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

本提案的研究目标是开发多尺度模型并设计控制实验，以定量研究活跃细胞骨架网络和多细胞显微组织中肌动球蛋白活性引起的力产生。肌动蛋白细胞骨架是由多种调节蛋白和交联蛋白作用的灵活动态的纤维网络，由肌动蛋白马达在肌动蛋白细胞骨架中产生的生物力学张力是许多病理过程的基础，如肿瘤生长、转移和纤维化。根据本奖项进行的研究包括：在基于主动有限元的肌动蛋白网络中结合关键的机械-生化过程来模拟收缩性，开发明确包括肌动球蛋白活性的粗粒度描述来模拟3D显微组织的变形，以及定量确定肌动蛋白活性在不同细胞类型中的作用的实验，其中马达位于皮层肌动蛋白或应力纤维中，以及两种细胞类型混合时发生的生物力学相互作用。如果成功，这些研究将大大增加我们对弹性应力如何导致活细胞收缩活动增强的理解。此外，可以预测多细胞三维系统行为的多尺度定量模型和支持实验将揭示复杂三维环境中细胞间力传递的机制。这反过来可能有助于理解多个细胞的肌动蛋白网络如何相互作用，以驱动对组织和器官功能（如组织形态发生、修复和再生）至关重要的多细胞事件。该奖项将为研究生和本科生提供开展实验工作和发展先进计算和建模技能的机会。在建模方法和实验技术方面取得的进展将包括在PI和co-PI创建的课程中，以促进动手模拟和实验室经验。

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.