NEURAL PLASTICITY--ROLE OF TROPHIC FACTORS AND RECEPTORS

这项研究提案的主要目的是调查 酪氨酸激酶受体的trk家族，它们已经被 在神经营养因子的成熟过程中被鉴定为神经营养因子的特异性受体 中枢神经系统(CNS)及其对损伤的反应。这些 实验将使用体内实验方法来评估 特异性神经营养因子(NGF、BDNF和NT-3)与血管内皮生长因子的相互作用 Trk受体家族(TrkA、TrkB和trkC)，存在于 出生后和成年啮齿动物的前脑和中脑。 免疫组织化学程序，免疫沉淀分析，原位 杂交技术和核糖核酸酶保护分析将用于 解决四个具体目标。第一个目标是确定 神经营养因子受体存在于成熟的星形胶质细胞中。这些 研究将使用视神经作为活体实验准备 用于确定成熟患者中存在哪种trk受体亚型 星形胶质细胞及其对NGF反应的磷酸化的特征， BDNF和NT-3。在第二个具体目标中，出生后表达 神经营养素受体的特征将在神经元和 胶质细胞和这些细胞群的分布将是 与成人中枢神经系统相比较。这些实验将 确定受体的哪个子类型(TrkA、TrkB或trkC) 一种特殊的神经元表型。目标三将调查这些影响 脑室和脑实质内注射NGF、BDNF和NT- 3在trk受体上。拟议的研究将集中于评估 隔-海马区的营养因子-受体相互作用 和黑质纹状体系统。剂量反应和时间进程 不同的神经营养因子选择性激活Trk受体 在出生后和成年大鼠身上被测定。在其他实验中， 神经营养因子的启动剂量将被用来评估 给予特定的营养因子改变其表达 受体。具体目标四的实验将集中在 评估损伤引起的不同trk表达的变化 隔-海马区和黑质纹状体系统的受体亚型。这个 机械轴突切断术和兴奋性毒性损伤的影响都将是 在未成熟和成年动物身上进行评估。据预计， 拟议的实验将为新的和重要的基础科学 这些信息将有助于我们理解 神经营养素受体在细胞成熟过程中的作用 中枢神经系统和它对受伤的反应。

The major objective of this research proposal is to investigate the role of the trk family of tyrosine kinase receptors, which have been identified as specific receptors for neurotrophins, in the maturation of the central nervous system (CNS) and in its response to injury. These experiments will use an in vivo experimental approach to evaluate the interactions between specific neurotrophins (NGF, BDNF, and NT-3) and the trk family of receptors (trkA, trkB, and trkC) that are present in the forebrain and mesencephalon of postnatal and adult rodents. Immunohistochemical procedures, immunoprecipitation assays, in situ hybridization techniques, and RNase protection assays will be used to address four specific aims. the first aim is to identify the neurotrophin receptor that is present in mature astrocytes. These studies will use the optic nerve as an in vivo experimental preparation for identifying which trk receptor subtype is present in mature astrocytes and for characterizing its phosphorylation in response to NGF, BDNF, and NT-3. In the second specific aim the postnatal expression of the neurotrophin receptors will be characterized in both neuronal and glial cells and the distribution of these cell populations will be compared with that observed in the adult CNS. These experiments will determine which subtype of receptor (trkA, trkB or trkC) is present on a specific neuronal phenotype. Aim three will investigate the effects of intraventricular and intraparenchymal injections of NGF, BDNF, and NT- 3 on trk receptors. The proposed studies will concentrate on evaluating trophic factor-receptor interactions that occur in the septohippocampal and nigrostriatal systems. A dose response and time course for the selective activation of trk receptors by the different neurotrophins will be determined in postnatal and adult rats. In additional experiments, priming doses of neurotrophins will be used to evaluate whether the administration of a specific trophic factor alters the expression of its receptor. The experiments in specific aim four will concentrate on evaluating lesion induced changes in the expression of the different trk receptor subtypes in the septohippocampal and nigrostriatal systems. The effects of both mechanical axotomy and excitotoxic lesions will be evaluated in immature and adult animals. It is anticipated that the proposed experiments will provide novel and important basic scientific information that will contribute toward our understanding of the possible role that neurotrophin receptors may play during the maturation of the CNS and in its response to injury.