Chemo-mechanical signaling in atrial myocytes

心房肌细胞中的化学机械信号传导

基本信息

批准号：
10064006
负责人：
William Jonathan Lederer
金额：
$ 66.17万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-15 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10064006
关键词：
Acute Affect Atrial Fibrillation Blood Blood flow Cardiac Output Cell physiology Cells Cellular biology Complex Conceptions Coupling Cytosol Dependence Development Disease Electrophysiology (science)Elements Foundations Frequencies Functional disorder Generations Genetic Health Heart Atrium Hydrogen Peroxide Image In Vitro Innovative Therapy Investigation Kinetics Length Link Maintenance Measures Mechanics Microscopy Microtubule Alteration Microtubules Molecular Mus Muscle Cells NADPH Oxidase Names Oxides Pathway interactions Pharmacology Phosphotransferases Physiological Physiology Play Process Production Reactive Oxygen Species Resolution Role RyR2 Shapes Signal Pathway Signal Transduction Signaling Protein Site Skeletal Muscle Stretching Structure Surface System Testing Transgenic Mice Translating Ventricular Work Workload alpha Tubulin bone calmodulin-dependent protein kinase II density effective therapy experimental study imaging modality in vivo inhibitor/antagonist innovation mechanotransduction mouse model new therapeutic target novel novel therapeutics spatiotemporal tool

项目摘要

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.

心肌细胞生物学将在体外的孤立单细胞和小鼠中检查到体内定量化学机械信号在健康和疾病中的作用。这个信号心肌形状的变化会激活途径，就像心房充满血液和心肌细胞时发生的那样伸展，在舒张期填充期间。使用极高的时间和空间分辨率成像PI将检查化学机械信号如何促进Ca2+的亚细胞变化，激发收缩耦合以影响电气和Ca2+不稳定性。初步结果表明，新近识别的大型心房心肌细胞（由PI发现）中的轴向小管以及Ca2+释放的“超级荷线” 在心肌细胞中发现的独特Ca2+信号系统。此外，机械X-ROS通路由PI在心室肌细胞中发现的可能在心肌细胞中起着特殊的作用。这信号通路将通过微管传播的细胞拉伸力学连接到生成局部亚细胞活性氧（ROS）可能靶向多个CA2+信号蛋白，例如 Camkii和Ryr2。初步结果表明，这种X-ROS信号在心肌细胞中非常活跃，可能与PIS所描述的新结构有关。拟议的工作将定量确定特殊结构，X-ROS信号传导和化学机械信号传导对正常的贡献房屋心肌细胞的生理学以及对房颤发展的贡献（AF）。两个非常 AF的不同小鼠模型将与特定的转基因小鼠一起定量表征心肌细胞中的Ca2+信号传导和细胞电生理学信号传导有助于细胞生理和病理生理学。这项调查将为批判性提供关于房屋肌细胞如何工作和健康和疾病失败的重要新信息。可能是新的拟议工作产生的发现将扩大我们对房细胞生物学的理解，并放置用于心房功能障碍和AF的创新，有效和新颖疗法的基础。