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 仅在美国就有260亿美元/年，占所有医疗保险支出的10%。使人衰弱的并发症 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卒中的基础， 女性比男性更容易患病除卒中外，房颤的几个风险因素、结局和治疗 显示出对机械理解有限的性别差异。常见的变化 非编码4 q25基因座与房颤风险密切相关，暗示了配对样基因的顺式调节元件。 同源结构域转录因子PITX 2。为了了解AF的分子驱动因素，必须 了解PITX 2的上游调节和下游作用。PITX 2在左心房表达， (LA)和人和小鼠的肺静脉（PV）心肌。虽然研究表明PITX 2与AF有关， LA心肌，也被认为是起源于PV的AF的基础，最常见的触发因素 心律不齐的病人。虽然Pitx 2的动物模型对AF易感，但其直接分子机制可能与AF相关。 Pitx 2调控的机制仍不确定。使用Pitx 2 CRISPR编辑的小鼠，研究了Pitx 2在LA中的作用。 和PV心肌将被询问，同时解决Pitx 2调节中的潜在性别差异。的 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 在男性和女性的房颤易感性中。为了解决这一假设，第一个目标提出检查 Pitx 2表达和AF风险中性别偏好的转录基础。基序分析发现了多种高度- 在4 q25-相关的一个保守的雄激素受体结合位点，包括雄激素和雌激素受体， 调控元件和Pitx 2启动子。CRISPR介导的4 q25相关调控基因缺失 元素赋予男性特异性的Pitx 2降低和心脏起搏引起的AF风险增加。因此，这一目标 将询问性激素依赖性表达是否通过直接作用影响AF负荷和Pitx 2表达。 转录调控在第二个目标中，将询问PITX 2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PITX 2与AF之间有很强的相关性，但PITX 2在LA/PV心肌中的功能 是很难理解的。此外，男性和女性之间在AF和其他方面存在显着差异。 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PITX 2在AF中的作用，同时采取渐进的方法， 将性别差异纳入和利用遗传和表观基因组研究。一切器皿的银子 拟议的项目旨在通过以下方式确定AF中PITX 2的上游调控和下游行动： 固有性别差异的透镜，旨在确定治疗男性和女性AF的新途径。