Chemo-mechanical signaling in atrial myocytes

将在体外分离的单细胞和小鼠体内检查心房肌细胞的细胞生物学， 定量表征化学机械信号在健康和疾病中的作用。该信令 当心房充满血液和肌细胞时， 舒张期充盈时的拉伸。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有助于Ca 2+，兴奋收缩的亚细胞变化 耦合以影响电和Ca 2+不稳定性。初步结果表明，新发现的大型 心房肌细胞中的轴向小管（由PI发现）沿着与Ca 2+释放“超级枢纽”一起在一个 在心房肌细胞中发现的独特Ca 2+信号系统。此外，机械化学X-ROS途径 PI在心室肌细胞中发现的一种蛋白质可能在心房肌细胞中起特殊作用。这 信号通路将通过微管传递的细胞拉伸机制与 局部亚细胞活性氧（ROS）可能靶向多种Ca 2+信号蛋白， CaMKII和RyR 2。初步结果表明，这种X-ROS信号在心房肌细胞中非常活跃， 与PI所描述的新结构相关联。拟议的工作将从数量上确定 特殊结构、X-ROS信号和化学机械信号对正常细胞的作用 心房肌细胞的生理学和对心房颤动（AF）发展的贡献。两个非常 不同的AF小鼠模型将与特定的转基因小鼠一起沿着用于定量表征 心房肌细胞中的Ca 2+信号传导和细胞电生理学，并确定化学机械 信号传导有助于细胞生理学和病理生理学。这项调查将提供关键的 关于心房肌细胞在健康和疾病中如何工作和失败的重要新信息。可能的新 这项工作的发现将拓宽我们对心房细胞生物学的理解， 为心房功能障碍和房颤的创新、有效和新型疗法奠定基础。

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.