Pitx2 in atrial fibrillation

Pitx2 在心房颤动中的作用

• 批准号: 10375242
• 负责人: James F Martin
• 金额: $ 54.41万
• 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 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10375242
• 关键词: 4q25; Ablation; Adult; Affect; Age; Age-Years; Aging; Alzheimer' s disease related dementia; Animal Model; Antioxidants; Arrhythmia; Atrial Fibrillation; BMP10 gene; Binding; Cardiac; Cardiac Myocytes; Cells; Chromatin; Chromosomes; Clinical; Counseling; Data; Defect; Development; Diabetes Mellitus; Diagnostic tests; Disease; Endothelial Cells; Familial atrial fibrillation; Family; Future; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Genome; Goals; Grant; Health Care Costs; Health Expenditures; Heart; Heart Atrium; Heart failure; Homeobox Genes; Homeostasis; Human; Human Chromosomes; Human Genetics; Hypertension; Incidence; Inflammation; Inflammatory; Injury; Knowledge; Left; Left atrial structure; Left ventricular structure; Link; Mechanical Stress; Mechanics; Methods; Molecular; Morphogenesis; Morphology; Multiomic Data; Mus; Mutant Strains Mice; Myocardial Infarction; Nuclear; Nuclear Receptors; Paper; Pathway interactions; Patient Care; Patients; Pharmacology; Population; Predisposition; Prevalence; Public Health; Pulmonary veins; Reactive Oxygen Species; Recurrence; Regulatory Element; Reporting; Resources; Role; Series; Signal Transduction; Single Nucleotide Polymorphism; Small Nuclear RNA; Solid; Source; Stroke; Testing; Tissues; Work; base; care costs; constriction; disability; early onset; environmental stressor; experimental study; gain of function; genome wide association study; genome-wide analysis; homeodomain; human genome sequencing; insight; multiple omics; novel; novel therapeutic intervention; response; response to injury; sham surgery; stressor; stroke incidence; syntax; transcription factor

Project Summary: The Pitx2 homeodomain transcription factor is a central transcriptional regulator in left right asymmetry that functions within the heart to control 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 happloinsufficient state. Our preliminary Multi-Omics analysis indicates that Pitx2 directly binds to a number of genes that have been implicated in AF and also genes that respond to reactive oxygen species and induce inflammation. There is poor understanding of the genetic mechanisms underlying AF. New genetic insights will be critical for diagnostic testing and family counseling in 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.

项目摘要： PITX2同源域转录因子是左右不对称的中央转录调节剂， 心脏内部的功能控制心脏形态发生。现在很明显pitx2从根本上是 与AF相连，尽管这种联系的基础仍然晦涩难懂。 pitx2-af的第一个证据 链接是在一项基因组广泛的关联研究（GWAS）中建立的，该研究暗示了4q25染色体区域 早期发作家庭AF。 PITX2是最接近疾病相关的单核苷酸的基因 多态性（SNP）。患有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的患者更容易出现心脏符号中风，增加了进一步的紧迫性 洞悉与4q25 SNP相关的基本分子机制。我们是第一个 报道PITX2杂合小鼠倾向于AF，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提供新颖，并且 从根本上重要的洞察力对PITX2 apploinsloinsunse nate的AF的分子机制。我们的 初步的多词分析表明，PITX2直接与许多已经存在的基因结合 与AF以及对活性氧响应并诱导炎症反应的基因有关。 对AF基础的遗传机制的理解不足。新的遗传见解至关重要 将来的诊断测试和家庭咨询。而且，对AF遗传学的深入了解将 随着人类基因组测序变得更多，为患者管理提供关键资源 平凡。最后，有一个长期目标是开发基于固体的新型治疗策略 来自模型生物和人类遗传学的工作的科学信息。