Microtubule Mechanics at the Nanoscale

纳米尺度的微管力学

• 批准号: 8518368
• 负责人: David J. Odde
• 金额: $ 29.79万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-21 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8518368
• 关键词: A-Microtubule; Address; Adverse effects; Affect; Alzheimer' s Disease; Antimitotic Agents; Antineoplastic Agents; Architecture; Behavior; Binding; Binding Proteins; Biological; Biological Assay; Biophysics; Cells; Chromosome Segregation; Clinical; Colchicine; Complex; Controlled Environment; Creutzfeldt-Jakob Syndrome; Cytoskeleton; Data; Dose; Drug resistance; Environment; Frequencies; Growth; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Hydrolysis; In Vitro; Kinetics; Malignant Neoplasms; Mammary Neoplasms; Measurement; Measures; Mechanics; Mediating; Methods; Microtubule Polymerization; Microtubule Stabilization; Microtubule-Associated Proteins; Microtubules; Modeling; Molecular; Molecular Models; Motor; Neurodegenerative Disorders; Neurofibrillary Tangles; Paclitaxel; Pharmaceutical Preparations; Physiological; Play; Polymers; Primary Lateral Sclerosis; Process; Proteins; RNA Interference; Regulation; Resistance; Resolution; Role; Science; Technology; Tubulin; Vinca Alkaloids; Work; chemotherapy; clinically relevant; depolymerization; fast axonal transport; human disease; in vivo; insight; molecular mechanics; molecular modeling; nanometer; nanoscale; neoplastic cell; neuronal transport; overexpression; polymerization; public health relevance; tau Proteins; tau expression; tumor

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.

描述（由申请人提供）：微管是在建立和维持细胞结构中起关键作用的聚合物。微管是重要的抗癌药物如长春花生物碱和紫杉醇（紫杉醇）的靶点，并被认为在神经退行性疾病如阿尔茨海默氏症中发挥作用。微管是蛋白质微管蛋白（一种GTP酶）的动态聚合物，GTP水解的能量驱动动态不稳定性，由此微管自发地在聚合和快速解聚的时期之间切换。这种行为是由细胞调节，以实现细胞骨架的快速重组。为了更好地理解动态不稳定性，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。这项工作导致了一个基本的重新评估的分子力学基础的动态不稳定性，并提供了重要的洞察机制，药物和微管相关蛋白可以调节微管动力学。在这里，我们结合联合收割机纳米分辨率的微管动力学研究与分子建模，以了解临床相关剂量的紫杉醇的详细行动，和微管调节蛋白tau，这在阿尔茨海默氏症和其他神经退行性疾病中起着重要作用。