Gender-Dependent Regulation of Pitx2 in Atrial Fibrillation

Pitx2 在心房颤动中的性别依赖性调节

• 批准号: 10450632
• 负责人: Jeffrey David Steimle
• 金额: $ 6.76万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2023-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450632
• 关键词: 3-Dimensional; 4q25; Address; Affect; Androgen Receptor; Androgens; Animal Model; Arrhythmia; Atrial Fibrillation; Automobile Driving; Binding; Binding Sites; Bioinformatics; Calcium; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Caring; Chromatin; Clustered Regularly Interspaced Short Palindromic Repeats; Conditioned Reflex; Data; Disease; Electrophysiology (science); Elements; Epigenetic Process; Estrogen Receptors; Estrogens; Female; Gender; Gene Expression; Genes; Genetic; Genetic Transcription; Genomics; Genotype; Goals; Gonadal Steroid Hormones; Heart Atrium; Heart failure; Homeostasis; Hormone Receptor; Human; Investigation; Ion Channel; Ischemic Stroke; Knowledge; Left; Link; Mediating; Medicare; Messenger RNA; Mission; Modeling; Molecular; Mus; Mutation; Myocardial; Myocardium; Names; Outcome; Patient Care; Patients; Population; Predisposition; Prevention strategy; Pulmonary veins; Regulation; Regulatory Element; Risk; Risk Factors; Role; Sex Bias; Site; Stroke; Testing; Tissues; Transcriptional Regulation; United States; United States National Institutes of Health; Untranslated RNA; Variant; Woman; Work; base; cardiac pacing; cardioprotection; cost; cryptogenic stroke; design; epigenome; epigenomics; gender difference; gender expression; gene regulatory network; genome wide association study; heart rhythm; high risk men; homeodomain; human disease; lens; lifetime risk; male; men; mutant; novel; novel strategies; promoter; research study; sex; transcription factor; transcriptome; treatment response; treatment strategy

PROJECT SUMMARY Atrial fibrillation (AF) is the most common sustained arrhythmia in the United States with a 25% lifetime risk, and accounts for one-third of all cardiovascular diseases. Treatment and care associated with AF costs roughly $26 billion/year in the US alone and accounts for 10% of all Medicare spending. Debilitating complications linked to AF include heart failure and stroke. Evidence suggests AF underlies most ischemic and cryptogenic strokes, with women at a higher risk than men. In addition to stroke, several risk factors, outcomes, and treatments of AF demonstrate gender differences for which there is limited mechanistic understanding. Common variation at the non-coding 4q25 locus is resoundingly linked to AF risk, implicating cis-regulatory elements of the paired-like homeodomain transcription factor, PITX2. To understand the molecular drivers of AF, it is imperative to understand both the upstream regulation and downstream actions of PITX2. PITX2 is expressed in the left atrial (LA) and pulmonary vein (PV) myocardium of humans and mice. While work has implicated PITX2 in AF in the LA myocardium, it has also been suggested to underlie AF originating from the PV, the most common trigger site for arrhythmia in human patients. Although animal models of Pitx2 are susceptible to AF, the direct molecular mechanisms regulated by Pitx2 remain undetermined. Using Pitx2 CRISPR-edited mice, the role of Pitx2 in LA and PV myocardium will be interrogated while addressing underlying gender differences in Pitx2 regulation. The central hypothesis is that gender-specific differences in gene regulatory networks underlie differences in AF-susceptibility in men and women. To address this hypothesis, the first aim proposes to examine the transcriptional basis for gender bias in Pitx2 expression and AF-risk. Motif analysis identifies multiple, highly- conserved hormone-receptor binding sites, including androgen- and estrogen-receptor, at a 4q25-associated regulatory element and the Pitx2 promoter. CRISPR-mediated deletion of the 4q25-associated regulatory element confers male-specific reduction in Pitx2 and increased risk of AF by cardiac pacing. Therefore, this aim will ask whether sex-hormone dependent expression influence AF burden and Pitx2 expression through direct transcriptional regulation. In the second aim, the downstream targets of PITX2 will be interrogated to discover whether epigenomic differences between the genders influence the transcription factor milieu in the LA and PV myocardium. Despite the strong association between PITX2 and AF, the function of PITX2 in LA/PV myocardium is poorly understood. Furthermore, significant differences between men and women are present in AF and other cardiovascular diseases; however, few epigenetic or genomic studies of the cardiovascular system examine gender. This aim is designed to illuminate the role of PITX2 in AF while taking a progressive approach to incorporating and leveraging gender differences in this genetic and epigenomic investigation. Altogether, the proposed project aims to identify the upstream regulation and downstream actions of PITX2 in AF through the lens of inherent gender differences with the goal of identifying novel avenues to treat AF in men and women.

项目概要 心房颤动 (AF) 是美国最常见的持续性心律失常，终生风险为 25%， 占所有心血管疾病的三分之一。与 AF 相关的治疗和护理费用大致为 仅在美国每年就有 260 亿美元，占所有医疗保险支出的 10%。相关的衰弱并发症 AF 包括心力衰竭和中风。有证据表明房颤是大多数缺血性和隐源性中风的基础， 女性比男性面临更高的风险。除中风外，房颤的几个危险因素、结果和治疗方法 表明性别差异的机制理解有限。常见的变异在 非编码 4q25 位点与 AF 风险密切相关，暗示配对样的顺式调控元件 同源域转录因子，PITX2。要了解 AF 的分子驱动因素，必须 了解 PITX2 的上游调控和下游作用。 PITX2 在左心房表达 人和小鼠的（LA）和肺静脉（PV）心肌。虽然工作表明 PITX2 与 AF 相关 LA 心肌，也有人认为是源自 PV 的 AF 的基础，这是最常见的触发因素 人类患者心律失常的部位。尽管 Pitx2 的动物模型对 AF 敏感，但直接分子 Pitx2 调节的机制仍未确定。使用 Pitx2 CRISPR 编辑的小鼠，研究 Pitx2 在 LA 中的作用 和 PV 心肌将受到质疑，同时解决 Pitx2 调节中潜在的性别差异。这 中心假设是基因调控网络中的性别特异性差异是差异的基础 男性和女性的 AF 易感性。为了解决这个假设，第一个目标是检查 Pitx2 表达和 AF 风险中性别偏见的转录基础。基序分析识别出多个、高度 保守的激素受体结合位点，包括雄激素和雌激素受体，位于 4q25 相关 调控元件和 Pitx2 启动子。 CRISPR 介导的 4q25 相关调控基因的缺失 该元素可导致男性特有的 Pitx2 减少，并增加心脏起搏引起的 AF 风险。因此，这个目标 将询问性激素依赖性表达是否通过直接影响 AF 负担和 Pitx2 表达 转录调控。在第二个目标中，将询问 PITX2 的下游靶标以发现 性别之间的表观基因组差异是否影响 LA 和 PV 中的转录因子环境 心肌。尽管 PITX2 和 AF 之间有很强的相关性，但 PITX2 在 LA/PV 心肌中的功能 人们对此知之甚少。此外，男性和女性在 AF 和其他方面也存在显着差异。 心血管疾病；然而，很少有心血管系统的表观遗传学或基因组研究检查 性别。这一目标旨在阐明 PITX2 在 AF 中的作用，同时采取渐进的方法 在遗传和表观基因组研究中纳入并利用性别差异。总而言之， 拟议项目旨在通过以下方法确定 PITX2 在 AF 中的上游调控和下游作用： 镜头中固有的性别差异，旨在确定治疗男性和女性房颤的新途径。