Mechanoelectrical Interactions Between Cardiac Myofibroblasts and Myocytes

 描述(申请人提供)：心肌梗死后心脏重塑涉及疤痕组织的形成，其中肌成纤维细胞，一种激活的和分化的成纤维细胞，扮演着积极和主要的角色。这个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，这可能有助于导致心律失常的底物。直到最近，心肌成纤维细胞被认为是电惰性的，在肌细胞之间扮演被动绝缘体的角色。然而，一个正在被广泛接受的概念是，肌成纤维细胞可以与心肌细胞电耦合，从而提供能够调节心肌传导速度的电负荷。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联系表明，通过其他信号机制进行异质细胞通讯是可能的。基于研究人员广泛发表的和初步的结果，该项目将检验这一假说，即肌成纤维细胞和肌细胞之间的机械和电气相互作用是导致传导减慢和心律失常的重要机制。中心假设是，这些相互作用是由肌纤维细胞和肌细胞之间施加的双向牵引力引起的，这种双向牵引力导致两个细胞中机械敏感离子通道的激活，从而降低了心肌细胞的兴奋性，减缓了传导，增加了传导。 心律失常的发生率。该项目将把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态实验准备相结合。这将是三名具有心脏病专业知识的研究人员共同努力的结果。 电生理学、光学测绘、图案化细胞生长、磁性、微制造、细胞力学、机械转导、细胞生物学和细胞-细胞信号转导。该项目有三个相辅相成、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细胞偶联、对心肌细胞兴奋性、收缩和传导的影响以及对组织尺度电生理的影响。相反，AIM 2研究了肌细胞收缩影响异细胞偶联、肌成纤维细胞力量产生和组织规模电生理学的相互作用过程。目的3更详细地研究组织中异质细胞黏附分子和缝隙连接的形成、稳定和数量。该项目的结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.