Pairing Modeling and Experiment to Understand Microtubule Behavior in Healthy and Injured Neurons

配对建模和实验以了解健康和受损神经元的微管行为

• 批准号: 10445753
• 负责人: Maria-Veronica Ciocanel
• 金额: $ 33.57万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-21 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10445753
• 关键词: Acute; Address; Architecture; Axon; Behavior; Biological Assay; Biophysical Process; Cells; Coupling; Cytoskeletal Modeling; Cytoskeleton; Dendrites; Development; Differential Equation; Drosophila genus; Equilibrium; Excision; Filament; Foundations; Generations; Genetic; Geometry; Growth; Health; Image; Individual; Injury; Markov Chains; Mathematics; Measurable; Measurement; Measures; Microtubules; Modeling; Natural regeneration; Neuronal Injury; Neurons; Outcome; Pattern; Regulation; Role; Selection Bias; Shapes; Stereotyping; System; Testing; Time; Validation; Work; axon injury; axon regeneration; base; cell injury; discrete time; experimental study; flexibility; in silico; in vivo; in vivo Model; in vivo evaluation; in vivo imaging; insight; mathematical methods; mathematical model; novel; predictive modeling; resilience; response; response to injury; theories

Project Summary Neurons rely on polarity and stability of the microtubule cytoskeleton to support long-range directed transport and long-term survival. However, both polarity and stability can be rapidly altered in response to injury and these rearrangements are critical for neuronal resilience. It is becoming clear that rather than a single master mechanism controlling neuronal microtubule organization through time and space, multiple mechanisms operate in parallel. This complexity makes it challenging to understand how each mechanism contributes to filament organization and how the system works as a whole. To overcome this challenge, a mathematical framework that incorporates known mechanisms will be built. This framework will be invaluable for understanding the dendrite microtubule system, and how it responds to perturbations induced by injury. Aim 1. Polarized organization of microtubules in neurons is critical for correct cargo delivery to axons and dendrites. A spatial stochastic model of the polarized array of dendritic microtubules will be constructed using known mechanisms of polarity control in Drosophila dendrites. This model will also incorporate known parameters for microtubule growth dynamics. Model validation will be carried out using experimental perturbations of polarity control mechanisms as well as using measurements of microtubule dynamics. This model will provide a framework for understanding how individual microtubule dynamics and local polarity mechanisms influence microtubule spatial organization and polarity. Aim 2. Neurons normally maintain the same polarized arrangement of microtubules for a lifetime. However, if the axon is removed, a dendrite can reverse polarity and become a regenerating axon. How polarity reversal occurs is not understood. The hypothesis that increased entry of microtubules from the cell body drives reversal will be tested in vivo and in silico. The role of other control mechanisms in polarity reversal will also be systematically addressed by testing the mathematical model and informing new experimental directions. Aim 3. Most neurons have several dendrites emerging from the cell body. After axon damage, only one dendrite switches polarity whereas the others revert to their pre-injury orientation. This selection bias is hypothesized to depend on branching patterns of the dendrites. The combination of axon removal experiments in neurons with distinct branching features and a reduced mathematical description of microtubule behavior will provide insights on how dendrite geometry influences polarity control, robustness, and regeneration. The combination of sophisticated live imaging of microtubules in neurons in vivo with new mathematical modeling of microtubule behavior will drive new insights on how neurons maintain a polarized, yet dynamic and flexible microtubule cytoskeleton for a lifetime. The challenges posed by axonal injury require radical cytoskeletal reorganization. Models developed and validated with measurements from healthy neurons will be used to gain deep understanding of microtubule control mechanisms that are critical for axonal regeneration.

项目总结