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.
