Understanding Neurodegeneration Across the Scales

随着预期寿命的延长，神经退行性变可以说已经成为本世纪最具挑战性的疾病。最常见的神经变性类型是阿尔茨海默病，它会导致毁灭性的进行性认知丧失，目前还没有治疗或治愈的方法。蛋白质缠结、轴突损伤和结构退化是阿尔茨海默病的典型特征。越来越多的证据表明，这些特征与其他一些神经退行性疾病相似，包括创伤性脑损伤、慢性创伤性脑病和帕金森氏症。然而，神经退行性变的分子机制仍然知之甚少。本研究计划的总体目标是建立神经退行性变的力学、生化-力学模型，以模拟和预测正常和异常的神经生理学。为了达到这一目标，本项目的目标是探索、建模和模拟tau-微管复合体，以揭示单个轴突的潜在失效机制。这个项目真正具有变革性，因为它将开辟新的途径，从生物化学-机械原理来理解神经退行性变。这个项目将成为力学和神经科学之间的一个新的多学科本科/研究生课程。我们团队的许多成员来自代表性不足的群体，他们积极在各种组织中充当榜样，在那里他们将促进这项工作，并招募代表性不足的个人加入这个项目。为了增进对科技的了解，我们将继续参加国家生物力学日、一年一度的国际脑蜂大赛和斯坦福脑日。本项目将以理论、实验和模拟相结合的综合方式，利用冷冻电子显微镜表征tau的结构，利用分子动力学模拟确定tau调控微管组装的分子机制，利用小角X射线散射表征tau-微管的功能，并使用基诺几何采样解释tau-微管复合体的分子破坏机制。这些知识将进入一个多尺度计算模型，根据生物化学-机械原理预测轴突的失效机制。这个模型将提供分子水平上的微管聚合、tau-微管结合和tau-tau交联以及细胞水平上的刚性、粘度和损伤与tau-微管和tau-tau界面、微管束和整个轴突的定量失效阈值之间的基本联系。该项目将产生广泛的科学、社会和经济影响，因为它将促进神经退行性疾病的发现，并提供使能的、基于生物力学的技术来表征损伤阈值，识别潜在的药物靶点，并设计抑制剂来减缓、阻止或逆转神经退行性疾病。

With an increasing life expectancy, neurodegeneration has arguably become the most challenging malady of the century. The most common type of neurodegeneration, Alzheimer's disease, causes a devastating and progressive loss of cognition for which there is currently no treatment or cure. Protein tangles, axonal injury, and structural degradation are classic hallmarks of Alzheimer's disease. Growing evidence suggests that these features are shared by a number of other neurodegenerative disorders including traumatic brain injury, chronic traumatic encephalopathy, and Parkinsonism. Yet, the molecular mechanisms of neurodegeneration remain poorly understood. The overall goal of this research program is to establish a mechanistic, bio-chemo-mechanical model of neurodegeneration to simulate and predict normal and abnormal neurophysiology. Towards this goal, the objective of this project is to probe, model, and simulate the tau-microtubule complex to reveal the underlying failure mechanisms of individual axons. This project is truly transformative in that it will open new avenues to understand neurodegeneration from bio-chemo-mechanical principles. This project will feed into a new multidisciplinary undergraduate/graduate course at the interface between mechanics and the neurosciences. Many members of our team are individuals from underrepresented groups who actively serve as role models in various organizations where they will promote this work and recruit underrepresented individuals to join this project. To enhance scientific and technological understanding, we will continue to participate in the National Biomechanics Day, the annual International Brain Bee competition, and Stanford Brain Day.In an integrative approach that combines theory, experiment, and simulation, this project will characterize tau structure using cryo-electron microscopy, identify the molecular mechanisms by which tau modulates microtubule assembly using molecular dynamics simulation, characterize tau-microtubule function using small angle X-ray scattering, and interpret the molecular failure mechanisms of the tau-microtubule complex using kino-geometric sampling. This knowledge will enter a multiscale computational model to predict the failure mechanisms of the axon from bio-chemo-mechanical principles. This model will provide fundamental links between microtubule polymerization, tau-microtubule binding, and tau-tau cross-linking on the molecular level and stiffness, viscosity, and damage on the cellular level to quantitative failure thresholds for the tau-microtubule and tau-tau interfaces, the microtubule bundle, and the axon as a whole. This project will have broad scientific, social, and economic impact, in that it will stimulate discovery in neurodegeneration and provide enabling, biomechanics-based technologies to characterize damage thresholds, identify potential drug targets, and design inhibitors to slow down, block, or reverse neurodegenerative disorders.