MECHANISM AND CONTROL OF BRAIN MICROTUBULE DYNAMICS

描述：微管(Mt)，由a-b组成的管状聚合物 微管蛋白异源二聚体和多种MT相关蛋白(MAP)， 对于发展、结构组织、稳定性和 神经元的轴突和树突的功能。然而，MT 神经元和其他细胞在分子水平上的功能很差 明白了。微管通过成核-伸长机制聚合 但它们不是简单的平衡聚合物。鸟苷-5‘-三磷酸是 在微管形成过程中被水解为鸟苷-5‘-二磷酸和正磷酸 对MT的补充结束了，这被认为是为了创造一个稳定的“上限” 在尽头。盖的得失创造了独特的生长和做空 对微管功能至关重要的动力学。其动因是 在细胞中调节得很好。MT动力学的调节受一种 MAP的多样性，通过MT的微管蛋白同种类型组成和按因素 按照“上限”机制行事。本研究的重点在于其作用机制和作用机制。 MT的体外动力学调节。我们的目标是阐明 决定和控制MT动态的机制。一个主要目标是 确定神经元映射tau、MAP1B、MAP2和MAPIA如何控制 稳态动力学。这些研究将涉及使用高分辨率 视频显微镜和放射性标记的鸟嘌呤核苷酸交换策略 调查与MAP绑定到MTS、MTS、 MAP对稳态GTP水解率的作用，以及对 地图对稳定盖的大小和化学性质的作用。 一种高度磷酸化的tau是主要的蛋白质成分 慢性阻塞性肺疾病患者神经原纤维缠结中的成对螺旋细丝 阿尔茨海默氏症。因此，了解tau如何控制MT稳定性可能 最终导致开发出治疗糖尿病的tau类药物 阿尔茨海默氏症。第二个目标是确定b-微管蛋白是如何 同型组成调节稳态MT的动态和功能。这个 第三个目的是阐明药物秋水仙碱是如何调节MT动力学的。 了解秋水仙碱的作用机制可能会揭示 作用于MT末端的细胞中的调节因子可能调节MT的动态和 功能。第四个目的是阐明负责的封顶机制 对于MT独特的动态行为。

DESCRIPTION: Microtubules (MTs), tube-shaped polymers composed of a-b tubulin heterodimers and a diverse array of MT-associated proteins (MAPs), are critical for the development, structural organization, stability, and functions of the axonal and dendritic processes of neurons. However, MT functions in neurons and other cells at the molecular level are poorly understood. Microtubules polymerize by a nucleation-elongation mechanism but they are not simple equilibrium polymers. Guanosine-5'-triphosphate is hydrolyzed to guanosine-5'-diphosphate and orthophosphate during tubulin addition to the MT ends, which is hypothesized to create a stabilizing "cap" at the ends. Gain and loss of the cap create unique growing and shortening dynamics that are critical for microtubule function. The dynamics are finely regulated in cells. Regulation of MT dynamics is effected by a variety of MAPs, by the tubulin isotype composition of a MT, and by factors acting on the "cap" mechanism. This study is focused on the mechanism and regulation of MT dynamics in vitro . The goals are to elucidate the mechanisms that determine and control MT dynamics. A major aim is to determine how the neuronal MAPs, tau, MAP1B, MAP2, and MAPIA, control steady-state dynamics. These studies will involve use of high resolution video microscopy and radiolabeled guanine-nucleotide exchange strategies to investigate dynamics in relation to MAP binding to the MTs, to the Mts, to the action of the MAPs on steady-state rates of GTP hydrolysis, and to the actions of the MAPs on the size and chemical nature of the stabilizing cap. A hyper-phosphorylated form of tau is the main protein component of the paired helical filaments in the neurofibrillary tangles of patients with Alzheimer's disease. Thus, understanding how tau controls MT stability may eventually lead to the development of tau-like drugs for the treatment of Alzheimer's disease. The second aim is to determine how the b- tubulin isotype composition regulated steady-state MT dynamics and function. The third aim is to elucidate how the drug colchicine modulates MT dynamics. Understanding the mechanism of action of colchicine may reveal how regulatory factors in cells acting at MT ends might modulate MT dynamics and function. The fourth aim is to elucidate the capping mechanism responsible for the MT's unique dynamic behaviors.