Understanding Neurodegeneration Across the Scales

随着人类预期寿命的延长，神经退行性疾病可以说已经成为本世纪最具挑战性的疾病。阿尔茨海默病是最常见的一种神经退行性疾病，它会导致认知能力的毁灭性和进行性丧失，目前尚无治疗方法或治愈方法。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，包括创伤性脑损伤、慢性创伤性脑病和帕金森病在内的许多其他神经退行性疾病也具有这些特征。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机械性、生化力学模型，以模拟和预测正常和异常的神经生理。为了实现这一目标，本项目的目标是探测、建模和模拟tau-微管复合物，以揭示单个轴突的潜在失效机制。这个项目是真正的变革，因为它将开辟新的途径，从生物化学-机械原理来理解神经变性。该项目将在力学和神经科学的界面上提供一个新的多学科本科/研究生课程。我们团队的许多成员都是来自弱势群体的个人，他们积极地在各种组织中充当榜样，在那里他们将促进这项工作，并招募弱势群体的个人加入这个项目。为了加强科学和技术的理解，我们将继续参加国家生物力学日、年度国际脑蜂比赛和斯坦福脑日。该项目将采用理论、实验和模拟相结合的综合方法，利用低温电子显微镜表征tau蛋白结构，利用分子动力学模拟确定tau蛋白调节微管组装的分子机制，利用小角x射线散射表征tau-微管功能，并利用kino-几何采样解释tau-微管复合物的分子失效机制。这些知识将进入多尺度计算模型，从生化力学原理预测轴突的失效机制。该模型将在分子水平上提供微管聚合、tau-微管结合和tau-tau交联之间的基本联系，并在细胞水平上提供tau-微管和tau-tau界面、微管束和轴突作为一个整体的定量失效阈值之间的刚度、粘度和损伤。该项目将具有广泛的科学、社会和经济影响，因为它将刺激神经退行性疾病的发现，并提供基于生物力学的技术来表征损伤阈值，确定潜在的药物靶点，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.