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.

项目概要 该项目的目标是调查 Pitx2 在心房颤动中的产后作用。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 传导至整个心脏。 AF 是一种衰老疾病，目前影响超过 300 万人 在美国人中，随着人口老龄化，这个数字估计会增加一倍。尽管遗传对 AF 的贡献仍然 正在调查中，多项全基因组关联研究证明了 AF-的存在 染色体 4q25 上的相关区域，Pitx2 是距离该区域最近的基因。 Pitx2 代码 重要的转录因子，对于形成心脏和其他器官中存在的左右不对称至关重要 器官。发育后，Pitx2 表达主要限于左心房心肌细胞，其中 持续功能尚未得到很好的表征。我们实验室最近的工作表明 Pitx2 表达 损伤后在出生后心室心肌细胞中被诱导，在其中转录调节 氧化应激反应。多种遗传小鼠模型已证明发育和 出生后 Pitx2 表达的减少足以引起房性心律失常；然而，该机制 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 Pitx2 在 产后左心房，希望开发新的疗法专注于治疗这一亚群 房颤患者。我们有初步数据表明转录谱发生了显着变化 在我们的遗传小鼠模型中，出生后从心肌细胞中删除 Pitx2 后左心房成纤维细胞的变化 AF。我们假设出生后 Pitx2 的减少会增加左脑活性氧的活性 心房心肌细胞并促进非自主成纤维细胞激活，导致心房颤动。 为了验证这一假设，我们将确定 Pitx2 之后心脏成纤维细胞激活的机制 使用小鼠遗传学进行删除。然后我们将确定成纤维细胞活化与 心律失常的形成。总之，拟议的研究将有助于深入了解 Pitx2 在产后的功能 心肌细胞并帮助我们实现开发治疗 AF 的新疗法的目标。