Mechanism & Control of Brain Microtubule Dynamics

描述(由申请人提供)： 微管(MTS)，由ab微管蛋白杂二聚体组成的管状聚合物 和一系列不同的MT相关蛋白(MAP)，对于 轴突的发展、结构组织、稳定性和功能 和神经元的树突。MTS不是简单的平衡聚合物。 鸟苷-5‘-三磷酸不可逆水解成 微管蛋白过程中的鸟苷-5‘-二磷酸和正磷酸盐， 它创建了两种独特的动态行为：踏板和动态 不稳定。这些行为对细胞中的MT功能至关重要，并且 监管严密。动力不稳定和跑动都是固有的。 MTS微管蛋白骨架的性质，而MAP作用于MT表面 末端控制着动态。一个主要的目标是阐明这些机制。 负责MT独特的动态行为。第二个主要目标是 确定神经元映射调节动力学的重要性。这些研究将 包括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。研究重点将放在重组脑的动力学上 MTS和体外特定的神经元图谱，以及活体神经元的MT动力学 和非神经细胞。一个主要的焦点将是tau蛋白和突变 形式的tau，与阿尔茨海默病有关，并有因果联系 到人类的额颞痴呆(FTDP-17)。

DESCRIPTION (provided by applicant): Microtubules (MTs), tube-shaped polymers composed of ab 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 dendntic processes of neurons. MTs are not simple equilibrium polymers. Guanosine-5'-triphosphate is irreversibly hydrolyzed to guanosine-5'-diphosphate and orthophosphate during tubulin addition to the MTs, which creates two unique dynamic behaviors, treadmilling and dynamic instability. These behaviors are critical for MT function in cells, and are finely regulated. Both dynamic instability and treadmilling are intrinsic properties of the tubulin backbone of MTs, while MAPs acting at the MT surfaces and ends control the dynamics. One major goal is to elucidate the mechanisms responsible for the MT's unique dynamic behaviors. A second major goal is to determine how important neuronal MAPs regulate dynamics. These studies will involve high-resolution video microscopy and radiolabeled guanine-nucleotide exchange strategies. Studies will focus on the dynamics of reconstituted brain MTs and specific neuronal MAPs in vitro, and on MT dynamics in living neuronal and non-neuronal cells. A main focus will be on the tau proteins and mutated forms of tau, which are involved in Alzheimer's disease and are causally linked to frontotemporal dementias (FTDP-17) in humans.