Mechanical Regulation of Cell Adhesion by Dynamic Cytoskeletal Assemblies

动态细胞骨架组件对细胞粘附的机械调节

基本信息

批准号：
10323268
负责人：
Margaret Lise Gardel
金额：
$ 31.74万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-21 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10323268
关键词：
Actins Actomyosin Adherens Junction Adhesions Behavior Biochemical Biological Biophysics Caveolae Cell Adhesion Cell Fate Control Cell Shape Cell-Cell Adhesion Cell-Matrix Junction Cells Cellular biology Clathrin Communication Complex Cytoskeletal Proteins Cytoskeleton Defect Development Diagnosis Disease Dynamin E-Cadherin Embryonic Development Endocytosis Epithelial Extracellular Matrix Feedback Focal Adhesions Generations Homeostasis Intercellular Junctions Kinetics Length Mechanics Mediating Membrane Modeling Modernization Molecular Molecular Target Morphogenesis Morphology Motion Neoplasm Metastasis Physiologic pulse Physiological Processes Process Proteins Regulation Rest Role Shapes Signal Pathway Signal Transduction Structure Testing Tissue Engineering Tissue Model Tissues Work biophysical properties cell behavior cohesion experimental study human disease improved innovation kinematics live cell imaging mathematical model migration optogenetics physical model quantitative imaging response rho rho GTPase-activating protein simulation spatiotemporal theories transmission process wound healing

项目摘要

Project Summary Mechanical Regulation of Cell Adhesion by Dynamic Cytoskeletal Assemblies Epithelial tissue is built by dynamic adhesions, cell-cell junctions, that connect neighboring cells to maintain tissue cohesion and barrier function yet also allow dynamic processes like wound healing and tissue morphogenesis. Contractile forces generated within the actomyosin cytoskeleton are transmitted to cell-cell junctions to control the local cell shape and motions that sculpt tissue morphogenesis and initiate downstream signaling pathways that control cell fate. Understanding how the biophysical properties of cell-cell junctions are regulated has widespread implications for understanding and treating defects during embryonic development, for tissue engineering and the diagnosis and treatment of metastatic tumors. This proposal leverages innovative combination of cell biophysics, molecular cell biology, live cell imaging, mathematical modeling and optogenetics to investigate how RhoA signals regulate contractile forces to drive changes in cell-cell junction length that control cell shape and, ultimately, tissue morphogenesis. We propose experiments to elucidate how force-dependent process regulating actomyosin contractility, membrane remodeling and RhoA signaling feedback to each other to control junction length and length changes. We approach this problem by integrating molecular cell biology approaches with advanced quantitative imaging of cytoskeletal dynamics and biophysical measurements. By obtaining kinetic and kinematic (motion) signatures of proteins at varying levels of tension, we identify mechanisms of force transmission within focal adhesions and the actin cytoskeleton. We then collaborate closely with theoretical physicists to test the predictions of analytical theory and simulations with our quantitative biophysical measurements. This work builds a biophysical understanding of cell adhesion, tension and shape that, ultimately, will provide the framework for theories and models of tissue morphogenesis that will have predictive power in understanding in complex physiological processes. More generally, the strategies developed in this proposal can be applied more generally to understand how force-sensitive feedbacks within the cytoskeletal conspire to facilitate cell morphogenic processes. This will enable the development of improved therapies to treat diseases involved in tissue homeostasis that currently remain elusive by solely treating molecular targets.

项目概要动态细胞骨架组件对细胞粘附的机械调节上皮组织由动态粘附、细胞间连接构成，连接相邻细胞维持组织凝聚力和屏障功能，同时也允许伤口等动态过程愈合和组织形态发生。肌动球蛋白内产生的收缩力细胞骨架被传递到细胞与细胞的连接处以控制局部细胞的形状和运动塑造组织形态发生并启动控制细胞命运的下游信号通路。人们广泛了解细胞与细胞连接的生物物理特性是如何调节的对理解和治疗胚胎发育过程中的缺陷以及组织的影响工程以及转移性肿瘤的诊断和治疗。该提案利用了细胞生物物理学、分子细胞生物学、活细胞成像、数学的创新组合建模和光遗传学研究 RhoA 信号如何调节收缩力以驱动细胞与细胞连接长度的变化控制细胞形状并最终控制组织形态发生。我们提出实验来阐明力依赖性过程如何调节肌动球蛋白收缩性、膜重塑和 RhoA 信号相互反馈以控制连接长度和长度变化。我们通过整合分子细胞生物学来解决这个问题细胞骨架动力学和生物物理的先进定量成像方法测量。通过获得蛋白质在不同条件下的动力学和运动学（运动）特征张力水平，我们确定了粘着斑内的力传递机制和肌动蛋白细胞骨架。然后我们与理论物理学家密切合作来测试预测分析理论和模拟与我们的定量生物物理测量。这部作品建立对细胞粘附、张力和形状的生物物理学理解，最终将为组织形态发生的理论和模型提供框架，这些理论和模型将具有预测性理解复杂生理过程的能力。更一般地说，策略该提案中开发的内容可以更广泛地应用，以了解力敏感度如何细胞骨架内的反馈共同促进细胞形态发生过程。这将能够开发改进的疗法来治疗与组织稳态有关的疾病目前仅通过治疗分子靶标仍难以实现。