Ion Channel Function in Arrhythmogenic Cardiac Cells

描述（由申请人提供）：Boyden/Wit实验室的长期目标是在细胞/亚细胞水平上了解在梗死心脏中存活的肌细胞中定义的电重构机制。在过去的支持期间，我们的实验室联合开发了一种映射/肌细胞方法（例如EBZ细胞对实验），以确定从映射的折返回路的选定区域分散的细胞的电生理学。这些发现导致了这一系列高度集中的，新定义的研究。我们的具体目标是：1）确定牵拉（冠脉闭塞后缺血环境的一个组成部分）是否是导致缺血犬心室中连接蛋白43间隙连接和肌膜离子通道结构重塑发生的刺激。2)确定心肌牵张引起的离子通道（间隙连接和离子通道）结构重构对电生理（功能重构）的功能影响，并将其与冠状动脉闭塞后心外膜边缘区的变化进行比较。3)确定牵张诱导的缝隙连接重构和离子通道重构对梗死愈合期间心外膜梗死边缘区传导和不应性改变的贡献。4)确定离子通道的分子组分（亚基）在缺血/牵张过程中发生的重构中的功能和作用。将使用原位标测、分子探测技术和电压钳技术（使用从冠状动脉闭塞后心脏心外膜边缘区的折返回路和拉伸心肌中分散的单（对）细胞）、计算机模拟以及体外和原位基因表达技术完成研究。我们的研究结果将提供一个详细的了解的离子基础上的电重构的细胞存活在愈合和愈合的心脏梗死后，以及在这些时间内发生的折返性心律失常的机制。

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.