PROPERTIES OF AXONAL TUBULIN RELATED TO NEURONAL GROWTH

描述（改编自申请人的摘要）： 神经元细胞骨架是一组动态的、高度特化的 在神经系统的许多方面起着关键作用的结构 系统，从神经元形态的产生和维持 来定义神经元的功能域。为了履行这些职能， 细胞骨架的成分必须在生化上专门化， 控制组织和稳定性。应用实验 解决神经元功能特化的本质， 细胞骨架和影响它们的细胞过程。这些是 细胞骨架元素的遗传和生物化学适应， 神经元的特定生物学要求。有些是程序的结果 在神经元和神经胶质细胞的分化过程中开始， 代表对当地环境的反应，并对 这种环境的变化。一种新的生化 神经元微管细胞骨架的特化已经被 它能稳定轴突微管。中的实验 目的：首先分析冷不溶性轴突微管蛋白的生物化学特性， 确定稳定的轴突微管节段的生理作用 神经元功能许多轴突的大尺寸要求轴突 细胞骨架受局部微环境的影响。工作 髓鞘形成缺陷突变小鼠品系的最后资助期 确定了髓鞘神经胶质细胞深刻地影响着 轴突细胞骨架的组成和局部性质。的 神经胶质微环境可以改变组织结构 和动力学的基础轴突细胞骨架将继续， 在脱髓鞘和有髓鞘神经中进行检查。目标下的实验 2寻求确定轴突局部调节的代谢途径 细胞骨架被神经胶质环境破坏。之间的相互作用 PNS和CNS中的髓鞘化神经胶质和轴突将进一步被 其特征在于确定髓鞘形成在多大程度上塑造了 轴突的功能结构。上一个供资期间 有证据表明，在中枢神经系统中形成致密的髓鞘， 这是神经细胞骨架成熟所必需的。实验 目3将鉴定髓鞘形成神经胶质调节神经元的途径 基因表达。这些实验将有助于确定机制， 轴突对其环境的特定分子反应是什么 生成的.我们的目标是了解神经元的动力学 细胞骨架在发育、再生和 神经病理学

DESCRIPTION (Adapted from Applicant's Abstract): The neuronal cytoskeleton is a dynamic, highly specialized set of structures that plays critical roles in many aspects of the nervous system, ranging from generation and maintenance of neuronal morphologies to defining functional domains of a neuron. To serve these functions, the components of the cytoskeleton must be biochemically specialized to control organization and stability. The experiments in the application address both the nature of functional specialization for the neuronal cytoskeleton and the cellular processes that affect them. These are genetic and biochemical adaptations of the cytoskeletal elements to specific biological requirements of neurons. Some result from programs initiated during differentiation of neurons and glia, while others represent responses to the local environment and are sensitive to subsequent changes in that environment. A novel biochemical specialization of the neuronal microtubule cytoskeleton has been identified that stabilizes axonal microtubules. The experiments in the first aim analyze the biochemistry of cold insoluble axonal tubulin and define physiological roles for stable axonal microtubule segments in neuronal function. The large size of many axons requires that the axonal cytoskeleton be influenced by the local microenvironment. Work in the last funding period on mutant strains of mice with defective myelination established that the myelinating glia profoundly influence both the composition and the local properties of the axonal cytoskeleton. The ext4nt to which the glial microenvironment can alter the organization and dynamics of the underlying axonal cytoskeleton will be continued to be examined in demyelinate and myelinated nerves. Experiments under aim 2 seek to define metabolic pathways for local modulation of the axonal cytoskeleton by the glial environment. The interaction between myelinating glia and axons in the PNS and CNS will be further characterized to determine the extent to which myelination sculpts the functional architecture of the axon. During the last funding period evidence accumulated that formation of compact myelin in the CNS was required for the maturation of the neuronal cytoskeleton. Experiments in aim 3 will identify pathways to myelinating glia modulate neuronal gene expression. These experiments will help identify mechanisms by which a specific molecular response of the axon to its environment is generated. The goal is to understand dynamics of the neuronal cytoskeleton that play critical roles in development, regeneration, and neuropathology.