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了高速公路。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，类似于交通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来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，轴突是神经元的长而薄的投影。研究结果将对理解肌萎缩侧索硬化症（ALS）等神经退行性疾病具有深远的意义。预计新的数学模型可以很容易地推广到其他细胞运输问题。关于相互作用粒子系统的新的数学理论将在生物学和社会科学中有广泛的应用。该研究计划将与教育计划紧密结合，该计划将让研究生参与跨学科研究，并通过住宿夏令营让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。轴突细胞骨架是一种细胞内聚合物系统，负责沿轴突主动运输各种货物。轴突细胞骨架和轴突运输的中断，包括细胞骨架的径向分离和货物的异常积聚，已经在许多神经退行性疾病中观察到，但潜在的机制尚不清楚。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，从微观模型推导出轴突细胞骨架横截面组织的宏观模型，并利用它们来研究疾病中轴突细胞骨架的显著径向分离。其次是开发新的多尺度模式，用于沿轴突运输货物，其中包括货物-货物相互作用，并利用它们来研究导致货物局灶性积聚的潜在机制，这是神经变性的早期标志。第三是开发轴突细胞骨架动力学和轴突运输的全三维随机模型，用于研究与Ranvier节点附近动力学有关的生物学问题，Ranvier节点是大轴突中自然发生的狭窄点。多尺度建模策略和与实验人员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.