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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：心肌梗塞后心脏的重塑涉及疤痕组织的形成，其中肌纤维细胞是成纤维细胞的激活和分化形式的成纤维细胞，起着积极和主要作用。该项目着重于肌纤维细胞和心肌细胞之间的细胞水平相互作用的性质，这些相互作用可以导致心律不齐的底物。直到最近，据信心脏肌纤维细胞是电惰性的，在肌细胞之间充当被动绝缘子。但是，获得广泛接受的概念是，肌成纤维细胞可以电到肌细胞，从而提供了可以介导心肌中传导速度的电荷。然而，这种功能电气耦合的存在仍然存在争议。通常观察到的肌纤维细胞和心肌细胞膜的紧密近端表明，通过其他信号传导机制进行杂细胞通信。基于研究人员获得的广泛发表和初步结果，该项目将检验以下假设：肌纤维细胞和心肌细胞之间的机械和电气相互作用是导致进行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成纤维细胞和心肌细胞之间施加的双向拉伸力引起的，这些力会导致任何一个细胞中机械敏感的离子通道激活，从心律不齐的事件。该项目将将高级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制剂。这将是三名具有心脏专家的调查员的共同努力电生理学，光学图，图案化细胞生长，磁性，微结合，细胞力学，机械转导，细胞生物学和细胞 - 细胞信号传导。该项目具有三个完整且相互联系的目标。 AIM 1研究了肌纤维细胞收缩的激活及其对杂细胞耦合，对心肌细胞兴奋，收缩和传导以及组织尺度电生理学的影响。相反，AIM 2考试肌细胞收缩影响杂细胞耦合，肌纤维细胞力产生和组织尺度电生理学的相互过程。 AIM 3更详细地研究在组织环境中的形成，稳定和杂细胞附着物的数量和间隙连接。该项目的结果将是获取关键信息，以制定肌纤维细胞和心肌细胞之间机电信号的概念模型。