Mechanoelectrical Interactions Between Cardiac Myofibroblasts and Myocytes

心脏肌成纤维细胞和肌细胞之间的机电相互作用

• 批准号: 9204715
• 负责人: LESLIE TUNG
• 金额: $ 50.84万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-11 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9204715
• 关键词: Action Potentials; Acute; Adherens Junction; Affect; Arrhythmia; Biophysics; Cadherins; Cardiac; Cardiac Electrophysiologic Techniques; Cardiac Myocytes; Cells; Cellular biology; Cicatrix; Communication; Complement; Connexins; Coupling; Cultured Cells; Electrophysiology (science); Engineering; Engraftment; Etiology; Experimental Models; Feedback; Fibroblasts; Fibrosis; Gap Junctions; Generations; Health; Heart; Heart Diseases; Heterogeneity; Impairment; Incidence; Individual; Infarction; Intercellular Junctions; Intervention; Ion Channel; Joints; Magnetism; Mechanics; Mediating; Membrane; Microfabrication; Modeling; Muscle Cells; Myocardial Infarction; Myocardium; Myofibroblast; Nanotechnology; Nature; Optics; Outcome; Paracrine Communication; Pattern; Play; Preparation; Process; Proteins; Publishing; Research; Research Personnel; Role; Secondary to; Signal Transduction; Slice; Stretching; Techniques; Testing; Time; Tissues; United States; Vinculin; Work; adherent junction; alpha catenin; base; cell growth; cell type; experimental study; immunocytochemistry; insight; intercellular communication; knock-down; mechanotransduction; migration; monolayer; novel; public health relevance

 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.

 描述（由申请人提供）：心肌梗塞后心脏的重塑涉及疤痕组织的形成，其中肌成纤维细胞（成纤维细胞的活化和分化形式）发挥着积极且重要的作用。该项目重点研究肌成纤维细胞和肌细胞之间细胞水平相互作用的性质，这种相互作用可能导致心律失常基质。直到最近，心脏肌成纤维细胞还被认为是电惰性的，充当肌细胞之间的被动绝缘体。然而，一个正在获得广泛接受的概念是，肌成纤维细胞可以与心肌细胞电耦合，从而提供可以介导心肌传导速度的电负载。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非常接近，这表明通过其他信号机制进行异细胞通讯是可能的。根据研究人员广泛发表的初步结果，该项目将检验以下假设：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。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拉力，导致任一细胞中机械敏感离子通道的激活，从而降低肌细胞的兴奋性，减慢传导并增加 心律失常的发生率。该项目将先进的生物物理和电生理学技术与从单细胞到组织切片的多状态实验准备相结合。这将是三位具有心脏病专业知识的研究人员的共同努力 电生理学、光学测绘、图案化细胞生长、磁性、微加工、细胞力学、机械转导、细胞生物学和细胞间信号传导。该项目具有三个互补且相互关联的目标。目标 1 研究肌成纤维细胞收缩的激活及其对异细胞耦合、肌细胞兴奋性、收缩和传导以及组织尺度电生理学的影响。相反，目标 2 检查肌细胞收缩影响异细胞耦合、肌成纤维细胞力产生和组织规模电生理学的相互过程。目标 3 更详细地研究组织环境中异细胞粘附和间隙连接的形成、稳定性和数量。该项目的成果将是获取关键信息，以制定肌成纤维细胞和肌细胞之间机电信号传导的概念模型。