Stochastic Simulation Of Excitation-contraction Coupling

在前一个项目期间的工作总结中，我们采用我们的算法来模拟心脏兴奋-收缩耦合的随机局部控制，以便在通过消息传递接口(MPI)连接的计算机集群上并行运行。利用增加的计算能力，我们对缓冲液对心肌和骨骼肌钙诱导钙释放的影响进行了模拟，帮助解释了有争议的实验结果，这些研究试图利用细胞内高浓度的BAPTA证明(或反驳)局部钙诱导骨骼肌钙释放的作用。我们还使用这个系统开始模拟钙火花的动力学，以便解释我们小组最近的实验结果，这些实验结果表明火花可以分解成更小的“量子”单位。模拟表明，火花持续时间与参与兰尼定受体的数量成反比的意外事实，实际上可以用强烈的钙诱导兰尼定受体失活的CICR过程来解释。未来的工作将结合实验结果完善这一模型，并为解释L类型的通道动力学在决定EC偶联效率中的作用提供一个框架。我们还开始研究在起搏细胞和从胚胎干细胞分化的原始心肌细胞中钙诱导钙释放的模型。这些模拟将有助于理解实验结果，这些实验结果表明，CICR在这些组织的搏动频率调节中发挥着关键作用。为了研究这一现象，我们的CICR模型将与起搏细胞动作电位的细胞电生理学的微分方程式模型相结合。

SUMMARY OF WORK During the previous project period we adapted our algorithm to simulate stochastic local control of cardiac excitation-contraction coupling to run in parallel on clusters of computers linked by the message-passing interfact (MPI). Using the added computational power, we carried out simulations of the effects of buffers on calcium induced calcium release in both cardiac and skeletal muscle, assisting in the interpretation of controversial experimental results of studies that have tried to prove (or disprove) the role of local calcium-induced calcium release in skeletal muscle using high concentrations of intracellular BAPTA. We have also used this system to begin simulating the dynamics of calcium sparks, in order to interpret recent experimental results from our group that showed that sparks can be decomposed into smaller "quantal" units. The simulations showed that the unexpected fact that spark duration is inversely correlated with number of participating ryanodine receptors could, in fact, be explained by a CICR process with strong calcium-induced inactivation of ryanodine receptors. Future work will refine this model in correlation with experimental results, and provide a framework for interpreting studies on the role of L-type channel kinetics in determining EC coupling efficiency. We have also begun studies to model calcium-induced calcium release in pacemaker cells and primitive myocytes differentiated from embryonic stem cells. These simulations will help to understand the experimental results that show that CICR plays a critical role in the regulation of beating rate in these tissues. In order to study this phenomenon, our CICR model will be combined with differential-equation models of the cellular electrophysiology of the action potential in pacemaking cells.