Ion Channel Function in Arrhythmogenic Cardiac Cells

描述（由申请人提供）：本项目的长期目标 应用是将博伊登和威特实验室的专业知识联合收割机， 在更多的细胞/亚细胞水平上理解电异常 定义为存活于心脏外膜边缘区的肌细胞， 冠状动脉闭塞后5天、14天和2个月的梗死心脏。 这些异常有助于发生严重危及生命的 心肌梗死后室性心律失常我们的具体目标是 主要内容如下：1）确定细胞中特定离子电流的功能 从所映射的重入电路的选择区域分散 5天梗塞心脏的心外膜边缘区，然后通过使用这些 实验数据开发EBZ的1D和2D计算机模型，2）以确定 分散细胞的比离子电流（INa、ICaL和IK）的功能 从梗塞14天和2个月的边缘区的选择区域 心脏，和3）确定延迟整流的功能和药理学 特别是边缘区细胞中的K+电流， 观察到的Kvl.5通道的细胞表面再分布模式的后遗症 proteins.研究将使用原位标测、全电池电压 钳位技术，使用分散在可重入电路中的单细胞， 冠状动脉闭塞后心脏的心外膜边缘区， 计算机模拟技术我们的研究结果将提供一个更详细的 了解存活细胞电重构的离子基础， 梗死后心脏的愈合和愈合以及 在此期间发生的折返性心律失常。这样做，他们将有助于 确定治疗折返性心室新分子靶点 心律不齐。

DESCRIPTION (provided by applicant): The long term objective of this application is to combine the expertise of the Boyden and Wit laboratories to understand at a more cellular/subcellular level the electrical abnormalities defined in myocytes that have survived in the epicardial border zone of the infarcted heart 5 days, 14 days and 2 months post coronary artery occlusion. These abnormalities contribute to the occurrence of serious life threatening ventricular arrhythmias post myocardial infarction. Our specific aims are as follows: 1) to determine the function of specific ionic currents in cells dispersed from the select regions of mapped reentrant circuits of the epicardial border zone of the 5 day infarcted heart and then by using these experimental data develop 1D and 2D computer models of the EBZ, 2) to determine the function of specific ionic currents (INa, ICaL and IK) of cells dispersed from select regions of the border zone of the 14 day and 2month infarcted heart, and 3) to determine the function and pharmacology of delayed rectifier K+ currents in border zone cells in particular to identify the electrical sequelae of observed cell surface redistribution pattern of Kvl.5 channel proteins. Studies will be completed using insitu mapping, whole cell voltage clamp techniques using single cells dispersed from the reentrant circuits of the epicardial border zone of hearts post coronary artery occlusion and computer simulation techniques. Our results will provide a more 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 this time. In so doing they will help to identify new molecular targets for treatment of reentrant ventricular arrhythmias in this remodeled substrate.