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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.

描述（由申请人提供）：细胞粘附和形态由动态细胞骨架组件调节，该组件介导跨细胞和周围环境的力传递。细胞力产生和粘附的时空调节驱动多种生理过程中的形态发生变化，包括细胞迁移、组织形态发生和 ECM 重塑。虽然在理解细胞粘附和力产生的分子机制方面已经取得了重大进展，但我们缺乏一个框架来理解粘附斑块和肌动蛋白细胞骨架的复杂生物物理行为如何从细胞骨架蛋白的动态整体中出现。我们假设，了解粘附斑块和肌动蛋白细胞骨架内的力传递将为将分子机制转化为细胞的复杂物理行为提供必要的见解。我们提出的实验将阐明通过粘着斑、细胞间粘附和肌动蛋白细胞骨架进行力传递的机制，以及如何协调这些机制来调节多细胞组织中的力传递。我们通过将分子细胞生物学方法与细胞骨架动力学和生物物理测量的先进定量成像相结合来解决这个问题。通过获得不同张力水平下蛋白质的动力学和运动学（运动）特征，我们确定了粘着斑和肌动蛋白细胞骨架内的力传递机制。然后，我们与理论物理学家密切合作，通过定量生物物理测量来测试分析理论和模拟的预测。这项工作建立了对细胞粘附、张力和形状物理学的定量理解，最终将为细胞迁移和组织形态发生的理论和模型提供框架，从而在理解复杂的生理过程方面具有预测能力。通过在这些目标中获得的知识，我们将确定细胞-ECM 和细胞-细胞粘附之间的机械耦合在控制多细胞组织形态重排中的作用。这将有助于开发改进的疗法来治疗与组织稳态有关的疾病，而目前仅通过治疗分子靶点仍然难以捉摸这些疾病。