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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：
10063995
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/10063995
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.

项目总结