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

描述（由申请人提供）：电细胞活性和细胞内钙（Ca 2+）动力学之间的紧密耦合是心肌细胞功能调节的基础。参与这些偶联过程的蛋白质和途径的各种改变现在被认为是各种常见病理学中心功能障碍的主要机制，包括1，4，5-三磷酸（IP 3）介导的心律失常和肥大。随着这些复杂过程及其相互作用的生物化学和生物物理学实验细节的积累，对新发现的直观解释变得越来越不切实际。本研究的目的是开发一种新的计算工具来模拟兔心室肌细胞中的Ca 2+和IP 3信号。该新工具将用于检验生理和某些病理条件（心律失常、肥大）下兴奋-收缩和兴奋-转录偶联的假设。具体目标是：（1）测试在对照条件下细胞质Ca 2+如何调节细胞核Ca 2 +;（2）测试在正常兴奋-收缩偶联期间如何发生局部IP 3介导的细胞核Ca 2+增加;（3）测试用IP 3延长刺激如何调节兔细胞内Ca 2+动力学。该项目产生的新计算工具和数据将以高度便携、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地亚哥分校的国家生物医学计算资源（www.nbcr.net/）维护。

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/).