Ion Channel Function in Arrhythmogenic Cardiac Cell

描述（由申请人提供）：Boyden/Wit实验室的长期目标是在细胞/亚细胞水平上了解梗死心脏中存活的肌细胞的电重构机制。在过去的支持期间，我们的实验室共同努力开发了一种绘图/肌细胞方法（例如EBZ细胞对实验），以确定从绘制的可重入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)确定拉伸作为冠状动脉闭塞后缺血环境的一个组成部分，是否是一种刺激，有助于缺血性犬脑室中连接蛋白43间隙、连接和肌层离子通道结构重构的发生。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，并与冠状动脉闭塞后心外膜边缘带的变化进行比较。3)确定拉伸诱导的间隙连接重构和离子通道重构对梗死愈合过程中心外膜梗死边界区传导和难熔性改变的贡献。4)确定离子通道分子组分（亚单位）在缺血/拉伸期间发生的重构中的功能和作用。研究将使用原位作图、分子探测技术和电压钳技术完成，这些技术使用冠状动脉闭塞后心脏心外膜边界区再入回路和拉伸心肌分散的单（对）细胞、计算机模拟以及体外和原位基因表达技术。我们的研究结果将提供一个详细的了解电重构的离子基础，在愈合和愈合的心脏梗塞后存活的细胞，以及在这段时间内发生的再入性心律失常的机制。

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.