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Universal Roles of Force Generation and Transmission in Biological Systems

生物系统中力的产生和传递的普遍作用

基本信息

批准号：
10245019
负责人：
Taeyoon Kim
金额：
$ 42.57万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10245019
关键词：
3-Dimensional Actins Actomyosin Address Affect Behavior Binding Biological Biological Process Biomechanics Biomimetics Biopolymers Blood capillaries Cell Communication Cell Shape Cell membrane Cell model Cells Chemicals Collagen Communication Complex Computer Models Consumption Coupled Cytokinesis Cytoskeleton Development Disease Distant Equilibrium Experimental Models Extracellular Matrix F-Actin Feedback Generations Grain Human In Vitro Knowledge Lead Length Light Mechanics Membrane Microfilaments Mission Modeling Molecular Motors Morphogenesis Morphology Motor Muscle Muscle Cells Myosin ATPase Neoplasm Metastasis Osmotic Pressure Outcome Pathogenesis Physics Physiological Play Process Property Proteins Relaxation Research Research Personnel Rheology Role Shapes Stress Structure Structure of thyroid parafollicular cell Study models System Talents Tissues Translating United States National Institutes of Health Vascular Diseases Walking base biological systems biophysical properties cell motility cell transformation disability experience experimental study extracellular field study in vitro Assay in vivo insight mechanical force multi-scale modeling novel novel therapeutic intervention simulation spatiotemporal theories transmission process viscoelasticity wound healing

项目摘要

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

项目摘要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。在细胞骨架水平产生的力被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。例如它赋予肌动蛋白细胞骨架复杂的、非平衡的粘弹性，基于热平衡的统计物理学理论。它还推动了剧烈的形态学变化，在细胞迁移、分裂和增殖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以及用于在伤口愈合中与其它细胞机械连通和毛细血管形态发生。在所有这些生物力学现象中，生成，传输和放松起着非常重要的作用，平衡的破坏对疾病的发病机制，如癌症转移，产生巨大影响。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，缺乏。通过开发多尺度计算模型和采用定量体外实验，我们将阐明力的产生、传递和松弛的普遍作用和基本原理，在细胞骨架、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）力是如何产生的，并导致非平衡粘弹性行为在混乱的肌动蛋白细胞骨架以及ii）这些力如何转化为细胞和组织尺度并调节细胞形状变化，通过与其他细胞的相互作用和竞争，细胞内和细胞外因子。拟议研究的结果将为以下方面提供重要见解：对由机械力调节的生理和病理生理过程有基本的了解。 1