Calcium Waves in Atrial Cells

描述(由申请人提供)： 这项培训补助金旨在为首席调查员(Pl) 具备必要的教学培训和实验室经验，以成为 独立的生物医学研究员。皮奥？S近期的职业生涯目标是 掌握使用超级计算机的知识和实验技能 电生理学和显微镜是发展定量的必要的 对心房兴奋-收缩(E-C)偶联的理解。长期留任的普莱斯？S 职业目标是领导一支多学科的生理学家团队， 数学家、医生和计算机程序员在开发一种 对正常和病理性E-C偶联的定量认识 心房细胞。哺乳动物的心室细胞有一个广泛的横形(T)管 从细胞快速传导动作电位的系统 从表面到内部触发几乎同步的钙(Ca)释放 来自肌浆网(SR)和肌原纤维的激活 牢房。心房细胞缺乏广泛的T管系统。案例说明 从远离细胞表面的SR释放是否被触发尚不清楚。这个 总体假设是，在心房细胞中，钙离子在一次动作中进入 电位触发细胞表面SR的再生性钙释放 这种再生的钙释放(“钙波”)以波的形式径向传播到 单元格中心。具体目标是：(1)通过以下方式检验这一假设 心房单细胞收缩速度和收缩幅度与心动过速的相关性 利用视频率进行二维共焦的S波速和波幅 显微镜和荧光钙指示剂。(2)建立数学模型 心房细胞钙调控系统及模型的数值求解 超级计算机。(3)通过与S预测模型的比较，对模型进行了评价。 电压钳心房细胞钙波的实验测量 使用共聚焦显微镜。心房钙调控的定量模型 系统是理解正常的E-C耦合和起源所必需的 病理性自发性钙波，最近的数据表明它可以触发 房性心律失常。

DESCRIPTION (provided by applicant): This training grant is designed to provide the principal investigator (Pl) with the necessary didactic training and laboratory experience to become an independent biomedical researcher. The PI?s immediate career goals are to acquire the knowledge in using supercomputers and the experimental skills of electrophysiology and microscopy necessary to develop a quantitative understanding of atrial excitation-contraction (E-C) coupling. The Pl?s long-term career goal is to lead a multidisciplinary team of physiologists, mathematicians, physicians, and computer programmers in developing a quantitative understanding of both normal and pathological E-C coupling in atrial cells. Mammalian ventricular cells have an extensive transverse(t)-tubular system that rapidly conducts the action potential from the cell surface to the interior triggering a near synchronous calcium (Ca) release from the sarcoplasmic reticulum (SR) and activation of myofibrils throughout the cell. Atrial cells lack an extensive t-tubular system. How Ca release from the SR far from the cell surface is triggered is unclear. The overall hypothesis is that in atrial cells, Ca entry during an action potential triggers regenerative Ca release from the SR at the cell surface and this regenerative Ca release ("Ca wave") propagates as a wave radially to the center of the cell. The Specific Aims are: (1) Test this hypothesis by correlating atrial single-cell contraction rate and magnitude with the Ca wave?s velocity and amplitude using video rate 2-dimensional confocal microscopy and fluorescent Ca indicators. (2) Develop a mathematical model of the atrial cell Ca control system and solve the model numerically using supercomputers. (3) Evaluate the model by comparing the model?s predictions with experimental measurements of Ca waves in voltage-clamped atrial cells using confocal microscopy. A quantitative model of the atrial Ca control system is necessary for understanding both normal E-C coupling and the origins of pathological spontaneous Ca waves, which recent data suggest can trigger atrial arrhythmias.