Defining the TBX5-Dependent Gene Regulatory Networks of Atrial Fibrillation

摘要 房颤是最常见的心律失常，影响3300多万人 世界各地的个人。年，40岁以上的美国人中将有1人被诊断为房颤 他或她的一生。房颤占所有中风的四分之一，也与风险增加有关 痴呆症、心力衰竭和死亡的风险，即使在接受最佳循证护理的患者中也是如此。尽管 房颤造成巨大的医疗负担，对其发病机制认识有限 引发患者心律失常。因此，对房颤易感性的新的病理生理学见解是 必须指导改进的治疗和预防战略，以减少不可接受的 与房颤相关的中风、死亡和住院。TBX5与房颤的关系通过 家族性遗传。然而，TBX5在成人心房中的作用还没有被研究过 调查过了。我们现在在成人中使用Tbx5的有条件删除来生成令人信服的初步数据 小鼠使用三苯氧胺可诱导的Cre重组酶。成年小鼠的这种条件性缺失策略 绕过TBX5的发育要求，允许在正常发育的情况下进行TBX5的研究 成人的心脏。我们发现在成熟心肌中Tbx5的缺失导致可重复性， 没有心脏病或任何结构异常的自发性心房颤动。初步 去除Tbx5后心房的基因表达分析显示许多与Tbx5相关的基因调控错误 房颤，包括一些离子通道和转录因子Pitx2，是最常受到影响的 房颤易感基因座。我们假设，TBX5在成人心房中驱动一个基因网络，包括 PITX2，并协调成人心脏的房性心律的维持。这项提案将定义 成人去除Tbx5导致心房颤动的机制，并通过以下途径描述 并维持正常的房性心律失常。定义这些心房转录网络将允许 房颤风险的预测和一级预防策略。

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.