Chemo-mechanical signaling in atrial myocytes

心房肌细胞生物学将在体外分离单个细胞和在体小鼠进行检测，以 定量描述化学机械信号如何在健康和疾病中发挥作用。这一信号 通路是由心肌细胞形状的变化激活的，当心房充血时就会发生这种情况，而心肌细胞 舒张期充盈时的伸展。使用极高的时间和空间分辨率成像，PI将 研究化学机械信号如何促进钙离子的亚细胞变化，即兴奋收缩 耦合影响电和钙的不稳定性。初步结果表明，新发现的大型 PI发现的心房肌细胞中轴向小管与钙释放的“超级中枢”一起在 在心房肌细胞中发现了独特的钙信号系统。此外，机械化化疗X-ROS途径 PI发现，心室肌细胞可能在心房肌细胞中发挥特殊作用。这 信号通路将细胞伸展的机制通过微管传递到 局部亚细胞活性氧簇(ROS)可能针对多种钙信号蛋白，如 CaMKII和RyR2。初步结果表明，这种X-ROS信号在心房肌细胞中非常活跃，并可能 与PI所描述的新结构相关联。拟议的工作将定量地确定 特殊结构、X-ROS信号和化学机械信号在正常人中的作用 心房肌细胞的生理学及其在房颤发生中的作用。两个非常 不同的房颤小鼠模型将与特定的转基因小鼠一起用于定量表征 心房肌细胞中CA2信号和细胞电生理及化学机械如何 信号对细胞生理学和病理生理学有重要作用。这项调查将提供关键的 关于心房肌细胞如何在健康和疾病中起作用和衰竭的重要新信息。可能的新消息 拟议工作产生的发现将拓宽我们对心房细胞生物学的理解，并为 为治疗心房功能障碍和房颤的创新、有效和新的治疗方法奠定基础。

Atrial myocyte cell biology will be examined in isolated single cells in vitro and mice in vivo to characterize quantitatively how chemo-mechanical signaling works in health and disease. This signaling pathway is activated by changes in myocyte shape as happens when the atria fill with blood, and myocytes stretch, during diastolic filling. Using extremely high temporal and spatial resolution imaging the PIs will examine how chemo-mechanical signaling contributes to subcellular changes in Ca2+, excitation-contraction coupling to influence both electrical and Ca2+ instability. Preliminary results suggest that newly identified large axial tubules in atrial myocytes (discovered by the PIs) along with Ca2+ release "super-hubs" play a role in a unique Ca2+ signaling system found in atrial myocytes. Furthermore, the mechano-chemo X-ROS pathway discovered by the PIs in ventricular myocytes is likely to have a special role to play in atrial myocytes. This signaling pathway links the mechanics of cellular stretch, transmitted through microtubules, to the generation of local subcellular reactive oxygen species (ROS) that likely target multiple Ca2+ signaling proteins such as CaMKII and RyR2. Preliminary results suggest this X-ROS signaling is very active in atrial myocytes and may be linked to the novel structures described by the PIs. The proposed work will identify quantitatively the contributions of the special structures, X-ROS signaling and chemo-mechanical signaling to the normal physiology of atrial myocytes and the contributions to the development of atrial fibrillation (AF). Two very different mouse models of AF will be used along with specific transgenic mice to quantitatively characterize Ca2+ signaling and cellular electrophysiology in atrial myocytes and determine how chemo-mechanical signaling contributes to cellular physiology and pathophysiology. This investigation will provide critically important new information on how atrial myocytes work and fail in health and disease. The likely new discoveries produced by the proposed work will broaden our understanding of atrial cell biology and lay the foundation for innovative, effective and novel therapies for atrial dysfunction and AF.