Microtubule Mechanics at the Nanoscale

描述(申请人提供)：微管是在建立和维持细胞结构中起关键作用的聚合物。微管是长春花碱和紫杉醇(紫杉醇)等重要抗癌药物的靶标，被认为在阿尔茨海默氏症等神经退行性疾病中发挥作用。微管是一种GTP酶-微管蛋白的动态聚合物，GTP水解酶的能量驱动动态不稳定性，使微管自发地在聚合期和快速解聚期之间切换。这种行为是由细胞调节的，以实现细胞骨架的快速重组。为了更好地了解动态不稳定性，我们开发了以纳米级分辨率跟踪微管聚合的方法，从而揭示了传统方法无法解决的基本行为。这项工作从根本上重新评估了动态不稳定性背后的分子力学，并为药物和微管相关蛋白调节微管动力学的机制提供了重要的见解。在这里，我们将微管动力学的纳米分辨率研究与分子模拟相结合，以了解临床相关剂量下紫杉醇的详细作用，以及在阿尔茨海默氏症和其他神经退行性疾病中发挥重要作用的微管调节蛋白tau。 与公共健康相关：拟议的研究结果将更好地理解微管组装的机制，以及有效的化疗药物和tau蛋白如何改变这些机制，tau蛋白在阿尔茨海默氏症和其他神经退行性疾病中发挥核心作用。除了提供对理解和治疗癌症和神经退行性疾病至关重要的过程的更好理解外，通过推进以纳米级精度研究生物力学的变革性技术，将在生物医学科学中产生广泛影响。

DESCRIPTION (provided by applicant): Microtubules are polymers that serve critical roles in establishing and maintaining cellular architecture. Microtubules are the target of important anticancer drugs such as the vinca alkaloids and taxol (paclitaxel), and are thought to play a role in neurodegenerative diseases such as Alzheimer's. Microtubules are dynamic polymers of the protein tubulin, a GTPase, and the energy of GTP hydrolysis drives dynamic instability whereby microtubules spontaneously switch between periods of polymerization and rapid depolymerization. This behavior is regulated by cells to achieve rapid restructuring of the cytoskeleton. To better understand dynamic instability we have developed methods to track microtubule polymerization with nanometer scale resolution, thereby revealing fundamental behaviors that were not resolved by traditional approaches. This work has led to a fundamental reassessment of the molecular mechanics underlying dynamic instability, and provides important insight into the mechanisms by which drugs and microtubule associated proteins can regulate microtubule dynamics. Here we combine nanometer resolution studies of microtubule dynamics with molecular modeling to understand the detailed actions of taxol at clinically relevant doses, and the microtubule regulating protein tau, which plays an important role in Alzheimer's and other neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: The results of proposed studies will yield a better understanding of the mechanics of microtubule assembly, and how these are altered by effective chemotherapy drugs, and the tau protein, which plays a central role in Alzheimer's and other neurodegenerative diseases. In addition to providing a better understanding of processes important for understanding and treating cancer and neurodegenerative disease, broad impact across the biomedical sciences will be achieved by advancing transformative technology for studying biological mechanics with nanometer scale precision.