DRUG INTERACTIONS WITH BRAIN MICROTUBULE PROTEINS

微管是真核生物细胞骨架的重要组成部分 细胞，并参与细胞形状的发育和维持， 在许多种类的细胞内运动中。 他们在中部地区很突出， 神经系统在组织中特别重要， 神经元的轴突和树突过程的功能。 微管 在体外和细胞中表现出多种聚合行为， 我们有充分的理由相信 行为在微管功能中很重要。 微管功能 例如与轴突的组织和发育有关的那些， 树突可以通过调节组件来确定和调节， 微管末端的分解反应。 聚合动力学在微管功能中的作用 机械水平不被理解。 专注于脑微管 系统，这项建议的主要战略是调查的动态 微管蛋白添加和微管末端损失的体外研究， 了解微管蛋白增加和丢失的机制， 识别和阐明微管的作用机制， 相关的蛋白质，控制组装和拆卸动力学， 神经元细胞 将采用一系列程序， 区分单个微管的微管蛋白添加和丢失事件 形接头. 微管蛋白的添加和损失的动力学在末端的 由未修饰和修饰后的大脑组成的微管 微管蛋白（脱酪氨酸、谷氨酰化、ADP-核糖基化）和特异性 将检查未修饰的和修饰的（磷酸化的）神经元MAP。 这项工作将集中在MAP-2和Tau的作用，这两个突出的神经元 微管相关蛋白在发育中很重要， 树突和轴突的组织和功能。 的 工作还将集中在微管GTP水解的作用 聚合法 目的是表征通量和动态 微管的不稳定性参数，并确定什么 特定微管相关蛋白，特定微管蛋白 同种型，微管蛋白和微管的翻译后修饰- 相关的蛋白质和药物秋水仙碱，调节和调节 微管聚合

Microtubules are important components of the cytoskeleton of eukaryotic cells, and participate in the development and maintenance of cell shape and in many kinds of intracellular movement. They are prominent in the central nervous system where they are especially important in the organization and function of axonal and dendritic processes of neurons. Microtubules exhibit a wide variety of polymerization behaviors in vitro and in cells, and there is strong reason to believe that the various polymerization behaviors are important in microtubule function. Microtubule functions such as those related to the organization and development of axons and dendrites may be determined and regulated by modulation of the assembly and disassemble reactions at microtubule ends. The role of polymerization dynamics in the function of microtubules at a mechanistic level is not understood. With a focus on brain microtubule systems, the main strategy of this proposal is to investigate the dynamics of tubulin addition and loss at microtubule ends in vitro, with the goals of understanding the mechanisms that govern tubulin addition and loss and identifying and elucidating mechanistically the actions of microtubule- associated proteins that control assembly and disassembly dynamics in neuronal cells. A combination of procedures will be employed that can distinguish tubulin addition and loss events at the individual microtubule ends. The dynamics of tubulin addition and loss at the ends of microtubules composed of unmodified and posttranslationally-modified brain tubulins (detyrosinated, glutamylated, ADP-ribosylated) and specific unmodified and modified (phosphorylated) neuronal MAPs will be examined. The work will focus on the actions of MAP-2 and Tau, two prominent neuronal microtubule-associated proteins that are important in the development, organization, and functions of dendrites and axons, respectively. The work will also focus on the role of GTP hydrolysis in microtubule polymerization. The objective is to characterize the flux and dynamic instability parameters of the microtubules, and to determine to what extent and how specific microtubule-associated proteins, specific tubulin isotypes, posttranslational modifications of tubulin and microtubule- associated proteins, and the drug colchicine, modulate and regulate microtubule polymerization.