NEURAL PLASTICITY--ROLE OF TROPHIC FACTORS AND RECEPTORS

神经可塑性——营养因子和受体的作用

• 批准号: 2269374
• 负责人: LAWRENCE F KROMER
• 金额: $ 17.59万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-12-01 至 1996-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2269374
• 关键词: RNase protection assay; astrocytes; cell population study; denervation; experimental brain lesion; glia; growth factor receptors; hippocampus; immunocytochemistry; immunoprecipitation; in situ hybridization; laboratory rat; mature animal; neural plasticity; neurogenesis; neuropharmacology; neurotrophic factors; newborn animals; optic nerve; phenotype; phosphorylation; protein tyrosine kinase; receptor expression

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.

本研究计划的主要目的是调查其作用 酪氨酸激酶受体 trk 家族的成员，已被 被鉴定为神经营养素的特异性受体，在成熟过程中 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 特定神经营养因子（NGF、BDNF 和 NT-3）与 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、免疫沉淀测定、原位 杂交技术和 RNase 保护测定将用于 解决四个具体目标。 第一个目标是确定 存在于成熟星形胶质细胞中的神经营养蛋白受体。 这些 研究将使用视神经作为体内实验制剂 用于鉴定成熟细胞中存在哪种 trk 受体亚型 星形胶质细胞并表征其响应 NGF 的磷酸化， BDNF 和 NT-3。 在第二个具体目标中，产后表达 神经营养蛋白受体的特征在于神经元和 神经胶质细胞和这些细胞群的分布将是 与在成人中枢神经系统中观察到的结果相比。 这些实验将 确定受体亚型（trkA、trkB 或 trkC）存在于 特定的神经元表型。 目标三将调查其影响 脑室内和实质内注射 NGF、BDNF 和 NT- 3 对trk 受体。 拟议的研究将集中于评估 发生在隔海马的营养因子-受体相互作用 和黑质纹状体系统。 剂量反应和时间进程 不同神经营养因子选择性激活 trk 受体 在出生后和成年大鼠中进行测定。 在额外的实验中， 神经营养素的启动剂量将用于评估是否 特定营养因子的施用会改变其表达 受体。 具体目标四的实验将集中于 评估病变引起的不同 trk 表达的变化 隔海马和黑质纹状体系统中的受体亚型。 这 机械轴索切断术和兴奋性毒性损伤的影响将是 在未成熟和成年动物中进行评估。 预计 所提出的实验将提供新颖且重要的基础科学 有助于我们理解可能发生的情况的信息 神经营养蛋白受体在神经元成熟过程中可能发挥的作用 中枢神经系统及其对损伤的反应。