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.

项目总结 在美国，房颤是中风的主要原因，也是发病率和死亡率的主要原因。自动对焦是 既有遗传因素，也有后天因素。全基因组关联研究已经确定ERBB4是一种 房颤的候选易感基因。后天的情况，如衰老、高血压和心力衰竭， 在被称为重塑的过程中导致左心房(LA)的电学和结构变化 易患房颤。我们的数据显示房颤患者左房ERBB4水平降低。我们还有 显示ErbB4在心脏病小鼠模型中表达下调。ErbB4在大鼠双侧心房中的作用 在电发展和获得性房颤机制中，我们已经产生了减少了 ERBB4在发育过程中或在成年期获得的表达。这两个模型系统都显示了一个重要的 正确的ErbB4基因剂量对维持正常心房电生理的依赖性。