrhythmia Ventricular Tachycardia clinical practice design experimental study fascinate gain of function genome wide association study human disease in vivo insight male mouse model mutant novel novel therapeutics public health relevance ranolazine voltage

项目摘要

DESCRIPTION (provided by applicant): Atrial fibrillation is the most frequently sustained arrhythmia observed in clinical practice, estimated to affect about six percent of Americans who are 65 years of age and older. Atrial fibrillation doubles the risk of death, and accounts for 15-20% percent of all strokes. The relatively low efficacy of pharmaceuticals and radiofrequency ablation/surgery, and high rates of recurrence have plagued the field for decades. In-depth laboratory studies of atrial fibrillation have been hindered by the lack of a bona fide mouse model that accurately recapitulates the typical spontaneous initiation and sustained episodes of atrial fibrillation observed in humans. Although systemic and cardiac disorders are predisposing contributors to atrial fibrillation, there is also likely an important component of genetic susceptibility, shown by recent genome-wide association studies and identification of relatively rare mutants in K+ channels, Na+ channels and ryanodine receptors, highlighting the role of ion channel dysfunction in the pathogenesis of atrial fibrillation. Our novel method of studying informative Na+ channel mutants in cardiomyocytes has enabled the development of a transgenic mouse with a phenotype of mild-moderate atrial enlargement, mild left ventricular dysfunction, and frequent and sustained episodes of spontaneous paroxysmal atrial fibrillation and ventricular arrhythmias as early as 5-6 weeks of age. These mice phenocopied gain-of-function human SCN5A mutations, which have been implicated in dilated cardiomyopathy and hypertrophy, and arrhythmias such as long QT syndrome, torsade de pointes and atrial fibrillation. The sustained and spontaneous nature of the atrial arrhythmias, a relatively unusual phenotype in mice, has enabled us to explore mechanisms of initiation and maintenance of atrial fibrillation using in vivo (telemetry), ex vivo (optical voltage mapping of Langendorff-perfused hearts), and in vitro (cellular electrophysiology) techniques. Two Specific Aims are proposed, designed to characterize the cellular electrophysiological mechanisms of atrial fibrillation caused by mutant SCN5A expression. The proposed experiments are designed to further develop and characterize this unique murine model of atrial fibrillation, with the ultimate goal of identifying and testing novel therapies.

描述（由申请人提供）：心房颤动是临床实践中观察到的最常见的持续性心律失常，估计影响约 6% 的 65 岁及以上的美国人，心房颤动使死亡风险增加一倍，并导致 15-15 岁的老年人死亡。占所有中风的 20%。数十年来，药物和射频消融/手术的疗效相对较低，且复发率较高。心房颤动的研究因缺乏真实的小鼠模型而受到阻碍，该模型能够准确地重现在人类中观察到的心房颤动的典型自发发作和持续发作。最近的全基因组关联研究以及 K+ 通道、Na+ 通道和兰尼碱受体中相对罕见的突变体的鉴定表明，离子通道是遗传易感性的重要组成部分，强调了离子通道的作用我们研究心肌细胞中信息丰富的 Na+ 通道突变体的新方法已经能够培育出具有轻度至中度心房扩大、轻度左心室功能障碍以及频繁和持续的自发性阵发性心律失常的表型的转基因小鼠。这些小鼠早在 5-6 周龄时就出现了心房颤动和室性心律失常，这些突变已被证实是人类 SCN5A 的功能获得性突变。与扩张型心肌病和肥厚以及长 QT 综合征、尖端扭转型室性心动过速和心房颤动等心律失常有关。房性心律失常是小鼠中相对不寻常的表型，其持续和自发的性质使我们能够探索房性心律失常的启动和维持机制。使用体内（遥测）、离体（Langendorff 灌注心脏的光电压映射）和体外（细胞电生理学）测量心房颤动提出了两个具体目标，旨在表征突变 SCN5A 表达引起的心房颤动的细胞电生理机制。所提出的实验旨在进一步开发和表征这种独特的心房颤动小鼠模型。识别和测试新疗法的目标。