MECHANISM AND CONTROL OF BRAIN MICROTUBULE DYNAMICS

脑微管动力学机制及控制

• 批准号: 2714417
• 负责人: LESLIE WILSON
• 金额: $ 24.22万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-07-01 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2714417
• 关键词: colchicine; guanosine triphosphate; intermolecular interaction; microtubule associated protein; microtubules; molecular dynamics; phosphoproteins; protein isoforms; protein structure function; tau proteins; tubulin; video microscopy

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.

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）， 对发展、结构组织、稳定和 神经元的轴突和树突过程的功能。 然而，MT 神经元和其他细胞在分子水平上的功能很差， 明白 微管通过成核-伸长机制生长 但它们不是简单的平衡聚合物。 鸟苷-5 '-三磷酸是 在微管蛋白形成过程中水解为鸟苷-5 '-二磷酸和正磷酸 除了MT结束，这是假设创造一个稳定的“帽” 在最后。 上限的增益和损失产生独特的增长和缩短 这对微管功能至关重要。 动力是 在细胞中被精细地调节。 MT动力学的调节受一个 各种地图，微管蛋白同种型组成的MT，并通过因素 作用于“帽”机制。 本研究着重探讨了其作用机制， 体外MT动力学的调节。 目标是阐明 决定和控制MT动力学的机制。 一个主要目标是 确定神经元MAP，tau，MAP 1B，MAP 2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， 研究MAP与MT结合的动力学， MAP对GTP水解的稳态速率的作用，以及对 MAP对稳定帽的尺寸和化学性质的作用。 tau蛋白的过度磷酸化形式是tau蛋白的主要蛋白组分。 神经纤维缠结中的成对螺旋丝 老年痴呆症 因此，了解tau蛋白如何控制MT的稳定性， 最终导致开发出类似tau的药物来治疗 老年痴呆症 第二个目的是确定B-微管蛋白如何 同种型组成调节稳态MT动力学和功能。 的 第三个目的是阐明药物秋水仙碱如何调节MT动力学。 了解秋水仙碱的作用机制可能会揭示如何 细胞中作用于MT末端的调节因子可能调节MT动力学， 功能 第四个目的是阐明负责的上限机制 MT独特的动态行为。