The Role of ERBB4 in Atrial Electrophysiology and Atrial Fibrillation

ERBB4 在心房电生理学和心房颤动中的作用

• 批准号: 10503131
• 负责人: David S Park
• 金额: $ 42.38万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10503131
• 关键词: Address; Adult; Aging; Alpha Rhythm; Arrhythmia; Atrial Fibrillation; Biological Models; Calcium; Candidate Disease Gene; Cardiac; Cardiac Electrophysiologic Techniques; Cardiac Myocytes; Cardiac development; Cardiovascular system; Cause of Death; Cell Line; Data; Defect; Dependence; Development; Disease; Down-Regulation; ERBB2 gene; ETV1 gene; Electrophysiology (science); Environment; ErbB4 Receptor Protein Tyrosine Kinase; ErbB4 gene; Evaluation; Functional disorder; Gene Dosage; Genes; Genetic Transcription; Heart; Heart Abnormalities; Heart Atrium; Heart Diseases; Heart failure; Histologic; Human; Hypertension; Ion Channel; Knockout Mice; Knowledge; Left; Left atrial structure; Link; MAPK3 gene; Maintenance; Medical; Modeling; Molecular; Morbidity - disease rate; Mus; Muscle Cells; Mutant Strains Mice; Myocardium; Neuregulin 1; Neuregulin Receptor; Nodal; Optics; Pathogenesis; Pathway interactions; Patients; Physiological; Physiology; Predisposition; Prevalence; Process; Public Health; Receptor Protein-Tyrosine Kinases; Research; Risk; Role; Signal Pathway; Signal Transduction; Sodium; Stroke; Structure; Susceptibility Gene; System; Tamoxifen; Therapeutic; Transcriptional Activation; Transgenic Mice; Tretinoin; acquired factor; base; calmodulin-dependent protein kinase II; defined contribution; effective therapy; gene regulatory network; genetic risk factor; genome wide association study; heart rhythm; hospital utilization; mortality; mouse model; postnatal; programs; side effect; stroke incidence; success; targeted treatment; therapeutic target; transcription factor; transcriptome; transcriptomics

PROJECT SUMMARY Atrial fibrillation (AF) is the leading cause of stroke and a major cause of morbidity and mortality in the US. AF is due to both inherited and acquired factors. Genome-wide association studies have identified ERBB4 as a candidate susceptibility gene for AF. Acquired conditions, such as aging, hypertension, and heart failure, are known to cause electrical and structural changes in the left atrium (LA) in a process known as remodeling that predisposes to AF. Our data show that left atrial ERBB4 levels are reduced in patients with AF. We have also shown that ErbB4 is downregulated in heart disease mouse models. To study the role of ErbB4 in both atrial electrical development and in acquired AF mechanisms, we have generated mouse models that have reduced ErbB4 expression during development or acquired during adulthood. Both model systems show an important dependency of correct ErbB4 gene dosage in the maintenance of normal atrial electrophysiology.

项目概要 心房颤动 (AF) 是中风的主要原因，也是美国发病和死亡的主要原因。自动对焦是 due to both inherited and acquired factors.全基因组关联研究已确定 ERBB4 是 candidate susceptibility gene for AF.后天性疾病，如衰老、高血压和心力衰竭， 已知会在称为重塑的过程中引起左心房 (LA) 的电气和结构变化 易患 AF。我们的数据显示 AF 患者左心房 ERBB4 水平降低。我们还有 表明 ErbB4 在心脏病小鼠模型中下调。 To study the role of ErbB4 in both atrial 电气发育和获得性 AF 机制中，我们生成了小鼠模型，这些模型减少了 ErbB4 在发育期间表达或在成年期间获得。 Both model systems show an important 正确的 ErbB4 基因剂量在维持正常心房电生理学中的依赖性。