CELLULAR MECHANISMS OF DELAYED AFTERDEPOLARIZATIONS

这个提议的目的是阐明特定的膜电流 和细胞内离子波动， 后去极化（DAD）。 延迟后去极化是短暂的 完成后发生的细胞膜电位的去极化 由前一个脉冲引起的复极 故，以其所持之道， 触发的有节奏的活动，被认为是负责某些类型的 临床观察到的心律失常。 DAD已经在一个 多种细胞类型，包括患病的人类心房和心室 在体外和各种条件下研究的纤维， 异常的细胞内钙波动（[Ca 2 +]i）。 但 [Ca 2 +]i异常波动与瞬态之间的精确关系 被认为产生DAD的内向膜电流（ITi）是未知的。 将创新的Ca 2+成像技术与成熟的全细胞技术相结合 电压钳位方法，提出了一个全面的研究测试 这一假说认为，这些ITis的调节障碍， [Ca2+]i波动在空间上是非均匀的， 异步，B）[Ca 2 +]i波动激活局部膜电流，c） [Ca ~（2+）]_i涨落及其局部涨落的时间同步性 电流通过动作电位产生ITi。 使用单元对， 研究计划还将澄清自发性的条件， [Ca2+]i;波动和局部ITi在小区之间传输， 产生DAD的同步电流激活。 该项目将 提供了[Ca 2 +]i波动的基本定量数据， 了解表面膜电流。 通过应用这些 定量方法电耦合细胞巴黎，该项目将 也提供了关于离子和电流事件 在分离的细胞中观察到的细胞间的影响和修改 通过缝隙连接介导的通讯。 这种方法将桥接 分离细胞研究和全组织模型之间的差距， 还允许测试脉冲传输的数学公式 细胞之间和组织之间。

The goal of this proposal is to elucidate the specific membrane currents and intracellular ionic fluctuations which produce delayed afterdepolarizations (DADs). Delayed afterdepolarizations are transient depolarizations of the cell membrane potential which occur after completion of repolarization from a preceding impulse. DADs thereby sustaining the triggered rhythmic activity that is believed responsible for certain types of clinically observed arrhythmias. DADs have been demonstrated in a variety of cell types including diseased human atrial and ventricular fibers studied in vitro and under a variety of conditions that cause abnormal intracellular calcium fluctuations ([Ca2+]i). However, the precise relation between abnormal [Ca2+]i fluctuations and the transient inward membrane currents (ITi) thought to generate DADs is not known. Combining innovative Ca2+ imaging techniques with established whole-cell voltage clamp methods, the proposed research tests a comprehensive hypothesis that relates these ITis to disorders in the regulation of [Ca2+]i fluctuations are spatially non-homogeneous and temporally asynchronous, b) [Ca2+]i fluctuations activate local membrane currents, c) the temporal synchronization of both [Ca2+]i fluctuations and their local currents by an action potential generates a ITi. Using cell pairs, the research plan would also clarify the conditions under which spontaneous [Ca2+]i; fluctuations and local ITis are transmitted between cells to produce the synchronized current activation of a DAD. This project will provide the fundamental quantitative data on [Ca2+]i fluctuations for the understanding of surface membrane currents. By the application of these quantitative methods to electrically coupled cell paris, this project will also provide direct information on how the ionic and current events observed in isolated cells are influenced and modified by intercellular communication mediated through gap junctions. This approach would bridge the gap between isolated cell studies and whole tissue models and would also allow the testing of mathematical formulations of impulse transfer between cells and through tissues.