Ion Channel Function in Arrhythmogenic Cardiac Cells

描述(由申请人提供)：这项计划的长期目标 应用程序是将博伊登和威特实验室的专业知识结合起来 在更多的细胞/亚细胞水平上理解电异常 在存活于心外膜交界区的肌细胞中定义 冠状动脉闭塞后5天、14天和2个月时心肌梗死。 这些异常导致了严重生命威胁的发生 心肌梗塞后的室性心律失常。我们的具体目标是 1)确定细胞内特定离子电流的功能 从被映射的可重入电路的选择区域分散 5天梗塞心脏的心外膜边缘区，然后用这些 实验数据开发了EBZ的一维和二维计算机模型，2)确定 分散细胞的比离子电流(Ina、Ic和Ik)的作用 从梗塞的第14天和2月的交界区的选定区域 3)测定延迟整流的功能和药理作用 K+电流在交界区细胞中的识别作用尤其明显 Kv1.5通道细胞表面重分布模式的后遗症 蛋白质。研究将使用原位标测完成，整个单元电压 使用从可重入电路分散的单个电池的钳位技术 冠状动脉闭塞后的心外膜交界区和 计算机模拟技术。我们的结果将提供更详细的 对存活细胞中电重构的离子基础的理解 心肌梗死后愈合与愈合的关系及其机制 在此期间发生的折返性心律失常。通过这样做，他们将有助于 寻找治疗室折返性心动过速的新分子靶点 在这个重塑的底物中出现心律失常。

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.