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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：
10323655
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 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10323655
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 innovation mechanical signal 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.

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方式。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。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cardiac Alternans Occurs through the Synergy of Voltage- and Calcium-Dependent Mechanisms.

心脏替代品通过电压和钙依赖性机制的协同作用。

DOI：
10.3390/membranes11100794
发表时间：
2021-10-18
期刊：
Membranes
影响因子：
4.2
作者：
Hoang-Trong MT;Ullah A;Lederer WJ;Jafri MS
通讯作者：
Jafri MS

A Stochastic Spatiotemporal Model of Rat Ventricular Myocyte Calcium Dynamics Demonstrated Necessary Features for Calcium Wave Propagation.

大鼠心室心肌钙动力学的随机时空模型证明了钙波传播的必要特征。

DOI：
10.3390/membranes11120989
发表时间：
2021-12-18
期刊：
Membranes
影响因子：
4.2
作者：
Hoang-Trong TM;Ullah A;Lederer WJ;Jafri MS
通讯作者：
Jafri MS

Parkin-independent mitophagy via Drp1-mediated outer membrane severing and inner membrane ubiquitination.

DOI：
10.1083/jcb.202006043
发表时间：
2021-06-07
期刊：
The Journal of cell biology
影响因子：
0
作者：
Oshima Y;Cartier E;Boyman L;Verhoeven N;Polster BM;Huang W;Kane M;Lederer WJ;Karbowski M
通讯作者：
Karbowski M

X-ROS Signaling Depends on Length-Dependent Calcium Buffering by Troponin.