Distinct Ion Channel Pools and Intercalated Disk Nanoscale Structure Regulate Cardiac Conduction

独特的离子通道池和闰盘纳米级结构调节心脏传导

基本信息

批准号：
10676368
负责人：
Thomas Jeffrey Hund
金额：
$ 76.65万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-20 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10676368
关键词：
Ablation Acute Adhesions Angiotensin II Anti-Arrhythmia Agents Arrhythmia Calcium Channel Cardiac Cells Chronic Closure by clamp Complex Computer Analysis Computer Models Connexin 43 Connexins Coupling Data Defect Disease Disease Progression Electric Stimulation Electron Microscopy Electrophysiology (science)Elements Experimental Models Formulation Gap Junctions Genetic Health Heart Heart failure Heterogeneity Human Intercalated disc Intercellular Junctions Ion Channel L-Type Calcium Channels Lateral Link Maps Measurement Measures Mechanics Mediating Membrane Microscopy Modeling Molecular Mus Mutation Myocardium Na(+)-K(+)-Exchanging ATPase Optics Pathologic Pathology Patients Peptides Predisposition Proteins Regulation Research Risk Site Sodium Channel Sodium-Calcium Exchanger Structural defect Structure Structure-Activity Relationship System TAC1 gene Techniques Testing Tissue Model Tissues Validation Ventricular Work data pipeline diagnostic value experimental study inhibitor interstitial inward rectifier potassium channel light microscopy nano nanoscale neglect novel novel therapeutic intervention pharmacologic plakoglobin preservation response simulation targeted treatment ultra high resolution voltage

项目摘要

PROJECT SUMMARY Critical electrogenic proteins responsible for maintaining cardiac excitability and conduction, including sodium channels (NaV1.5), inward-rectifying potassium channels (Kir2.1), L-type calcium channels (Cav1.2), sodium-potassium ATPase (NKA), and sodium-calcium exchanger (NCX) have been identified to reside in distinct ion channel ‘pools,’ with localization at the cell-cell junction, the intercalated disk (ID). These distinct ion channel pools suggest regulation via both ‘global’ and ‘local’ control mechanisms. Within the ID, heterogeneous nanoscale structure results in channels concentrating around gap junctions and mechanical junctions, forming specialized nanodomains. ID nanodomains perturbation can induce proarrhythmic conduction defects, and disruption of these nanodomains has been identified in human arrhythmia patients, suggesting that these sites are key determinants of conduction. However, ID nanoscale structure and molecular organization and their implications for functional electrophysiology have yet to be systematically investigated in health or disease. In this project, we will undertake the first-ever comprehensive and granular quantification of ID structure and molecular organization using cutting-edge light and electron microscopy techniques and computational analysis. Further, we will develop a novel computational modeling framework to incorporate experimental measurements of these distinct ion channel pools (lateral membrane and ID) and ID nanoscale structure to assess regulation of tissue-scale cardiac conduction, for direct comparison with optical mapping of murine myocardium. Simulations will extend predictions to conduction in human ventricles and predict how both chronic and acute ID perturbations impact conduction in conjunction with additional functional defects, including non-ischemic heart failure. Upon successful completion of these aims, we will produce a new theoretical underpinning for which distinct ion channel pools and intercalated disk nanoscale structure confer a ‘global/local control’ of cardiac conduction and suggest new therapeutic approaches to preserve conduction during disease progression.

项目概要负责维持心脏兴奋性和传导的关键生电蛋白，包括钠通道 (NaV1.5)、内向整流钾通道 (Kir2.1)、L 型钙通道 (Cav1.2)、钠-钾 ATP 酶 (NKA) 和钠-钙交换器 (NCX) 已被确定驻留在不同的离子通道“库”中，定位于细胞与细胞的连接处，这些不同的离子通道池表明通过“全局”和“局部”进行调节。在 ID 内，异质纳米级结构产生通道。集中在间隙连接和机械连接周围，形成专门的纳米域。 ID 纳米域扰动可诱发致心律失常传导缺陷，并破坏这些缺陷纳米结构域已在人类心律失常患者中被发现，表明这些位点是关键然而，ID 纳米级结构和分子组织及其它们。功能性电生理学的影响尚未在健康或健康方面进行系统研究疾病。在这个项目中，我们将首次对ID结构进行全面、细粒度的量化使用尖端光学和电子显微镜技术进行分子结构和此外，我们将开发一种新颖的计算建模框架来进行计算分析。结合这些不同离子通道池（侧膜和 ID）的实验测量和 ID 纳米级结构，以评估组织尺度心脏传导的调节，以直接与小鼠心肌光学图谱的比较将预测扩展到人类心室的传导并预测慢性和急性 ID 扰动的影响传导与其他功能缺陷有关，包括非缺血性心力衰竭。成功完成这些目标后，我们将提出新的理论基础不同的离子通道池和闰盘纳米级结构赋予了“全局/局部控制” 心脏传导并提出在疾病期间保持传导的新治疗方法进展。