Intermediate filaments: timescales, intracellular transport and aggregation phenomena

中间丝：时间尺度、细胞内运输和聚集现象

• 批准号: RGPIN-2018-04967
• 负责人: Portet, Stephanie
• 金额: $ 4.66万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=758563
• 关键词: Intermediate; filaments; timescales; intracellular; transport

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.

我的研究的长期重点是开发一个数学框架，代表中间丝（IF）动力学的生化和生物力学特性，中间丝是真核细胞细胞骨架网络的重要组成部分。 IF 蛋白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，例如细胞运动、信号转导和机械转导。 IF 组织和动力学依赖于翻译后修饰调节的组装、拆卸和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中频结构局部重组，尽管细胞内保持了全局稳态配置。 IF 动力学缺陷会损害其细胞功能。我的提案的第一个目标是研究 IF 动力学的主要贡献者，即细胞中的 IF 运输。一些竞争过程，例如拮抗运动蛋白驱动的运输和肌动蛋白逆行流在细胞中移动 IF。我打算研究调节细胞内 IF 运动的机制。 IF 蛋白基因突变与 IF 网络组织缺陷和细胞质 IF 蛋白聚集体的出现有关，通常与 IF 蛋白周转或运动失调同时发生。聚集体的功能、结构和动力学仍不清楚。我的建议的第二个目标是识别导致 IF 聚集现象的 IF 动态紊乱。要解决与 IF 功能和结构相关的知识的关键空白，需要结合数学、生物物理学和生物学。为了实现我提案的两个目标，我的小组将开发数学和计算模型以及理论工具来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。将实验的易处理性与模型的概念相结合将提高模型的描述和预测能力。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中 IF 运动的机制以及引起聚集的 IF 动态扰动。了解 IF 的动态对于破译细胞中 IF 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训能够处理数学工具和生物实验的新一代科学家提供独特且堪称典范的多学科环境。