Universal Roles of Force Generation and Transmission in Biological Systems

项目总结 细胞产生机械力的能力主要归因于F-肌动蛋白之间的分子相互作用 以及细胞骨架中的肌球蛋白分子马达。在细胞骨架水平上产生的力被转化为 细胞和组织尺度，促进在多个尺度上有趣的生物力学现象。例如，它 赋予肌动蛋白细胞骨架以无法描述的复杂的、非平衡的粘弹性性质 根据基于热平衡的统计物理理论。它还推动了剧烈的形态 细胞迁移、分裂和迁移过程中伴随细胞骨架大规模流动的细胞转化 形态发生。此外，细胞利用细胞骨架产生的力进行结构重塑。 伤口愈合过程中细胞外基质的包围以及与其他细胞的机械通讯 毛细血管形态发生。在所有这些生物力学现象中，力与力之间的微妙平衡 产生、传递和松弛起着非常重要的作用，平衡的破坏 对疾病的发病机制产生重大影响，如癌症转移。尽管重要的是 机械力，对调节生物结构中微妙平衡的原理的理解仍然 缺乏。通过开发多尺度计算模型和采用定量的体外实验，我们将 阐明了力的产生、传递和松弛的普遍作用和基本原则 细胞骨架、细胞和组织尺度上的生物过程。我们的目标是解决两个基本问题：i) 无序肌动蛋白细胞骨架中力是如何产生并导致非平衡粘弹性行为的 和ii)力如何转化为细胞和组织的尺度并调节细胞形状的变化，基质 通过与其他细胞相互作用和竞争来重塑和机械地沟通遥远的细胞 胞内和胞外因子。拟议研究的结果将为以下方面提供关键的见解 对机械力调节的生理和病理生理过程有基本的了解。 1

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