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-之间的分子相互作用 细胞骨架中的肌动蛋白和肌球蛋白分子马达。在细胞骨架水平上产生的力是 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。为 例如，它赋予肌动蛋白细胞骨架复杂的、非平衡的粘弹性属性，而不能 可以用基于热平衡的统计物理理论来描述。它还推动了激烈的 伴随细胞内细胞骨架大规模流动的细胞形态变化 迁移、分裂和形态发生。此外，细胞利用细胞骨架产生的力 细胞外基质周围的结构重塑以及与 其他细胞参与创面愈合和毛细血管形态发生。在所有这些生物力学现象中，一个微妙的 力的产生、传递和松弛之间的平衡起着非常重要的作用，而破坏 这种平衡对癌症转移等疾病的发病机制有重大影响。尽管 机械力的意义，对调节生物微妙平衡的原理的理解 结构仍然缺乏。通过开发多尺度计算模型和采用体外定量 实验，我们将阐明普遍作用和潜在的力量产生，传递， 以及细胞骨架、细胞和组织尺度上的生物过程的松弛。我们的目标是解决两个问题 基本问题：i)力是如何产生并导致非平衡粘弹性行为的 无序的肌动蛋白细胞骨架和II)力量如何转化为细胞和组织的尺度和调节 通过相互作用，细胞形状改变、基质重塑和远距离细胞之间的机械通讯 并与其他细胞内和细胞外因子竞争。拟议研究的结果将 提供对生理和病理生理过程的基本理解的重要见解 受机械力调节的。 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