CAREER: Multiscale Modeling of Axonal Cytoskeleton Dynamics and Axonal Transport

细胞骨架是一个动态的细胞内聚合物系统，为细胞内各种蛋白质和细胞器的主动运输提供高速公路。细胞内运输的扰动会导致细胞内交通堵塞、细胞死亡和各种疾病，类似于运输系统崩溃时对城市的破坏。研究人员将开发多尺度模型和方法，以了解细胞骨架和细胞内运输如何在轴突内的疾病中受到影响，轴突是神经元的细长投影。研究结果将对理解神经退行性疾病如肌萎缩侧索硬化症（ALS）产生深远的影响。预计新的数学模型可以很容易地推广到其他蜂窝运输问题。相互作用粒子系统的新的数学理论在生物学和社会科学中有着广泛的应用。 研究计划将与教育计划紧密结合，该计划将使研究生从事跨学科研究，并通过住宅夏令营使K-12学生接触数学生物学和科学计算。该项目还将扩大代表性不足的群体在STEM领域的参与。轴突细胞骨架是细胞内的聚合物系统，其负责各种货物沿着轴突的主动运输。在许多神经退行性疾病中已经观察到轴突细胞骨架和轴突运输的破坏，包括细胞骨架的径向分离和货物的异常积聚，但其潜在机制仍不清楚。研究者将开发多尺度模型来研究健康和疾病中的轴突细胞骨架动力学和轴突运输。有三个目标。首先是从微观模型中推导出轴突细胞骨架在横截面中的组织的宏观模型，并使用它们来研究疾病中轴突细胞骨架的显著径向分离。第二个是开发新的多尺度模式，货物运输沿着一个轴突，纳入货物货物的相互作用，并使用它们来研究潜在的机制，导致局灶性积累的货物，这是神经退行性变的早期标志。第三个是开发完全三维随机模型的轴突细胞骨架动力学和轴突运输的生物学问题的调查，关注的动态节点附近的朗维尔，这是自然发生的大轴突变窄点。多尺度建模策略和与实验学家的密切合作将导致对生物学问题的重要见解，并有助于指导新的实验。

The cell cytoskeleton is a dynamic intracellular polymer system providing highways for the active transport of various proteins and organelles inside a cell. Perturbations of intracellular transport can lead to intracellular traffic jams, cell death, and various diseases, analogous to the damage to a city when the transportation system breaks down. The investigator will develop multiscale models and methods to understand how the cytoskeleton and intracellular transport are affected in diseases inside an axon, which is a long thin projection of a neuron. The research results will have profound implications for understanding neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). It is anticipated that the new mathematical models can be readily generalized to other cellular transport problems. The new mathematical theory on interacting particle systems will have wide applications in biology and social sciences. The research plan will be tightly integrated with the educational plan that will engage graduate students on interdisciplinary research and expose K-12 students to mathematical biology and scientific computing through residential summer camps. This project will also broaden the participation of underrepresented groups in STEM fields. The axonal cytoskeleton is an intracellular polymer system that is responsible for the active transport of various cargoes along an axon. Disruptions of the axonal cytoskeleton and axonal transport, including radial segregation of the cytoskeleton and abnormal accumulations of cargoes, have been observed in many neurodegenerative diseases, but the underlying mechanisms remain unclear. The investigator will develop multiscale models to study the axonal cytoskeleton dynamics and axonal transport in health and disease. There are three aims. The first is to derive macroscopic models for the organization of the axonal cytoskeleton in cross-section from microscopic models, and use them to investigate the striking radial segregation of the axonal cytoskeleton in disease. The second is to develop new multiscale modes for cargo transport along an axon that incorporate cargo-cargo interactions, and use them to investigate potential mechanisms that cause focal accumulations of cargoes, which are early hallmarks of nerve degeneration. The third is to develop fully three-dimensional stochastic models for the axonal cytoskeleton dynamics and axonal transport for investigation of biological questions that concern dynamics near the nodes of Ranvier, which are naturally occurring narrowing points in large axons. The multiscale modeling strategy and the close collaboration with experimentalists will lead to significant insights into the biological problem and help guide new experiments.