Pitx2 in atrial fibrillation

Pitx2 在心房颤动中的作用

• 批准号: 8702782
• 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/8702782
• 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; Functional RNA; Future; Gene Dosage; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Suppression; Genetic Transcription; Goals; 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; Variant; Work; base; cost; disability; early onset; genome sequencing; genome wide association study; genome-wide; homeodomain; in vivo; insight; loss of function; novel; novel therapeutics; postnatal; prevent; public health relevance; 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同源结构域转录因子是心脏左右不对称的中心转录调节因子，在心脏内起控制心脏形态发生的作用。现在很清楚，Pitx2从根本上与AF相连，尽管这种连接的基础仍然不清楚。Pitx2-AF联系的第一个证据是在一项全基因组关联研究（GWAS）中发现的，该研究表明，早发性家族性房颤中存在4q25染色体区域。Pitx2是最接近疾病相关单核苷酸多态性（SNP）的基因。携带4q25 SNP的房颤患者无高血压、糖尿病和瓣膜缺损。此外，携带4q25 SNP的患者更容易发生心脏栓塞性卒中，这进一步增加了深入了解与4q25 SNP相关的潜在分子机制的紧迫性。我们是第一个报道Pitx2杂合小鼠易患房颤的小组，这表明Pitx2水平降低导致房颤。随后，三个不同的小组重复了我们的发现。由于Pitx2在房颤中的关键作用，我们假设对Pitx2转录靶基因的全基因组分析将为房颤在Pitx2单倍体不足状态下的分子机制提供新的和根本重要的见解。我们的初步染色质免疫沉淀（ChIP）序列（seq）数据表明，Pitx2直接结合了许多基因，这些基因在人类GWAS研究中与AF和PR间隔有关。此外，ChIPseq数据的基序分析进一步表明，Pitx2与其他转录因子（如Nkx2.5）协同调节AF相关的基因表达。最后，我们的ChIPseq和其他初步数据表明，Pitx2调节对AF易感性重要的microrna。我们建议深入研究Pitx2调控传导系统发展和维持的分子基础。人们对房颤的遗传机制了解甚少。新的遗传见解将对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更加普遍，对房颤遗传学的深入了解将为患者管理提供关键资源。最后，还有一个长期的目标是开发基于可靠的科学信息的新的治疗策略，这些信息将来自模式生物和人类遗传学的工作。