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.

项目概要： Pitx2 同源域转录因子是左右不对称的中央转录调节因子 在心脏内发挥控制心脏形态发生的功能。现在很清楚，Pitx2 从根本上来说是 与 AF 相连，尽管这种连接的基础仍然不清楚。 Pitx2-AF 的第一个证据 一项全基因组关联研究 (GWAS) 中建立了关联，暗示染色体 4q25 的一个区域 早发性家族性房颤。 Pitx2是与疾病相关的单核苷酸最接近的基因 多态性（SNP）。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，这进一步增加了获取药物的紧迫性 深入了解与 4q25 SNP 相关的潜在分子机制。我们是第一批 据报道，Pitx2 杂合子小鼠易患 AF，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提供新颖且 对 Pitx2 happlo 不足状态下 AF 的分子机制有根本性的重要见解。我们的 初步的多组学分析表明 Pitx2 直接与许多已被研究的基因结合 与 AF 相关的基因以及对活性氧做出反应并诱发炎症的基因。 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。此外，对 AF 遗传学的深入了解将有助于 随着人类基因组测序变得更加重要，为患者管理提供关键资源 平凡。最后，长期目标是开发基于固体的新型治疗策略 来自模式生物和人类遗传学工作的科学信息。