PROJECT SUMMARY The ability of cells to generate mechanical forces is attributed primarily to molecular interactions between F- actin and myosin molecular motors in the cell cytoskeleton. Force generated at the cytoskeleton level is translated to cellular and tissue scales, facilitating interesting biomechanical phenomena at multiple scales. For example, it endows the actin cytoskeleton with complex, non-equilibrium viscoelastic properties which cannot be described by theories from statistical physics based on thermal equilibrium. It also drives drastic morphological transformations of cells accompanied by large-scale flow of the cell cytoskeleton in cell migration, division, and morphogenesis. In addition, cells use the force produced from the cytoskeleton for structurally remodeling surrounding extracellular matrices as well as for mechanically communicating with other cells in wound healing and capillary morphogenesis. In all these biomechanical phenomena, a delicate balance between force generation, transmission, and relaxation plays a very important role, and the disruption of the balance has dramatic impacts on the pathogenesis of disease, such as cancer metastasis. Despite the significance of mechanical forces, understanding of principles that regulate the delicate balance in biological structures still lacks. By developing multi-scale computational models and employing quantitative in vitro experiments, we will shed light on universal roles and underlying principles of force generation, transmission, and relaxation in biological processes at cytoskeleton, cell, and tissue scales. We aim to address two fundamental questions: i) how forces are generated and lead to non-equilibrium viscoelastic behaviors in disorganized actin cytoskeleton and ii) how the forces are translated to cellular and tissue scales and regulate cell shape changes, matrix remodeling, and mechanical communication between distant cells by interacting and competing with other intracellular and extracellular factors. Outcomes from the proposed research will provide critical insights into fundamental understanding of physiological and pathophysiological processes regulated by mechanical forces. 1