细胞骨架微管力化学耦合动态行为的理论与数值研究

As a kind of cytoskeleton filaments, microtubules play a vital role in various physiological processes of cells and are closely relevant to many diseases. They have complicated and elegant structures and show some highly dynamic and mechanical-chemical coupled behaviors. The present project aims at investigating the dynamic processes of microtubules at different physiological conditions. Firstly, a theoretical framework will be constructed based on statistical mechanics and thermodynamics. By considering the GTP hydrolysis and their complex structures, a coarse-grained mechanochemical model will be built, which can characterize the transformation between chemical and mechanical energy in microtubules. Using this model, we will simulate the polymerizing and depolymerizing processes of microtubules and reveal the underlying mechanisms by analyzing the evolutions of conformation and energy. Secondly, the role of microtubule associated proteins, especially the plus end-tracking proteins, will be incorporated in the model to examine their influences and acting mechanisms on microtubule dynamics. Thirdly, the nucleation process of microtubules will be simulated and integrated with the modeled microtubule growth. A complete simulation of nucleation and the subsequent tubulin assembly and disassembly will be carried out. Besides, we will also analyze the force generation mechanisms during microtubule polymerization and depolymerization, and the influence of applied forces on the dynamic behaviors of microtubules. This project will be helpful for understanding the relations among the structures, properties, and funtions of microtubules, and also beneficial to the researches of, for instacne, cell mitosis and motility of cilia.

作为细胞骨架的一种主要组成单元，微管在细胞的生命活动中至关重要，也与多种疾病密切相关。本项目将基于微管复杂而精巧的几何结构，对其在不同生理条件下的力化学耦合动态行为进行理论分析和数值模拟。首先，根据统计力学和热力学，建立描述微管力化学耦合动态行为的理论框架。并以此为基础，进一步考虑微管的微观结构及其在动态演化过程中化学能和弹性变形能的相互转化，建立微管的粗粒化分子计算模型。利用该模型，研究微管的加聚和解聚行为，揭示微管动态行为的物理机制。进而在理论模型中引入微管结合蛋白（如正端跟踪蛋白）、离子浓度、外加载荷等，分析这些因素对微管动态行为的影响，从而理解在不同生理条件下微管动态行为的差异。此外，将统一微管的形核过程与后续的加聚和解聚过程，实现对微管生长全过程的模拟。本项研究将有助于理解微管的结构-性能-功能之间的内在联系，对于细胞有丝分裂、纤毛鞭毛的运动等问题的研究也有一定的帮助。

细胞微管和微丝的动态力学行为在微观尺度上涉及多种力化学耦合过程，微管蛋白和微管自身的生化状态与其精细的几何结构、分子构象存在着复杂的相关性，涉及化学结合能、弹性变形能等能量的演化机制，进而决定着微管的力学行为、细胞骨架的变形以及整个细胞的粘附、铺展等生物学过程。综合考虑微管和微丝的微纳结构、力化学特性和动态特性，建立了微管的力学模型和计算方法，揭示了微管构型与能量演化的基本特征。本项目对微管及其细胞骨架的多场耦合动力学问题开展了比较系统的研究。.首先，针对细胞骨架微管力化学耦合的动态行为，建立了一个粗晶化模型。该模型考虑了GTP水解等化学因素的影响，能刻画微管在生长过程中的形貌和能量演化，据此确定了微管生长的稳定性机制。.其二，基于Lifeact 与Utr230，开展了微管、微丝肌动蛋白组装的实验研究。证明了NIH3T3、MDCK、Hela和原代MEF细胞中的微丝状结构是由于细胞内肌动蛋白聚集而成的。构建了lifeact-AcGFP-NLS载体，发现了肌动蛋白在细胞核内的组装。.其三，建立了一个研究细胞微管、微丝骨架响应循环载荷的张拉整体动力学模型。发现细胞在双轴静态加载条件下，细胞骨架沿着最大加载幅值方向排布。而双轴循环加载条件下，细胞方位与加载频率、双轴的加载幅值比等有关，并给出了相应的解析数学表达式。.第四，发展了描写细胞粘附的力化学耦合模型。通过实验证明了整合素内吞在细胞粘附中的重要作用。基于实验结果，建立了一个基于分子机制的细胞粘附力学模型，可以反映基底弹性对整合素状态以及细胞粘附的影响。

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