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：
9136667
负责人：
Jeffrey M Abrams
金额：
$ 4.47万
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 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9136667
关键词：
Accounting Action Potentials Affect Age Age-Years American Antibodies Appearance Arrhythmia Atrial Fibrillation Binding Binding Sites Biochemical Breeding Cardiac Cardiac Myocytes Cessation of life Collagen 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 Hematoxylin and Eosin Staining Method Hour Human Hypertrophy Immunohistochemistry In Vitro Ion Channel Laboratory Study Lead Left Left Ventricular Dysfunction Limb structure Local Anesthetics Long QT Syndrome Maintenance Maps Methods Mission Molecular Mus Muscle Cells Mutation Myocardial Nature Operative Surgical Procedures Optics Patch-Clamp Techniques Pathogenesis Pharmacologic Substance Phenocopy Phenotype Plague 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 fascinate gain of function genome wide association study human disease in vivo insight male mouse model mutant novel novel therapeutics public health relevance ranolazine research study 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（由适用提供）：心房颤动是临床实践中最常见的心律不齐，估计会影响65岁及以上的美国人中约6％。心房颤动增加了死亡的风险，占所有中风的15％至20％。药物和射频消融/手术的相对低效率以及高复发率困扰着该领域数十年。缺乏真正的小鼠模型，可以准确地概括了典型的富含赞助商的启动和持续的房颤发作，从而阻碍了对房颤的深入实验室研究。尽管系统性和心脏疾病诱发了心房颤动的促成因素，但遗传易感性的重要组成部分可能是通过最近全基因组关联的研究以及K+通道，Na+通道和瑞氏菌受体的相对罕见突变体的鉴定所表明的，这突显了离子通道功能障碍在病原体中的作用。我们在心肌细胞中研究信息丰富的NA+通道突变体的新方法使转基因小鼠具有轻度中度心房增强的表型，轻度左心室功能障碍，以及经常且持续的自发性阵发性阵发性的阵发性阵发性的手提纤维纤维纤维化和次生型嗜好，年龄在5-6周中。这些小鼠在膨胀的心肌病和肥大中暗示的功能功能获得的人类SCN5A突变以及心律不齐，例如长QT综合征，扭转点和心房颤动。心房心律失常的持续和赞助性质是一种相对不寻常的表型，这使我们能够探索使用体内（遥测）（远程测定仪），Ex vivo（langendorff-perfused hearts）和cylly electoply（cylluque）和interoply（cyliuper offerfys）（远程电压映射）和cyl offys and vittross（远程）和interoply（cyliqury）和interofly（cyliument offelys and vittys）（远程电压映射），探索主动和维持心房颤动的机制。提出了两个特定的目标，旨在表征突变体SCN5A表达引起的心房颤动的细胞电生理机制。提出的实验旨在进一步发展和表征这种独特的房颤模型，并具有最终识别和测试新疗法的目标。