CELLULAR MECHANISMS OF DELAYED AFTERDEPOLARIZATIONS

这项提议的目的是阐明特定的膜电流。 以及产生延迟的细胞内离子波动 后去极化(爸爸)。延迟后除极是暂时的 完成后发生的细胞膜电位的去极化 从先前的脉冲中恢复极化。父亲们因此维持着 被认为对某些类型负责的触发的节律性活动 临床观察到的心律失常。爸爸们已经在一场 多种细胞类型，包括患病的人心房和心室 在体外和各种条件下研究的纤维会导致 细胞内钙异常波动([Ca~(2+)]i)。然而， [Ca~(2+)]i异常波动与瞬变的精确关系 被认为产生DAD的内向膜电流(ITI)尚不清楚。 将创新的钙离子成像技术与成熟的全细胞相结合 电压钳位方法，提出了一种全面的研究测试方法 将这些联系起来的假说与调节中的紊乱有关 [Ca~(2+)]i波动在空间上和时间上都是非均匀的 非同步，b)[Ca+]i波动激活局部膜电流，c) [Ca~(2+)]_i波动及其局域的时间同步性 动作电位产生的电流会产生ITI。使用细胞对， 研究计划还将澄清自发的条件 [Ca2+]i；波动和局部炎症在细胞间传递 产生DAD的同步电流激活。这个项目将 提供有关[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 电耦合电池的定量方法巴黎，本项目将 还提供有关离子事件和当前事件的直接信息 在分离的细胞中观察到的是细胞间的影响和修改 通过缝隙连接进行沟通。这一方法将架起 分离细胞研究和全组织模型之间的差距将 也允许测试脉冲传输的数学公式 在细胞之间和通过组织。

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.