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的中央转录调节因子，其在心脏内发挥作用以控制心脏形态发生。现在很清楚，Pitx2 与 AF 从根本上有联系，尽管这种联系的基础仍然不清楚。 Pitx2-AF 联系的第一个证据是在全基因组关联研究 (GWAS) 中得出的，该研究表明染色体 4q25 的一个区域与早发家族性 AF 有关。 Pitx2 是与疾病相关的单核苷酸多态性 (SNP) 最接近的基因。具有 4q25 SNP 的 AF 患者没有高血压、糖尿病和瓣膜缺陷。此外，具有 4q25 SNP 的患者更容易发生心源性卒中，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。我们是第一组报告 Pitx2 杂合子小鼠易患 AF 的研究，表明 Pitx2 水平降低会导致 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 转录靶基因进行全基因组分析将为了解 Pitx2 单倍体不足状态下 AF 的分子机制提供新颖且具有根本性重要意义的见解。我们的初步染色质免疫沉淀 (ChIP) 序列 (seq) 数据表明，Pitx2 直接结合许多与人类 GWAS 研究中的 AF 和 PR 间期有关的基因。此外，我们的 ChIPseq 数据的基序分析进一步表明，Pitx2 与 AF 相关的其他转录因子（例如 Nkx2.5）协调调节基因表达。最后，我们的 ChIP seq 和其他初步数据表明 Pitx2 调节对 AF 易感性很重要的 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。人们对 AF 的遗传机制了解甚少。新的遗传学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资源。最后，长期目标是基于来自模型生物和人类遗传学工作的可靠科学信息来开发新的治疗策略。