Intermediate filaments: timescales, intracellular transport and aggregation phenomena

我的研究的一个长期的重点一直是一个数学框架的发展代表的生化和生物力学性能的动态的中间丝（IF），真核细胞的细胞骨架网络的重要组成部分。IF蛋白质从可溶形式转变为复杂的不溶性丝状纤维网络，为细胞提供机械强度。网络动力学调节基本的细胞功能，如细胞运动，信号转导和机械转导。IF的组织和动力学依赖于组装、拆卸和由翻译后修饰调节的细胞内转运之间的相互作用。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结构局部重组，尽管细胞内维持全局稳态配置。IF动力学的缺陷损害了它们的细胞功能。** 我的提案的第一个目标是研究IF动力学的主要贡献者，即IF在细胞中的运输。几个竞争过程，如拮抗马达蛋白驱动的运输和肌动蛋白逆行流动移动细胞内的IF。我打算研究IF在细胞中调节运动的机制。** IF蛋白基因的突变与IF在网络中的组织缺陷和细胞质IF蛋白聚集体的出现有关，通常与IF蛋白的周转或运动性的失调一致。聚集体的功能、结构和动力学仍然不清楚。我的建议的第二个目标是确定在IF动态导致IF聚集现象的障碍。** 要填补与综合框架的功能和结构有关的知识空白，需要将数学、生物物理学和生物学结合起来。为了实现我的建议的两个目标，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响应。模型设计将以实验数据和与我在巴斯德研究所（法国）、莫卡（德国）、DKFZ（德国）和U威斯康星州（美国）的实验合作者的反复讨论为指导。从模型的概念中整合实验的易处理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。这种方法将允许鉴定调节细胞中IF运动性的机制和引起聚集的IF动力学扰动。了解IF的动力学对于破译细胞中的IF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处理数学工具和生物实验的新一代科学家提供独特和示范性的多学科环境。

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.