Microtubule Mechanics at the Nanoscale

纳米尺度的微管力学

• 批准号: 7259066
• 负责人: ALAN J HUNT
• 金额: $ 27.86万
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7259066
• 关键词: Microtubule; Mechanics; Nanoscale

DESCRIPTION (provided by applicant): Microtubules (MTs) 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 cytoskeleton. 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 dynamics this 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.

描述（由申请人提供）：微管（MT）是刚性聚合物，在细胞结构中作为结构支撑和马达蛋白的轨道发挥关键作用。在这种能力中，MT是从有丝分裂染色体分离到细胞形态和囊泡运输变化的细胞过程的中心。MT也是抗癌药物如长春花生物碱和紫杉醇的重要靶点。MT是固有的动态的，并且它们的聚合由细胞调节以实现细胞骨架的快速重构。MT聚合动力学的分子机制还没有很好地理解，这混淆了对MT如何被细胞结构化和调节以及化疗药物作用机制的严格理解。这一建议的特点微管聚合过程中的分子事件。通过将光镊与一种新的由电子照相产生的屏障系统相结合，以纳米精度跟踪动态MT尖端的事件。这揭示了由于光分辨率限制而先前未观察到的聚合的关键细节。本试验将用于表征介导微管生长、缩短和稳定性的分子事件。进一步的研究将探讨紫杉醇和微管相关蛋白tau对微管动力学调节的分子动力学基础。为了建立一个微管动力学/这些结果的机械理解将被解释的物理模型的上下文中描述的演变结构之间的相互作用在微管尖端和亚基添加和损失的动力学。相关性：这项工作将提供对维持生命的基本细胞力学的理解。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的疾病过程的理解，如有丝分裂失败（例如，在衰老和遗传疾病，如唐氏综合征）和神经退行性疾病。具体解决的是重要的化疗药物紫杉醇的机制，和MT结合蛋白tau在各种神经退行性疾病中起着核心作用。