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Mechanical Regulation of Cell Adhesion by Dynamic Cytoskeletal Assemblies - Resubmission 01

动态细胞骨架组件对细胞粘附的机械调节 - 重新提交 01

基本信息

批准号：
9341353
负责人：
Margaret Lise Gardel
金额：
$ 30.77万
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 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9341353
关键词：
Actins Adherens Junction Adhesions Architecture Atomic Force Microscopy Behavior Biophysics Cell Adhesion Cell model Cell-Cell Adhesion Cells Cellular Morphology Cellular biology Characteristics Complex Computer Simulation Coupling Cytoskeletal Modeling Cytoskeletal Proteins Cytoskeleton Data Development Disease Environment Event Extracellular Matrix Focal Adhesions Generations Genetic Homeostasis Intercellular Junctions Kinetics Knowledge Mechanics Mediating Modeling Modernization Molecular Molecular Target Morphogenesis Morphology Motion Movement Multicellular Process Physics Physiological Processes Process Proteins Regulation Role Shapes Testing Tissue Model Tissues Traction Translating Work adhesion receptor biophysical properties cell behavior cell growth regulation cell motility density experimental study human disease improved insight kinematics migration monolayer optogenetics public health relevance quantitative imaging self organization simulation spatiotemporal theories three-dimensional modeling transmission process

项目摘要

DESCRIPTION (provided by applicant): Cell adhesion and morphology are regulated by dynamic cytoskeletal assemblies that mediate force transmission across the cell and to the surrounding environment. Spatiotemporal regulation of cellular force generation and adhesion drive morphogenic changes in diverse physiological processes including cell migration, tissue morphogenesis and ECM remodeling. While significant progress has been made to understand the molecular mechanisms of cell adhesion and force generation, we lack a framework to understand how the complex biophysical behaviors of adhesion plaques and the actin cytoskeleton emerge from dynamic ensembles of cytoskeletal proteins. We hypothesize that understanding force transmission within adhesion plaques and the actin cytoskeleton will provide the necessary insight to translate molecular mechanisms to complex physical behaviors of cells. We propose experiments that will elucidate mechanisms of force transmission through focal adhesions, cell-cell adhesions and the actin cytoskeleton and how these are coordinated to regulate force transmission in multicellular tissue. 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 quantitative understanding of the physics of cell adhesion, tension and shape that, ultimately, will provide the framework for theories and models of cell migration and tissue morphogenesis that will have predictive power in understanding complex physiological processes. Through knowledge gained in these aims, we will identify the role of mechanical coupling between cell-ECM and cell-cell adhesions in controlling morphological rearrangements in multi-cellular tissue. This will enable the development of improved therapies to treat diseases involved in tissue homeostasis that currently remain elusive by solely treating molecular targets.