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.

项目摘要通过动态细胞骨架组件对细胞粘附的机械调节上皮组织是由动态粘附，细胞 - 细胞连接的建造的，连接相邻的细胞维持组织的凝聚力和屏障功能，但也允许动态过程等动态过程愈合和组织形态发生。肌动蛋白中产生的收缩力细胞骨架传播到细胞细胞连接处，以控制局部细胞形状和运动雕刻组织形态发生并启动控制细胞命运的下游信号通路。了解细胞 - 细胞连接的生物物理特性如何受到调节对胚胎发育期间理解和治疗缺陷的影响，组织工程以及转移性肿瘤的诊断和治疗。该提议利用细胞生物物理学，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，以研究Rhoa信号如何调节收缩力驱动控制细胞形状并最终是组织形态发生的细胞 - 细胞连接长度的变化。我们提出了实验，以阐明如何调节肌动蛋白的力依赖性过程收缩力，膜重塑和RhoA信号反馈相互控制以控制连接处长度和长度变化。我们通过整合分子细胞生物学来解决这个问题用细胞骨架动力学和生物物理的高级定量成像的方法测量。通过获得蛋白质的动力学和运动学（运动）特征张力水平，我们确定了局灶性粘连中力传播的机制和肌动蛋白细胞骨架。然后，我们与理论物理学家紧密合作以测试预测通过我们的定量生物物理测量值进行的分析理论和模拟。这项工作建立对细胞粘附，张力和形状的生物物理理解，最终将提供组织形态发生的理论和模型的框架，该框架具有预测性理解复杂生理过程的能力。更一般地，策略在此提案中开发的开发可以更普遍地用于了解对力敏感的方式细胞骨架中的反馈共谋促进细胞形态发生过程。这会使改进的疗法的发展能够治疗涉及组织稳态的疾病目前，仅通过仅处理分子靶标，这仍然难以捉摸。