基于连续介质力学与半柔性聚合物分子理论的细胞骨架结构力学性质研究

Inside an eukaryotic cell, there exists a highly cross-linked and entangled network of three different types of polymers (actin filaments, microtubules, and intermediate filaments) collectively called the cytoskeleton. The cytoskeleton determines the morphology and mechanical properties of the cell and makes the cell to respond small disturbances very sesitively and nonlinearly. These intrinsically dynamic natures are compatible to and are reciprocally influnced by the cell's biological behaviors and functions, in which the couplings between mechanics and biology in cell level, and the coupling between mechanics and chemistry in molecular level are involved, making the construction of quantitative models on the cytoskeleton and its substructures, and the development of corresponding numerical and experimental techniques, a challenge in theory and technique, having great scientical significance. In the present project, we develop theoretical descriptions on various cytosketal structures from single filaments, their simple composites and the whole cytoskeleton by adopting the continnum mechanics, theory of confined semiflexible polymer chains and statistical thermodynamics. And we quantify the poposed theories by means of Brownian dyanmics simulations and AFM experiments. We explore methods of quantitative analysis to the proposed nonlinear models based on wavelet theory. We eventually apply the obtained results to the identification of mechanics characteritics of cells, and the analysis of specific contact behavior of cell-cell, cell-nanoparticles (viruses), aiming to explore efficient quantitative tools for cellular biological systems with intrinsic nonlinearities.

主要由蛋白质纤丝交联纠缠形成的细胞骨架结构决定着真核细胞的形态与力学性质，使其普遍具有外界微小作用的敏感性和响应的非线性等特征。这些特征通过细胞层次的力学与生物学耦合及分子层次的力学与化学耦合，与细胞的某些生物学行为和功能相互匹配、影响。使得构建定量描述细胞骨架及其子结构力学性质的理论模型、发展相应数值与实验技术成为一种理论和技术上的挑战，具有重要科学意义。本项目拟围绕细胞骨架结构，利用连续介质力学，半柔性聚合物分子理论与统计热力学等手段通过跨尺度建模方式建立描述从单一纤丝，纤丝复合结构到整个细胞骨架非线性力学性质的理论模型，并基于布朗动力学仿真和生物型原子力显微镜细胞实验进行定量化。利用小波理论这一先进数学工具探索针对所建立非线性模型的定量分析方法。最终将相关结果应用到癌细胞力学特征识别，细胞与细胞及纳米颗粒特异性接触等力学行为分析中，探索具有非线性本质定量化细胞生物力学系统有效分析途径

本项目的研究计划要点是通过建立有效的理论、数值和实验手段，研究细胞生物学行为与其骨架力学性质的内在关联规律。遵循该计划，我们在前期已有工作的基础上，通过进一步建立涉及细胞连续介质粘弹性变形与粘附分子群簇的扩散、键的断开/闭合等随机行为相耦合的定量理论模型与数值仿真技术，得到了细胞骨架粘弹性力学性质对细胞粘附行为以及纳米颗粒细胞内吞行为的影响规律；针对构成细胞骨架生物高分子复杂微环境影响下的力学行为，我们基于统计热力学理论，得到了在不同形式几何约束下半柔性聚合物分子拉力与伸长关系的定量解析表达式，对著名的Odijk扰动尺度进行了有效修正，极大拓展了其适用范围；针对细胞生物力学实验，我们发展了基于原子力显微镜的细胞蠕变与松弛粘弹性力学性质测量技术与标定理论，并通过对不同侵袭阶段癌细胞力学性质与骨架排布结构的测量结果，揭示出了不同侵袭能力癌细胞骨架结构演化的生物力学机理。并基于离子辐射诱导作用建立了体外细胞凋亡与动物体内细胞损伤的细胞骨架生物力学模型，为临床碳离子放射治疗中更深入的认识癌症杀伤机制提供了实验支持及理论依据。针对研究中必然涉及到的强非线性问题的定量分析，我们进一步建立并完善了具有时空分离解耦特征的高精度强非线性动力学问题小波求解方法体系。本项目已在国内外核心期刊发表研究论文全文21篇，其中SCI 收录18篇。