Universal Roles of Force Generation and Transmission in Biological Systems

项目摘要 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。 肌动蛋白和肌球蛋白分子马达在细胞骨架。在细胞骨架水平产生的力是 转化为细胞和组织尺度，促进有趣的生物力学现象在多个尺度。为 例如，它赋予肌动蛋白细胞骨架复杂的非平衡粘弹性， 可以用基于热平衡的统计物理学理论来描述。它也会导致剧烈的 细胞形态的转变伴随着细胞骨架在细胞中的大规模流动 迁移、分裂和形态发生。此外，细胞利用细胞骨架产生的力 在结构上重塑周围的细胞外基质以及用于与 其他细胞在伤口愈合和毛细血管形态发生中的作用。在所有这些生物力学现象中， 力的产生、传递和松弛之间的平衡起着非常重要的作用， 这种平衡对疾病的发病机制，如癌症转移，有着巨大的影响。尽管 机械力的意义，理解调节生物学微妙平衡的原理 结构仍然缺乏。通过开发多尺度计算模型和采用定量体外 实验，我们将阐明普遍的作用和基本原则的力量产生，传输， 以及在细胞骨架、细胞和组织尺度上的生物过程中的松弛。我们的目标是解决两个 基本问题：i）力是如何产生的，并导致非平衡粘弹性行为， 混乱的肌动蛋白细胞骨架和ii）如何将力转化为细胞和组织尺度并调节 细胞形状变化，基质重塑，以及通过相互作用在远处细胞之间进行机械通信 并与其他细胞内和细胞外因子竞争。拟议研究的成果将 提供对生理和病理生理过程的基本理解的重要见解 由机械力调节。 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