From Reconstituted Actin Networks to 3D Multi-cellular Microtissues: Multi-scale Models and Experiments on Contractility in Active Cytoskeletal Networks

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The research objective of this proposal is to develop multiscale models and to design controlled experiments to quantitatively study force generation due to actomyosin activity in active cytoskeletal networks and in multicellar microtissues. The biomechanical tension generated by myosin motors in the actin cytoskeleton, which is a flexible and dynamic network of filaments that is acted upon by a variety of regulatory and crosslinking proteins, is fundamental to many pathologic processes such as tumor growth, metastasis and fibrosis. Studies to be conducted under this award include: incorporation of key mechano-bio-chemical processes in a active finite-element based actin network to model contractility, development of a coarse-grained description that explicitly includes actomyosin activity to model deformation of 3D microtissues and experiments to quantitatively determine the role of actomyosin activity in different cell types where motors are localized in the cortex actin or in stress fibers and the biomechanical interplay that occurs when two cell types are mixed. If successful, these studies would add significantly to our understanding of how elastic stresses lead to an enhancement of contractile activity in living cells. Moreover, multi-scale quantitative models that can predict the behavior of multicellular 3D systems and supporting experiments will reveal the mechanisms of force transfer through cell-to-cell in complex 3D environments. This in turn may help understand how the actin networks of multiple cells interact with each other to drive multi-cellular events critical to the function of tissues and organs such as histomorphogenesis, repair and regeneration. The award will provide an opportunity for graduate and undergraduate students to both carry out experimental work and to develop advanced computational and modeling skills. The progress made in the modeling methods and experimental techniques will be included in the courses that the PI and the co-PI have created to promote hands-on simulation and laboratory experience.