Stochastic Simulation Of Excitation Contraction Coupling

在前期的工作总结中，我们开发了一种算法来模拟心脏兴奋-收缩耦合的随机局部控制。由于可用计算能力的原因，大多数这些模拟都是使用简化版本的算法来完成的，该算法忽略了钙离子在双子连接缝隙中的扩散动力学，因此也不能考虑局部钙缓冲和钙离子通过通道的双向流动的影响。在本项目期间，算法已被重新编码，以利用MPI(消息传递接口)系统，该系统使得在通过快速以太网连接的多个工作站之间并行分配计算成为可能。这一重大的重新开发使计算速度提高了10倍，这使得使用完整的动态扩散模拟变得可行。动态扩散的研究正在进行中，并已证实局部钙通过裂隙扩散的时间依赖性对兴奋-收缩耦合的宏观行为有重要影响，固定的和可扩散的钙缓冲液，包括内源性ATP，都有主要影响。最重要的是，模拟结果表明，通过L型肌膜钙通道的短尾电流响应的肌浆网钙释放通量具有直接反映钙诱导钙释放(CICR)在Diad？我们之前实际上在实验中观察到了一个签名，但没有意识到它的重要性。模拟预测，这一特征可以通过外源可扩散缓冲区来操纵，这将使一系列实验成为可能，可以直接探测局部再生的CICR，它是心脏EC偶联的核心。

SUMMARY OF WORK During the previous project period we developed an algorithm to simulate stochastic local control of cardiac excitation-contraction coupling. For reasons of available computational power, most of these simulations were done using a simplified version of the algorithm which ignores the dynamics of diffusion of calcium ions in the diadic junctional cleft, and therefore also cannot take into account the effects of local calcium buffers and bi-directional flux of calcium ions through channels. During this project period, the algorithm has been re-coded to make use of the MPI (message passing interface) system which makes it possible to distribute the computations in parallel among multiple workstations linked by fast ethernet. This major redevelopment has resulted in a 10-fold increase in computational speed, which has made it practical to use the full dynamic-diffusion simulation. Studies with dynamic diffusion are underway, and have confirmed that the time-dependence of the spread of local calcium through the cleft has an important effect on the macroscopic behavior of excitation-contraction coupling, and that both fixed and diffusible calcium buffers, including endogenous ATP, have major effects. Most importantly, the simulations showed that SR calcium release fluxe in response to brief tail currents through the L-type sarcolemmal calcium channel carry a signature that directly reflects the dynamics of spread of calcium-induced calcium release (CICR) among the ryanodine receptors in the diad ? a signature which we had actually previously observed experimentally without realizing its significance. Simulations predict that this signature can be manipulated with exogenous diffusible buffers, which will make possible a series of experiments that can directly probe the local regenerative CICR which is at the heart of cardiac EC coupling.