Mechanoelectrical Interactions Between Cardiac Myofibroblasts and Myocytes

 描述（由申请人提供）：心肌梗死后的心脏重塑涉及瘢痕组织的形成，其中肌成纤维细胞（成纤维细胞的活化和分化形式）发挥积极和主要的作用。该项目的重点是肌成纤维细胞和肌细胞之间的细胞水平的相互作用的性质，可以有助于促炎底物。直到最近，心脏肌成纤维细胞被认为是电惰性的，充当肌细胞之间的被动绝缘体。然而，一个得到广泛接受的概念是肌成纤维细胞可以电耦合到肌细胞，从而提供可以介导心肌中的传导速度的电负载。然而，这种功能性电耦合的存在仍然存在争议。通常观察到的肌成纤维细胞和肌细胞膜的紧密接近表明，通过其他信号传导机制的异细胞通信是可能的。基于研究者获得的大量已发表和初步结果，该项目将测试肌成纤维细胞和肌细胞之间的机械和电相互作用是导致传导减慢和心律失常的重要机制的假设。中心假设是，这些相互作用源于肌成纤维细胞和肌细胞之间施加的双向牵引力，其导致任一细胞中的机械敏感性离子通道的激活，其降低肌细胞的兴奋性，减缓传导并增加肌细胞的收缩。 心律失常的发生率。该项目将结合先进的生物物理和电生理技术与从单细胞到组织切片的多状态实验制备。这将是三名具有心脏病学专业知识的研究者的共同努力 电生理学、光学映射、模式化细胞生长、磁性、微加工、细胞力学、机械转导、细胞生物学和细胞-细胞信号传导。该项目有三个相互补充和相互关联的目标。目的1研究肌成纤维细胞收缩的激活及其对异源细胞偶联、肌细胞兴奋性、收缩和传导以及组织电生理的影响。相反，目的2检查肌细胞收缩影响异细胞偶联、肌成纤维细胞力产生和组织尺度电生理学的相互过程。目的3更详细地研究了在组织环境中异质细胞粘附和缝隙连接的形成、稳定和数量。该项目的成果将是获得关键信息，以制定肌成纤维细胞和肌细胞之间的机电信号的概念模型。

 DESCRIPTION (provided by applicant): Remodeling of the heart following myocardial infarction involves the formation of scar tissue, in which myofibroblasts, an activated and differentiated form of fibroblasts, play an active and major role. This project focuses on the nature of cellular-level interactions between myofibroblasts and myocytes that can contribute to an arrhythmogenic substrate. Until recently, cardiac myofibroblasts were believed to be electrically inert, acting as passive insulators between myocytes. However, a concept that is gaining wide acceptance is that myofibroblasts can couple electrically to myocytes, thereby providing an electrical load that can mediate conduction velocity in the myocardium. Nevertheless, the existence of such functional electrical coupling remains controversial. The commonly observed close proximity of myofibroblast and myocyte membranes suggests that heterocellular communication through other signaling mechanisms is possible. Based on extensive published and preliminary results obtained by the Investigators, this project will test the hypothesis that combined mechanical and electrical interactions between myofibroblasts and myocytes is an important mechanism that leads to conduction slowing and arrhythmia. The central postulate is that these interactions arise from bidirectional tugging forces exerted between myofibroblast and myocyte that result in the activation of mechanosensitive ion channels in either cell that diminish the excitability of the myocyte, slow conduction and increase the incidence of arrhythmia. This project will couple advanced biophysical and electrophysiological techniques with multistate experimental preparations ranging from single cell to tissue slice. It will be a joint effort among three Investigators with expertise in cardiac electrophysiology, optical mapping, patterned cell growth, magnetism, microfabrication, cell mechanics, mechanotransduction, cell biology and cell-cell signaling. The project has three complementary and interconnected Aims. Aim 1 investigates the activation of myofibroblast contraction and its influence on heterocellular coupling, on myocyte excitability, contraction and conduction, and on tissue-scale electrophysiology. Conversely, Aim 2 examines the reciprocal process in which myocyte contraction influences heterocellular coupling, myofibroblast force generation, and tissue-scale electrophysiology. Aim 3 studies in greater detail the formation, stabilization and numbers of heterocellular adherents and gap junctions in a tissue context. The outcome of this project will be the acquisition of key information to formulate conceptual models of electromechanical signaling between myofibroblasts and myocytes.