Intermediate filaments: timescales, intracellular transport and aggregation phenomena

长期以来，我的研究重点一直是建立一个数学框架，代表中间丝(IF)动力学的生化和生物力学特性，IF是真核细胞细胞骨架网络的重要组成部分。如果蛋白质从一种可溶的形式转变为复杂的不溶的丝状纤维网络，为细胞提供机械强度。网络动力学调节细胞的基本功能，如细胞运动、信号转导和机械转导。如果组织和动力学依赖于组装、拆卸和翻译后修饰调控的细胞内运输之间的相互作用。这些过程在不同的时间尺度上发挥作用，它们的相互作用导致IF结构局部重新组织，尽管细胞内保持了全局稳定状态配置。IF动力学上的缺陷损害了它们的细胞功能。 我的提议的第一个目标是研究IF动力学的一个主要贡献者，即IF在细胞中的运输。一些相互竞争的过程，如拮抗的运动蛋白驱动的运输和肌动蛋白逆行流动，如果在细胞内移动。我打算研究IF在细胞内运动的调节机制。 IF蛋白基因的突变与IF网络中IF的组织缺陷和细胞质IF蛋白聚集的出现有关，通常与IF蛋白的周转或运动性的放松调控相一致。团聚体的功能、结构和动力学仍不清楚。我提议的第二个目标是识别导致IF聚集现象的IF动力学中的紊乱。 要解决与IF功能和结构相关的关键知识空白，需要结合数学、生物物理学和生物学。为了达到我的提议的两个目标，我的团队将开发数学和计算模型以及理论工具，以量化模型对扰动的短期和长期反应。模型设计将以实验数据为指导，并与我在巴斯德研究所(法国)、MOCA(德国)、DKFZ(德国)和威斯康星大学(美国)的实验合作者进行迭代讨论。从模型的概念中整合实验可控性将增加它们的描述和预测能力。数据将用于校准模型和交叉验证预测。这种方法将允许识别调节细胞内IF运动性的机制和IF动力学中导致聚集的扰动。了解IF的动力学对于破译IF在细胞中的组织至关重要。 重要的是，我的研究计划及其在国际合作网络中的实施将为培养能够使用数学工具和生物实验的新一代科学家提供一个独特的、模范的多学科环境。

A long-standing focus of my research has been the development of a mathematical framework representing the biochemical and biomechanical properties of the dynamics of intermediate filaments (IF), an essential component of cytoskeletal networks of eukaryotic cells. IF proteins transition from a soluble form into complex insoluble filamentous fibre networks providing mechanical strength to cells. Network dynamics regulates fundamental cellular functions such as cell movement, signal transduction and mechanotransduction. IF organization and dynamics relies on the interplay between assembly, disassembly and intracellular transport regulated by post-translational modifications. These processes play a role at different timescales and their interplay results in IF structures that locally re-organize despite the maintenance of a global steady state configuration within the cell. Defects in IF dynamics impair their cellular function. The first objective of my proposal is to study a major contributor to IF dynamics, namely IF transport in cells. Several competing processes such as antagonistic motor protein driven transport and actin retrograde flow move IF in cells. I intend to investigate the mechanisms regulating motility of IF in cells. Mutations in IF protein genes are linked to defects in the organisation of IF in networks and appearance of cytoplasmic IF proteins aggregates, often coinciding with deregulation of turnover or motility of IF proteins. The function, structure and dynamics of aggregates is still not understood. The second objective of my proposal is to identify disorders in IF dynamics leading to IF aggregation phenomena. To tackle key gaps in knowledge related to the function and structure of IF requires a combination of mathematics, biophysics and biology. To attack the two objectives of my proposal, my group will develop mathematical and computational models and theoretical tools to quantify the short- and long-term responses of models to perturbations. Model design will be guided by experimental data and iterative discussions with my experimentalist collaborators at Institut Pasteur (France), MOCA (Germany), DKFZ (Germany) and U Wisconsin (USA). Integrating experimental tractability from the conception of models will increase their descriptive and predictive power. Data will be used to calibrate models and cross-validate predictions. This approach will allow the identification of mechanisms regulating the IF motility in cells and perturbations in the IF dynamics causing aggregation. Understanding the dynamics of IF is essential to decipher IF organisation in cells. Importantly, my research program and its implementation in an international collaboration network will provide a unique and exemplary multidisciplinary environment for the training of a new generation of scientists able to handle mathematical tools and biological experimentations.