ION CHANNEL FUNCTION IN MYOCARDIAL CELLS FROM INFARCTS

说明(摘自申请者的申请)这一更新项目的长期目标是在更多的细胞/亚细胞水平上了解心肌细胞/亚细胞水平上的电异常，即在冠状动脉闭塞后5天、14天和2个月内存活在梗死心脏心外膜交界区的肌细胞中所定义的电异常。这些异常导致心肌梗死后危及生命的室性心律失常的发生。其具体目的如下：1)确定从中心共同通路分散的细胞中特定离子电流相对于定位折返者的外周组织的功能，2)确定从14天和2个月梗死心脏的心外膜交界区分散的细胞的特定离子电流的功能，3)确定在单个通道水平上心脏钠通道的哪些变化是在观察到的5天边缘区细胞钠电流幅度降低和动力学改变的基础上，4)确定酪氨酸激酶功能改变在5天交界区细胞钙电流和钾电流变化中的作用及其药理作用；5)确定交界区细胞延迟整流钾电流的功能和药理学，特别是鉴定Kvl1.5通道蛋白。研究将利用冠状动脉闭塞后心脏的全细胞和细胞边界区来完成。这些研究的结果将提供一个更详细的了解在愈合和愈合的心肌梗死后存活的细胞中电重构的离子基础，这样做将有助于确定在这些时间段发生的折返性室性心律失常的治疗新的分子靶点。

Description (Adapted from Applicant's Application) The long-term objective of this renewal project is to understand, at a more cellular/subcellular level, the electrical abnormalities defined in myocytes 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 life threatening ventricular arrhythmias post myocardial infarction. The specific aims are as follows: 1) to determine the function of specific ionic currents in cells dispersed from the central common pathway versus the peripheral tissues of mapped reentrant the central common pathway versus the peripheral tissues of mapped reentrant circuits of the epicardial border zone of the 5 day infarcted heart, 2) to determine the function of specific ion currents of cells dispersed from the border zone of the 14 day and 2 month infarcted heart, 3) to determine what changes in the cardiac sodium channel at the level of the single channel underlie the observed reduced amplitude and altered kinetics of the Na current in 5 day border zone cells, 4) to determine the role of altered tyrosine kinase function in altered Ca2+ and K+ currents and their pharmacology in 5 day border zone cells, and 5) to determine the function and pharmacology of delayed rectified K+ currents in border zone cells in particular to identify Kvl1.5 channel proteins. Studies will be completed using whole cell and cell border zone of hearts post coronary artery occlusion. The results of these studies will provide a more detailed understanding of the ionic basis of electrical remodeling in cells surviving in the healing and healed hearts post infarction and in so doing will help identify new molecular targets for treatment of reentrant ventricular arrhythmias that occur during these times.