Modeling Cytosolic and Nuclear Ca2+ and IP3 Signaling in Ventricular Myocytes

描述(由申请人提供)：心肌细胞功能的调节是细胞内钙(Ca~(2+))动态和电信号活动之间的紧密耦合。参与这些偶联过程的蛋白质和通路的各种变化现在被认为是包括1，4，5-三磷酸盐(IP3)介导的心律失常和肥大在内的一系列常见病理中心脏功能障碍的主要机制。随着关于这些复杂过程的生物化学和生物物理及其相互作用的更多实验细节的积累，对新发现的直观解释变得越来越不切实际。这项研究的目的是开发新的计算工具来模拟兔心室肌细胞中的钙和IP3信号。这一新工具将用于在生理和某些病理条件(心律失常、肥大)下测试有关兴奋-收缩和兴奋-转录耦合的假说。具体目的是：(1)测试控制条件下胞浆钙离子如何调节细胞核钙离子；(2)测试在正常兴奋-收缩偶联过程中，如何发生IP3介导的核内钙离子局部增加；(3)测试IP3长时间刺激如何调节兔细胞内钙离子动力学。该项目产生的新计算工具和数据将以高度可移植、模块化和易于使用的软件和数据格式实施，这些软件和数据格式将由加州大学圣迭戈分校的国家生物医学计算资源维护(：//www.nbcr.net/)。

DESCRIPTION (provided by applicant): A tight coupling between the electrical cell activity and intracellular calcium (Ca2+) dynamic underlies the regulation of cardiac muscle cell function. Various alterations in the proteins and pathways involved in these coupled processes are now recognized to be the primary mechanisms of cardiac dysfunction in a diverse range of common pathologies including 1,4,5- trisphosphae(IP3)-mediated arrhythmias and hypertrophy. As more experimental detail on the biochemistry and biophysics of these complex processes and their interactions accumulates, the intuitive interpretation of the new findings becomes increasingly impractical. The goal of the proposed research is to develop new computational tool for modeling Ca2+ and IP3 signaling in rabbit ventricular myocytes. The new tool will be used to test hypotheses regarding excitation- contraction and excitation-transcription coupling under physiological and certain pathological conditions (arrhythmias, hypertrophy). The specific aims are: (1) Test how the cytoplasmic Ca2+ regulates nuclear Ca2+ under control conditions; (2) Test how localized IP3-mediated increases in nuclear Ca2+ can occur during normal excitation-contraction coupling; (3) Test how prolonged stimulation with IP3 modulates the intracellular Ca2+ dynamics in rabbits. The new computational tool and data resulting from this project will be implemented in highly portable, modular and readily used software and data formats that will be maintained by the National Biomedical Computational Resource at UCSD (://www.nbcr.net/).