Defining the TBX5-Dependent Gene Regulatory Networks of Atrial Fibrillation

定义心房颤动的 TBX5 依赖性基因调控网络

• 批准号: 9192867
• 负责人: Rangarajan Nadadur
• 金额: $ 4.86万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2020-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9192867
• 关键词: Accounting; Action Potentials; Adult; Affect; Age; American; Arrhythmia; Atrial Fibrillation; Binding; Bioinformatics; Bypass; Calcium; Cardiac; Cardiac Myocytes; Caring; Cessation of life; Complex Genetic Trait; Data; Dementia; Dependency; Development; Diagnosis; Disease; Elements; Enhancers; Excision; Gene Expression Profiling; Gene Targeting; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Healthcare; Heart; Heart Atrium; Heart Diseases; Heart failure; Heritability; Hospitalization; Individual; Ion Channel; Lead; Link; Linkage Disequilibrium; Maintenance; Membrane; Morbidity - disease rate; Morphology; Mus; Mutant Strains Mice; Myocardium; Pathway interactions; Patients; Play; Predisposition; Prevention strategy; Primary Prevention; Publishing; Regulation; Regulator Genes; Risk; Role; RyR2; Stroke; Structural defect; Sudden Death; Susceptibility Gene; Tamoxifen; Therapeutic; base; cardiogenesis; cohort; evidence base; genetic variant; genome wide association study; improved; in vitro activity; in vivo; insight; mortality; mouse model; novel; recombinase; transcription factor

ABSTRACT Atrial fibrillation (AF) is the most commonly-diagnosed cardiac arrhythmia, affecting more than 33 million individuals throughout the world. One in four Americans above the age of 40 will be diagnosed with AF in his or her lifetime. AF accounts for one-fourth of all strokes and is also associated with an increased risk of dementia, heart failure, and death, even in patients receiving optimal evidence-based care. Despite the profound healthcare burden caused by AF, there is a limited understanding of the mechanisms that provoke the arrhythmia in patients. Hence, new pathophysiologic insights into AF susceptibility are essential to guide improved therapeutic and preventive strategies to reduce the unacceptable burden of stroke, death, and hospitalizations associated with AF. TBX5 has been associated with AF both through GWAS and familial inheritance. However, the role of TBX5 specifically in the adult atrium has not been investigated. We now generate compelling preliminary data using conditional deletion of Tbx5 in the adult mouse using a tamoxifen-inducible Cre recombinase. This strategy of conditional deletion in adult mice bypasses the developmental requirements of TBX5 and permits study of TBX5 in normally developed adult hearts. We found that deletion of Tbx5 in the mature myocardium leads to reproducible, spontaneous atrial fibrillation in the absence of heart disease or any structural abnormalities. Preliminary gene expression analysis in the atria after removal of Tbx5 reveals misregulation of many genes linked to AF, including a number of ion channels and the transcription factor Pitx2, the most frequently implicated AF susceptibility locus. We hypothesize that TBX5 drives a gene network in the adult atria which includes PITX2 and coordinates the maintenance of atrial rhythm in the adult heart. This proposal will define the mechanisms by which adult removal of Tbx5 results in atrial fibrillation, and delineate the pathways by which TBX5 and maintains normal atrial rhythm. Defining these atrial transcriptional networks will allow prediction of AF risk and a strategy for primary prevention.

摘要 心房颤动（AF）是最常见的心律失常，影响超过3300万人 世界各地的个人。四分之一的40岁以上的美国人将被诊断为AF， 他或她的一生。房颤占所有中风的四分之一，并且也与风险增加有关 痴呆、心力衰竭和死亡的风险，即使是在接受最佳循证护理的患者中。尽管 由于AF造成的严重医疗负担，对AF的机制了解有限， 引起患者心律失常。因此，房颤易感性的新病理生理学见解是 至关重要的是指导改进的治疗和预防战略，以减少不可接受的负担， TBX5与AF相关，包括中风、死亡和住院。 GWAS和家族遗传。然而，TBX5在成人心房中的特异性作用尚未被证实。 研究了我们现在使用成人Tbx5的条件性缺失产生令人信服的初步数据， 使用他莫昔芬诱导的Cre重组酶的小鼠。成年小鼠的这种条件性缺失策略 绕过了TBX5的开发要求，并允许在正常开发的环境中研究TBX5。 成人的心我们发现，成熟心肌中Tbx5的缺失导致可重复的， 无心脏病或任何结构异常的自发性房颤。初步 去除Tbx5后心房中的基因表达分析揭示了与Tbx5相关的许多基因的失调。 AF，包括一些离子通道和转录因子Pitx2，最常涉及 房颤易感基因我们假设TBX5在成人心房中驱动一个基因网络，包括 PITX2和协调成人心脏心房节律的维持。该提案将定义 成年人去除Tbx5导致心房颤动的机制，并通过以下方式描绘通路： TBX5和维持正常的心房节律。定义这些心房转录网络将允许 预测房颤风险和一级预防策略。