CAREER: Multiscale Modeling of Axonal Cytoskeleton Dynamics and Axonal Transport

职业：轴突细胞骨架动力学和轴突运输的多尺度建模

• 批准号: 2051661
• 负责人: Chuan Xue
• 金额: $ 19.14万
• 依托单位: University of Minnesota-Twin Cities
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-31 至 2021-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2051661&HistoricalAwards=false
• 关键词: CAREER; Multiscale; Modeling; Axonal; Cytoskeleton

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.

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通道。细胞内运输的干扰可能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，以了解轴突内的疾病如何影响细胞骨架和细胞内运输，轴突是神经元的细长投影。这一研究结果将对了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。可以预期，新的数学模型可以很容易地推广到其他蜂窝传输问题。关于相互作用的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。研究计划将与教育计划紧密结合，教育计划将吸引研究生进行跨学科研究，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。该项目还将扩大任职人数不足的群体在科技、经济和经济领域的参与。轴突细胞骨架是一种细胞内聚合物系统，负责沿着轴突主动运输各种货物。在许多神经退行性疾病中都观察到轴突细胞骨架和轴突运输的中断，包括细胞骨架的放射状分离和异常堆积，但其潜在的机制尚不清楚。研究人员将开发多尺度模型来研究健康和疾病中轴突细胞骨架的动力学和轴突运输。有三个目标。第一种是从微观模型中推导出轴突细胞骨架在横截面上组织的宏观模型，并用它们来研究疾病中轴突细胞骨架的显著径向分离。第二个是沿着轴突开发新的多尺度货物运输模式，包括货物与货物的相互作用，并利用它们来研究导致货物局灶性堆积的潜在机制，这是神经退化的早期特征。三是为轴突细胞骨架动力学和轴突运输建立全三维随机模型，用于研究涉及Ranvier结点附近动力学的生物学问题，这些结点是大轴突中自然出现的窄化点。多尺度建模策略和与实验者的密切合作将导致对生物学问题的重大洞察，并有助于指导新的实验。