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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.