The Postnatal Role of Pitx2 in Atrial Fibrillation

项目摘要 本项目的目的是研究出生后Pitx 2在房颤中的作用。心房颤动（AF）是 最常见的持续性心律失常，一类以异常电脉冲为特征的疾病 传导到整个心脏AF是一种衰老性疾病，目前影响超过300万人 美国人，随着人口老龄化，这个数字估计会翻一番。虽然遗传因素对AF的贡献仍然存在， 正在调查中，多个全基因组关联研究已经证明了AF的存在， 在染色体4 q25上的相关区域中，Pitx 2是最接近该区域的基因。Pitx 2代码，用于 一种在心脏和其他组织中形成左右不对称性中至关重要的重要转录因子 机关发育后，Pitx 2表达主要局限于左心房心肌细胞， 连续函数没有很好地表征。我们实验室最近的工作表明，Pitx 2表达 在出生后的心室心肌细胞损伤后被诱导，在那里它转录调节 氧化应激反应多个遗传小鼠模型已经证明，发育和 出生后Pitx 2表达的减少足以引起房性心律失常;然而， 这些结果的背后很大程度上是未知的。我们的长期目标是深入了解Pitx 2在 出生后的左心房，希望开发新的治疗方法，重点是治疗这一亚群 房颤患者。我们有初步的数据表明，有一个显着的转变，在转录概况 在我们的遗传小鼠模型中，出生后从心肌细胞中删除Pitx 2后，左心房成纤维细胞的 AF.我们假设出生后Pitx 2的减少增加了左心室中活性氧的活性。 心房心肌细胞，并促进非自主性成纤维细胞活化，导致心房颤动。 为了验证这一假设，我们将确定Pitx 2诱导心肌成纤维细胞活化的机制。 使用小鼠遗传学进行缺失。然后我们将确定成纤维细胞活化与 心律失常形成。总之，拟议的研究将深入了解Pitx 2在出生后发育中的功能。 并帮助我们实现开发治疗AF的新疗法的目标。

Project Summary The goal of this project is to investigate the postnatal role of Pitx2 in atrial fibrillation. Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, a class of diseases characterized by abnormal electrical impulse conduction throughout the heart. AF is a disease of aging, currently affecting more than three million Americans, a number estimated to double as the populace ages. While the genetic contributions to AF are still being investigated, multiple genome wide association studies have demonstrated the presence of an AF- associated region on chromosome 4q25, with Pitx2 being the closest gene to the region. Pitx2 codes for an essential transcription factor that is critical in forming left-right asymmetry present in the heart and other organs. Following development, Pitx2 expression is restricted largely to left atrial cardiomyocytes, where its continued function is not well characterized. Recent work from our lab has demonstrated that Pitx2 expression is induced in postnatal ventricular cardiomyocytes following injury, where it transcriptionally regulates the oxidative stress response. Multiple genetic mouse models have demonstrated that both developmental and postnatal reductions in Pitx2 expression are sufficient to cause atrial arrhythmias; however, the mechanism behind these results are largely unknown. Our long-term goal is to gain insight into the role of Pitx2 in the postnatal left atrium, with the hopes of developing novel therapeutics focused on treating this subpopulation of AF patients. We have preliminary data demonstrating that there is a significant shift in the transcriptional profile of left atrial fibroblasts following postnatal deletion of Pitx2 from cardiomyocytes in our genetic mouse model of AF. We hypothesize that postnatal reductions in Pitx2 increase reactive oxygen species activity in left atrial cardiomyocytes and promotes nonautonomous fibroblast activation, resulting in atrial fibrillation. To test this hypothesis, we will determine the mechanism of cardiac fibroblast activation following Pitx2 deletion using mouse genetics. We will then determine the relationship between fibroblast activation and arrhythmia formation. Together, the proposed studies will lend insight into the function of Pitx2 in postnatal cardiomyocytes and help us achieve our goal of developing novel therapeutics for the treatment of AF.