Pitx2 in atrial fibrillation

Pitx2 在心房颤动中的作用

• 批准号: 9012837
• 负责人: James F Martin
• 金额: $ 46.63万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9012837
• 关键词: 4q25; Address; Adult; Affect; Age; Age-Years; Animal Model; Arrhythmia; Atrial Fibrillation; Binding; Binding Sites; Biological Assay; Calcium; Cardiac; Chromatin; Chromosomes; Code; Counseling; Cultured Cells; Data; Data Set; Defect; Development; Diabetes Mellitus; Diagnostic tests; Disease; Electric Stimulation; Electrophysiology (science); Family; Future; Gene Dosage; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Suppression; Genetic Transcription; Goals; Health; Health Care Costs; Heart; Heart Atrium; Homeostasis; Human; Human Genetics; Human Genome; Hypertension; Incidence; Investigation; Knowledge; Left; Left atrial structure; Link; Maintenance; MicroRNAs; Molecular; Morphogenesis; Motion; Mus; Nucleotides; Pathologic; Patient Care; Patients; Phosphorylation; Physiological; Population; Precipitation; Predisposition; Prevalence; Public Health; Publishing; Regulation; Regulator Genes; Reporter; Reporting; Resources; Risk Factors; Role; RyR2; Sarcoplasmic Reticulum; Single Nucleotide Polymorphism; Solid; Stroke; Systems Development; Transgenic Mice; Untranslated RNA; Variant; Work; base; cost; disability; early onset; genome wide association study; genome-wide; genome-wide analysis; homeodomain; human genome sequencing; in vivo; insight; loss of function; novel; novel therapeutics; postnatal; prevent; transcription factor

DESCRIPTION (provided by applicant): The Pitx2 homeodomain transcription factor is a central transcriptional regulator in left right asymmetry that functions within the heart to contro cardiac morphogenesis. It is now clear that Pitx2 is fundamentally connected to AF although the basis for this connection remains obscure. The first evidence for the Pitx2-AF link was made in a Genome Wide Association Study (GWAS) implicating a region of chromosome 4q25 in early onset familial AF. Pitx2 was the gene in closest proximity to the disease associated single nucleotide polymorphism (SNP). AF patients with the 4q25 SNP were free of hypertension, diabetes and valve defects. Moreover, patients with the 4q25 SNP were more prone to cardioembolic stroke adding further urgency to gain insight to the underlying molecular mechanisms associated with the 4q25 SNP. We were the first group to report that Pitx2 heterozygous mice were predisposed to AF indicating that reduced levels of Pitx2 led to AF. Three different groups have subsequently replicated our findings. Because of its critical role in AF, we hypothesized that genome wide analysis of Pitx2 transcriptional target genes would provide novel and fundamentally important insight into the molecular mechanisms for AF in the Pitx2 haplo-insufficient state. Our preliminary Chromatin Immuno Precipitation (ChIP) sequence (seq) data indicate that Pitx2 directly binds to a number of genes that have been implicated in AF and also PR interval in human GWAS studies. Moreover, motif analysis of our ChIPseq data further suggests that Pitx2 coordinately regulates gene expression with other transcription factors such as Nkx2.5 that are implicated in AF. Lastly, our ChIP seq and other preliminary data suggest that Pitx2 regulates microRNAs that are important for AF predisposition. We propose to thoroughly investigate the molecular basis for Pitx2 regulated conduction system development and maintenance. There is poor understanding of the genetic mechanisms underlying AF. New genetic insights will be critical for diagnostic testing and family counseling i the future. Moreover, an in depth knowledge of genetics of AF will provide critical resources for patient management as human genome sequencing becomes more commonplace. Finally, there is the long term goal to develop novel therapeutic strategies based on solid scientific information that will come from work in model organisms and human genetics.

描述（由申请人提供）：PITX2同源域转录因子是左右不对称中的中央转录调节因子，在心脏内部起作用，可控制心脏形态发生。现在很明显，PITX2从根本上与AF相连，尽管这种联系的基础仍然晦涩难懂。 PITX2-AF链接的第一个证据是在基因组广泛的关联研究（GWAS）中提出的，该研究暗示了早期发作家族性AF中的4q25染色体区域。 PITX2是与疾病相关的单核苷酸多态性（SNP）最接近的基因。患有4Q25 SNP的AF患者没有高血压，糖尿病和瓣膜缺陷。此外，患有4Q25 SNP的患者更容易容易出现心脏肌中风，这增加了进一步的紧迫性，以了解与4q25 SNP相关的基本分子机制。我们是第一个报告说，PITX2杂合小鼠的AF倾向于AF，这表明PITX2降低导致AF。三个不同的小组随后复制了我们的发现。由于其在AF中的关键作用，我们假设对PITX2转录靶基因的基因组广泛分析将为PITX2单倍体不足的状态中AF的分子机制提供新颖和根本上重要的见解。我们的初步染色质免疫沉淀（CHIP）序列（SEQ）数据表明，PITX2直接与与AF有关的许多基因结合，也与人类GWAS研究中的PR间隔结合。此外，对我们的Chipseq数据的基序分析进一步表明，PITX2与其他转录因子（例如NKX2.5）相协调的基因表达，例如与AF有关的NKX2.5。最后，我们的芯片SEQ和其他初步数据表明，PITX2调节对AF倾向很重要的microRNA。我们建议彻底研究PITX2调节传导系统开发和维护的分子基础。对AF基础的遗传机制的理解不足。新的遗传见解对于未来的诊断测试和家庭咨询至关重要。此外，随着人类基因组测序变得越来越普遍，对AF遗传学的深入了解将为患者管理提供关键的资源。最后，有一个长期目标是基于扎实的科学信息来制定新的治疗策略，这些信息将来自模型生物体和人类遗传学的工作。