The Postnatal Role of Pitx2 in Atrial Fibrillation

Pitx2 在心房颤动中的产后作用

• 批准号: 9913991
• 负责人: Zachary Allen Kadow
• 金额: $ 4.59万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9913991
• 关键词: 4q25; Ablation; Affect; Age; Aging; American; Arrhythmia; Atrial Fibrillation; Cardiac; Cardiac Myocytes; Cardiac development; Choristoma; Chromosomes; Code; Communication; Data; Development; Disease; Environmental Risk Factor; Fibroblasts; Fibrosis; Functional disorder; Genes; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Goals; Heart; Heart Atrium; Impairment; Injury; Knockout Mice; Lead; Left; Left atrial structure; Link; Measures; Modeling; Molecular; Organ; Outcome; Oxidative Stress; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Population; Predisposition; Protein Isoforms; Reactive Oxygen Species; Role; Signal Transduction; Single Nucleotide Polymorphism; Sinus; Testing; Therapeutic; Time; Ventricular; Work; biological adaptation to stress; cardiogenesis; combat; conditional knockout; coronary fibrosis; experimental study; genetic association; genome wide association study; homeodomain; human old age (65+); improved; insight; mouse genetics; mouse model; novel; novel therapeutic intervention; novel therapeutics; postnatal; single-cell RNA sequencing; transcription factor

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.

项目摘要 该项目的目的是研究PITX2在房颤中的产后作用。心房颤动（AF）是 最常见的持续性心律不齐，这是一种以异常电脉冲为特征的疾病 整个心脏传导。 AF是一种衰老的疾病，目前影响超过300万 美国人，估计是民众年龄的一倍。而对AF的遗传贡献仍然是 经过研究，多个基因组的关联研究表明存在AF- 染色体4q25上的相关区域，PITX2是距该区域的最接近的基因。 PITX2代码 基本的转录因子对于形成心脏和其他中存在的左右不对称性至关重要 器官。在开发之后，PITX2的表达在很大程度上限制为左心肌细胞，其中 持续功能没有很好地表征。我们实验室的最新工作表明PITX2表达 受伤后出生后的心室心肌细胞诱导，在转录中调节 氧化应激反应。多种遗传小鼠模型已经表明发育和 PITX2表达的产后减少足以引起心律不齐；但是，机制 这些结果的背后是未知的。我们的长期目标是深入了解pitx2在 产后左心房，希望开发新的治疗剂，重点是治疗这种亚种群 AF患者。我们有初步数据，表明转录轮廓发生了重大变化 在我们的遗传小鼠模型中，左心房删除PITX2的左心房成纤维细胞的pitx2 AF。我们假设PITX2的产后减少增加了左侧的活性氧活性 心房心肌细胞并促进非自治成纤维细胞激活，从而导致心房颤动。 为了检验这一假设，我们将确定PITX2后心脏成纤维细胞激活的机制 使用小鼠遗传学的缺失。然后，我们将确定成纤维细胞激活与 心律不齐的形成。拟议的研究一起将深入了解pitx2在产后的功能 心肌细胞并帮助我们实现了开发新型治疗剂治疗AF的目标。