Microtubule Mechanics at the Nanoscale

微管是一种刚性聚合物，在细胞结构中起着重要的结构支撑作用 以及马达蛋白质的轨迹。在这一能力中，MTS是从有丝分裂到细胞过程的中心 染色体分离导致细胞形态和囊泡运输的变化。MT也很重要 长春花碱和紫杉醇等抗癌药物的靶标。MT本质上是动态的，它们的 聚合是由细胞调节的，以实现细胞骨架的快速重组。 MT聚合动力学的分子机制还不是很清楚，这使人感到困惑 严格理解MT是如何由细胞构建和调节的，以及作用机制 化疗药物。这一建议描述了微管中的分子事件。 聚合反应。通过将光学镊子与一种新的光刻系统相结合 通过设置障碍物，动态MT尖端的事件以纳米级精度进行跟踪。这揭示了关键 由于光分辨率的限制，以前没有观察到的聚合细节。这个化验 将被应用于表征调节微管生长、缩短和稳定性的分子事件。 更多的研究将考察微管动力学调控的分子动力学。 紫杉醇和微管相关蛋白tau。建立对微管的力学理解 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 微管顶端的演变结构和亚基添加和丢失的动力学之间的关系。 相关性：这项工作将提供对细胞力学的理解，这是维持 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MTS的疾病过程，如有丝分裂失败(例如，衰老和遗传性疾病，如 唐氏综合征)和神经退行性疾病。具体讨论的是 重要的化疗药物紫杉醇，以及MT结合蛋白tau，它在各种 神经退行性疾病。

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.