GLIA AND GLYCOCONJUGATES IN THE NEOSTRIATUM

在大脑发育过程中和损伤后，神经胶质细胞 产生各种影响定位和生长的分子 神经元和它们的过程。最近，神经胶质和糖共轭 (糖蛋白、糖脂和糖胺聚糖)边界有 在大脑模式形成过程中被发现，而这些结构 封锁发育中的功能不同的神经元和它们的 神经突起。在发育中的尾壳核(新纹状体)，这些 新纹状体镶嵌的不同隔间周围的边界， 补丁和矩阵，很可能用于分离不断增长的过程 两个不同隔室中的细胞在关键时期 他们的队形。以下提案将测试以下可能的角色 星形胶质细胞和糖结合物在正常和异常发育中的作用 在临床上很重要的大脑区域，黑质纹状体回路。 在目标1中，星形胶质细胞出现和消失的时间进程- 衍生的细胞外基质(ECM)分子将在此确定 巡回赛。具体目标2将重点放在潜在的再现 黑质纹状体回路内不同病变的边界 在发育过程中和在成体中，抗体扰动 对Tenascin基因敲除小鼠的实验和研究将提供 关于特定ECM边界的可能函数的补充数据 神经性生长的分子。第三组实验将利用 两种体外生物测定对某些边界功能的影响 发育过程中细胞-边界相互作用中的分子 黑质纹状体环路以及受损的成人环路 导致另一种类型的神经胶质/糖结合物的出现 边界--星形胶质疤痕。这些研究将在 正常和Tenascin缺乏的动物，其中其他ECM分子 (例如DSD-1)现在可以在黑质纹状体中进行研究和操作 例如，一直缺乏Tenascin的电路。在具体4中， 星形胶质细胞和细胞外基质在神经退行性疾病中的潜在作用 将对影响人类基底节的基因进行广泛的 收集亨廷顿、帕金森和其他疾病和控制 允许对边界元素进行彻底对比的样本 与黑质纹状体环路中神经元丢失的关系 疾病。总而言之，这里提出的研究将建立起 星形胶质细胞及其相关的发育调节的作用 分子在发育过程中塑造正常的基础电路，以及 也许它们是如何对神经元和可能的轴突产生不利影响的 创伤或慢性病后的再生。正常的 黑质纹状体环路的形成和损伤 胶质/糖共轭边界元的函数。神经胶质细胞和 糖偶联物可能在脑模式中发挥重要作用 形成，但细胞和分子相互作用的概括 在正常发育过程中可能发生的这种情况可能会产生有害的影响 成熟受损者神经元存活和神经再生的研究 大脑。

During brain development and again following injury, glial cells produce a variety of molecules that affect the positioning and growth of neurons and their processes. Recently, glial and glycoconjugate (glycoproteins, glycolipids, and glycosaminoglycans) boundaries have been discovered during brain pattern formation, and these structures cordon off developing groups of functionally distinct neurons and their neurites. In the developing caudate-putamen (neostriatum), these boundaries surround different compartments of a neostriatal mosaic, the patch and matrix, and most likely serve to separate growing processes of cells in the two different compartments during a critical period of their formation. The following proposal will test possible roles for astrocytes and glycoconjugates during normal and abnormal development of a clinically important area of the brain, the nigrostriatal circuit. In Aim 1, the time course of appearance and disappearance of astrocyte- derived extracellular matrix (ECM) molecules will be determined in this circuit. Specific Aim 2 will focus on the potential reappearance of boundaries following different lesions within the nigrostriatal circuit during development and in the adult, and antibody perturbation experiments versus studies on a tenascin-knockout mouse will provide complementary data on possible functions of particular ECM boundary molecules on neuritic growth. A third set of experiments will exploit two in vitro bioassays to affect the functions of certain boundary molecules during cell-boundary interactions in the developing nigrostriatal circuit, as well as in the lesioned adult circuit that results in the appearance of another type of glial/glycoconjugate boundary - the astroglial scar. These studies will be performed in normal as well as tenascin-deficient animals where other ECM molecules (e.g. DSD-1) can now be studied and manipulated in a nigrostriatal circuit that, e.g., has always lacked tenascin. In Specific 4, the potential roles of astrocytes and ECM in neurodegenerative diseases that affect the human basal ganglia will be explored in an extensive collection of Huntington's, Parkinson's, and other disease and control specimens that allow a thorough correlation of boundary elements in relation to neuronal loss that occurs in nigrostriatal circuit in these diseases. In all, the studies proposed here will establish functional roles for astrocytes and associated, developmentally-regulated molecules in shaping normal basal circuitry during development, and perhaps how they adversely affect neurons and possible neurite regeneration following traumatic injury or chronic disease. The normal developing and injured nigrostriatal circuit is amenable to studies of functions of glial/glycoconjugate boundary elements. Glia and glycoconjugates may play important roles during brain pattern formation, but the recapitulation of cell and molecular interactions that might occur during normal development may have deleterious effects on neuron survival and neuritic regrowth in the compromised, mature brain.