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.

项目摘要 心房颤动（AF）是美国最常见的持续性心律失常，终身风险为25％， 占所有心血管疾病的三分之一。与AF成本相关的治疗和护理大致 仅在美国，每年260亿美元，占所有医疗保险支出的10％。连接的使并发症的并发症 AF包括心力衰竭和中风。有证据表明，AF是大多数缺血性和隐性中风的基础， 女性的风险高于男性。除了中风，AF的几个危险因素，结果和治疗 证明机械理解有限的性别差异。常见变化 非编码4q25基因座与AF风险相互吻合，暗示了配对样的顺式调节元素 同源域转录因子，PITX2。要了解AF的分子驱动因素，必须 了解PITX2的上游调节和下游动作。 pitx2在左图中表示 （LA）和肺静脉（PV）人类和小鼠的心肌。虽然工作已在AF中暗示PITX2 LA心肌，还建议它是由PV起源的AF的基础，这是最常见的触发器 人类心律不齐的部位。尽管PITX2的动物模型易于AF，但直接分子 由PITX2调节的机制仍未确定。使用PITX2 CRISPR编辑的小鼠，Pitx2在LA中的作用 在解决PITX2调节中基本的性别差异时，将询问PV心肌。这 中心假设是基因调节网络的性别特异性差异是差异的基础 在男性和女人的AF敏感性中。为了解决这一假设，第一个目的提议检查 PITX2表达和AF风险中性别偏差的转录基础。主题分析确定了多个，高度 - 在4q25相关的情况下，保守的激素受体结合位点，包括雄激素和雌激素受体。 调节元件和PITX2启动子。与4Q25相关调节的CRISPR介导的删除 元素赋予了PITX2中男性特异性的减少，并通过心脏起搏增加了AF的风险。因此，这个目标 会询问性激素依赖性表达是否会通过直接影响AF负担和PITX2表达 转录调节。在第二个目标中，PITX2的下游目标将被审问以发现 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与AF之间存在很强的关联，但PITX2在LA/PV心肌中的功能 理解很差。此外，AF和其他其他男女之间存在显着差异 心血管疾病；但是，心血管系统的表观遗传学或基因组研究很少 性别。该目标旨在阐明Pitx2在AF中的作用，同时采取渐进式方法 在这种遗传和表观基因组学研究中纳入和利用性别差异。总共 拟议的项目旨在确定PITX2在AF中的上游法规和下游行动 固有的性别差异的镜头旨在识别男性和女性治疗AF的新途径。