Microtubule Mechanics at the Nanoscale

纳米尺度的微管力学

• 批准号: 7921996
• 负责人: ALAN J HUNT
• 金额: $ 27万
• 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7921996
• 关键词: A-Microtubule; Address; Aging; Antineoplastic Agents; Architecture; Behavior; Binding Proteins; Biochemical; Biological Assay; Cell physiology; Cells; Cellular Morphology; Cellular Structures; Chromosome Segregation; Cryoelectron Microscopy; Cytoskeleton; Disease; Down Syndrome; Event; Failure; GTP Binding; Growth; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Hereditary Disease; Hydrolysis; Individual; Kinetics; Life; Light; Mechanics; Mediating; Microtubule Polymerization; Microtubules; Mitotic; Mitotic Chromosome; Modeling; Molecular; Motor; Movement; Neurodegenerative Disorders; Paclitaxel; Play; Polymers; Process; Proteins; Regulation; Relaxation; Resolution; Role; Sampling; Structure; Subcellular structure; System; Testing; Time; Transport Vesicles; Tubulin; Vinca Alkaloids; Work; chemotherapy; depolymerization; laser tweezer; nanometer; nanoscale; novel; physical model; polymerization; tau Proteins

Vlicrotubules (Mis) are rigid polymers that serve a critical role in cellular architecture as structural buttresses and tracks for motor proteins. In this capacity MTs are central to cellular processes ranging from mitotic chromosome segregation to changes in cellular morphology and vesicle transport. MTs are also important targets for anticancer drugs such as the vinca alkaloids and taxol. MTs are inherently dynamic, and their polymerization is regulated by cells to achieve rapid restructuring of the cytoskeletdn. The molecular mechanisms of MT polymerization dynamics are not well understood, and this confounds rigorous understanding how MTs are structured and regulated by cells, as well as the mechanism of action of chemotherapy agents. This proposal characterizes the molecular events during microtubule polymerization. By combining optical tweezers with a novel system of photolithographically produced barriers, the events at the tip of a dynamic MT are tracked with nanometer precision. This reveals critical details of polymerization that have not been previously observed due to the light resolution limit. This assay will be applied to characterize molecular events that mediate microtubule growth, shortening, and stability. Additional studies will examine the molecular kinetics underlying modulation of microtubule dynamics by taxol and the microtubule associated protein tau. To build a mechanistic understanding of microtubule dynamics/these results will be interpreted in the context of physical models that describe the interplay between the evolving structure at a microtubule tip and the kinetics of subunit addition and loss. Relevance: This work will provide an understanding of cellular mechanics fundamental to the sustenance of life. By describing the fundamental mechanics of MT dynamicsthis work will increase our understanding of disease processes that involve MTs, such as mitotic failures (e.g. in aging and genetic diseases such as Down's syndrome), and neurodegenerative disease. Specifically addressed are the mechanisms of the important chemotherapy agent taxol, and the MT binding protein tau which plays a central role in a variety of neurodegenerative diseases.

微管是一种刚性聚合物，在细胞结构中起着重要的支撑作用 和马达蛋白的轨迹。在这种能力中，MT是从有丝分裂到细胞分裂的细胞过程的中心。 染色体分离的细胞形态和囊泡运输的变化。MT也很重要 抗癌药物如长春花生物碱和紫杉醇的靶点。MT具有内在的动态性， 聚合由细胞调节以实现细胞色素的快速重组。 MT聚合动力学的分子机制还没有很好地理解，这使得 严格理解MT是如何被细胞构造和调节的，以及作用机制 化疗药物。这一建议的特点是微管过程中的分子事件 聚合法通过将光镊与一种新颖的光学成像系统相结合， 障碍，动态MT尖端的事件以纳米精度跟踪。这表明， 由于光分辨率限制，以前没有观察到的聚合细节。该测定 将适用于表征介导微管生长，缩短和稳定性的分子事件。 进一步的研究将检查微管动力学调制的分子动力学基础， 紫杉醇和微管相关蛋白tau。建立对微管的机械理解 动力学/这些结果将在描述相互作用的物理模型的背景下进行解释 在微管尖端的演变结构和亚基添加和损失的动力学之间。 相关性：这项工作将提供一个基本的维持细胞力学的理解， 生活通过描述MT动力学的基本机制，这项工作将增加我们对 涉及MT的疾病过程，例如有丝分裂失败（例如衰老和遗传疾病， 唐氏综合征）和神经退行性疾病。具体讨论的是 重要的化疗剂紫杉醇，和MT结合蛋白tau，其在多种化疗中起着中心作用。 神经退行性疾病