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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.