Modelling intermediate filament networks

中间丝（IF）网络是细胞骨架的一部分，细胞骨架是一种由蛋白质聚合成丝在细胞质中形成网络组成的细胞内结构。IF网络主要参与细胞的稳定和机械弹性、细胞迁移和信号转导。细胞骨架网络的组织是其机械性质的主要决定因素，因此它们在细胞中的功能。细胞骨架蛋白的组装或运输缺陷导致网络错误组织，与许多疾病的发病机制有关。 结合实验和数学建模的方法允许严格验证模型假设，从而构成了一个非常强大的和廉价的工具，在细胞生物学的调查。与实验学家密切合作，我建议开发数学和计算框架，以广泛研究IFs在单个细丝水平以及整个网络水平的组装和组织。数学和计算模型的设计将考虑到生物化学和物理性质的IF。模型将进行定量和定性研究，以提取瞬态和渐近行为。对于模型校准和验证，将模型响应与实验数据进行比较。模型选择将用于在竞争模型中识别最佳模型。 使用这种方法，我的研究将为实验人员提供一个分析框架，允许1）不同类型的IF的组装动力学的量化，2）IF网络形成及其粘弹性的计算机研究和3）IF材料在细胞中运动的表征。 了解细胞中IF网络的组织机制以及网络结构与其粘弹性之间的联系对于阐明细胞中IF功能至关重要，并可能导致新的治疗策略。

The intermediate filament (IF) network is part of the cytoskeleton, an intracellular structure made of proteins polymerized in filaments forming networks in the cytoplasm. The IF network is mainly involved in the stabilization and mechanical resilience of the cell, cell migration and signal transduction. The organization of cytoskeletal networks is the main determinant of their mechanical properties and so their functions in the cell. Defects in the assembly or the transport of cytoskeletal proteins, resulting in network misorganizations, are linked to the pathogenesis of many diseases. Combining experimental and mathematical modelling approaches allows a rigorous validation of model hypotheses, thereby constituting a very powerful and inexpensive tool of investigation in cell biology. Working in close collaboration with experimentalists, I propose to develop mathematical and computational frameworks to extensively investigate the assembly and organization of IFs at the individual filament level, but also at the level of the entire network. Mathematical and computational models will be designed by taking into account both the biochemical and physical properties of IFs. Models will be quantitatively and qualitatively studied to extract transient and asymptotic behaviour. For model calibration and validation, model responses will be compared with experimental data. Model selection will be used to identify the best models amongst competing models. Using this approach, my research will provide experimentalists with an analytical framework allowing 1) the quantification of the assembly dynamics of different types of IFs, 2) the in silico investigation of IF network formation and their viscoelastic properties and 3) the characterization of movements of IF material in cells. Understanding the organization mechanisms of the IF networks in cells and the link between network architectures and their viscoelastic properties is essential to elucidate the IF functions in cells and could lead to new therapeutic strategies.