Stochastic Simulation Of Excitation-contraction Coupling

工作概述我们已经开始对所谓的自发钙释放事件给予更多的关注，这些事件在形态上从单个火花到局部小波再到全球钙波。这些事件已被证明在控制起搏细胞的频率以及在病理条件下触发心律失常方面发挥着关键的时钟作用。一个简化的窦房结细胞膜下空间CICR的二维模型表明，存在一个健壮的局部子波产生、随机移动和消亡的机制，这与我们在实验中观察到的非共焦2D增强成像的结果相似。这些事件的周期性从随机火花到周期波不等，随着事件规模和频率的增加，周期性逐渐增加。这种可变的周期性可以用“随机过滤”理论定性地解释，在“随机过滤”理论中，真正随机的事件启动与释放单元的固定不应期的相互作用导致了一个随机过程，其中事件间周期聚集在不应时间附近。 为了定量地研究这一过程，我们需要将以前的随机EC耦合模型扩展到三维和细胞尺度。这将需要(除了正在进行的广泛的软件再开发之外)创建一个全面的最先进的计算集群。该集群的架构规划正在进行中。

SUMMARY OF WORK We have begun devoting more attention to so-called spontaneous calcium release events, which vary morphologically from single sparks to localized wavelets to global calcium waves. These events have been shown to play a critical "clock" role in controlling rate in pacemaker cells, as well as triggering arhythmias under pathological condition. A simplified two dimensional model of CICR in the sub-membrane space of sino-atrial node cells demonstrated that there is a robust regime of localized wavelets that are created, move randomly and die out, similar to what we have observed using non-confocal 2D intensified imaging experimentally. These events vary in periodicity from random sparks to periodic waves, with gradually increasing periodicity as event size and frequency increase. This variable periodicity is qualitatively accounted for by a theory of "stochastic filtering" in which the interaction of truly random event initiation with the fixed refractory period of release units leads to a random process with inter-event periods clustered near the refractory time. In order to study this process quantitatively, we will need to extend our previous stochastic EC coupling model to 3 dimensions and cell scale. This will require (in addition to extensive redevelopment the software, which is underway) the creation of a full-scale state-of-the-art computational cluster. Planning for the architecture of this cluster is underway.