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.
A fundamental challenge in modern cell biology is to understand how complex morphological and physical behaviors of cells arise from hierarchical interactions of cytoskeletal proteins. We propose biophysical measurements that will identify the mechanical regulation of cell-ECM, cell-cell adhesions, and the actin cytoskeleton. These experiments will provide greater understanding of the regulation of adhesion, shape and migration in single cells and multicellular tissue and assist in understanding of how these behaviors are mis-regulated in human disease.
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| Ramirez-San Juan, G R; Oakes, P W; Gardel, M L (2017) Contact guidance requires spatial control of leading-edge protrusion. Mol Biol Cell 28:1043-1053 |
