Ion Channel Function in Arrhythmogenic Cardiac Cells

致心律失常心肌细胞中的离子通道功能

• 批准号: 7418562
• 负责人: PENELOPE Altman BOYDEN
• 金额: $ 45.48万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7418562
• 关键词: Action Potentials; Address; Affect; Anatomic Models; Appendix; Arrhythmia; Calcium; Canis familiaris; Cardiac; Cell membrane; Cells; Characteristics; Complex; Computer Simulation; Connexin 43; Coronary Occlusions; Coronary artery; Data; Dependence; Device Designs; Electrophysiology (science); Environment; Epicardium; Gap Junctions; Gene Expression; Healed; Heart; Hour; In Situ; In Vitro; Individual; Infarction; Intercalated disc; Interleukins; Ion Channel; Ion Channel Gating; Ion Channel Protein; Ischemia; Laboratories; Lead; Life; Localized; Location; Macromolecular Complexes; Maps; Measurement; Messenger RNA; Modeling; Molecular; Molecular Biology Techniques; Molecular Probe Techniques; Muscle Cells; Myocardial; Myocardial Infarction; Myocardium; Pathway interactions; Phase; Potassium Channel; Principal Investigator; Property; Protein Binding; Proteins; Refractory; Research Personnel; Role; Scaffolding Protein; Series; Stimulus; Stretching; Tachyarrhythmias; Techniques; Time; Tissues; Ventricular; Voltage-Clamp Technics; Western Blotting; Wit; artery occlusion; base; cytokine; day; gap junction channel; healing; immunocytochemistry; innovation; mathematical model; programs; protein function; protein protein interaction; research study; voltage

DESCRIPTION (provided by applicant): The long term objective of the Boyden/Wit laboratories is to understand at a cellular/subcellular level the mechanisms of the electrical remodeling defined in myocytes that have survived in the infarcted heart. During the past period of support, our labs combined efforts developing a mapping/myocyte approach (e.g. EBZ cell pair experiments) to determine the electrophysiology of cells dispersed from select regions of mapped reentrant circuits. These findings have led to this series of highly focused, newly defined studies. Our specific aims are; 1)To determine if stretch, a component of the ischemic environment after coronary occlusion, is a stimulus that contributes to the occurrence of connexin43 gap junctional and sarcolemmal ion channel structural remodeling in the ischemic canine ventricle. 2) To determine the functional consequences of ion channel (gap junctional and ion channel) structural remodeling caused by myocardial stretch on electrophysiology (functional remodeling) and compare it to changes in the epicardial border zone after coronary occlusion. 3) To determine the contribution of stretch induced gap junction remodeling and ion channel remodeling to alterations in conduction and refractoriness of epicardial infarct border zone during infarct healing. 4) To determine the function and role of molecular components (subunits) of ion channels in the remodeling that occurs during ischemia/stretch. Studies will be completed using in situ mapping, molecular probing techniques, and voltage clamp techniques using single (pairs) cells dispersed from the reentrant circuits of the epicardial border zone of hearts post coronary artery occlusion and from stretched myocardium, computer simulations and in vitro and in situ gene expression techniques. Our results will provide a detailed understanding of the ionic basis of electrical remodeling in cells surviving in the healing and healed hearts post-infarction as well as the mechanism of the reentrant arrhythmias occurring during these times.

描述(申请人提供)：博伊登/威特实验室的长期目标是在细胞/亚细胞水平上了解存活在梗死心脏中的心肌细胞中定义的电重构的机制。在过去的支持期间，我们的实验室联合开发了一种标测/肌细胞方法(例如EBZ细胞对实验)，以确定从标测折返电路的选定区域分散的细胞的电生理。这些发现导致了这一系列高度集中、新定义的研究。我们的具体目标是：1)确定Stretch是冠脉闭塞后缺血环境的一个组成部分，是否是一种刺激因素，导致犬缺血室间隙连接和肌膜离子通道结构重构的发生。2)探讨心肌牵张引起的离子通道(缝隙连接通道和离子通道)结构重构对电生理(功能重构)的影响，并与冠脉闭塞后心外膜交界区的变化进行比较。3)探讨牵张诱导的缝隙连接重塑和离子通道重塑在心外膜梗死边缘带在心梗愈合过程中传导和不应性改变中的作用。4)确定离子通道分子组分(亚单位)在缺血/牵张重塑中的功能和作用。研究将使用原位标测、分子探测技术和电压钳技术完成，使用分散在冠状动脉闭塞后心外膜交界区折返回路和拉伸心肌的单个(对)细胞、计算机模拟以及体外和原位基因表达技术。我们的结果将提供一个详细的基础，在愈合和愈合的心肌梗死后存活的细胞电重塑的离子基础，以及在此期间发生折返性心律失常的机制。