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: 2269373
• 负责人: LAWRENCE F KROMER
• 金额: $ 16.81万
• 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/2269373
• 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.

该研究建议的主要目的是调查角色 酪氨酸激酶受体的TRK家族 被确定为神经营养蛋白的特定受体 中枢神经系统（CNS）及其对伤害的反应。 这些 实验将使用体内实验方法来评估 特定神经营养蛋白（NGF，BDNF和NT-3）与 TRK的受体家族（TRKA，TRKB和TRKC）存在于 产后和成年啮齿动物的前脑和中脑。 免疫组织化学程序，免疫沉淀试验，原位 杂交技术和RNase保护分析将用于 解决四个具体目标。 第一个目的是确定 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 用于识别成熟中存在哪种TRK受体亚型 星形胶质细胞并表征其响应于NGF的磷酸化， BDNF和NT-3。 在第二个特定目标中，产后表达 神经营养蛋白受体将在神经元和 神经胶质细胞和这些细胞种群的分布将是 与在成年中枢神经系统中观察到的相比。 这些实验会 确定哪种受体（TRKA，TRKB或TRKC）的亚型存在 特定的神经元表型。 目标三将调查效果 NGF，BDNF和NT-的脑室室内和核内注射 3在TRK受体上。 提出的研究将集中于评估 septohappocampal中发生的营养因子受体相互作用 和黑质系统。 剂量响应和时间课程 通过不同神经营养蛋白对TRK受体的选择性激活将 在产后和成年大鼠中确定。 在其他实验中， 启动剂量的神经营养蛋白将用于评估是否是否 特定营养因子的给药改变了其表达 受体。 特定目标中的实验四大将集中在 评估病变引起的不同TRK表达的变化 septohampocampal和nigrostriatal Systems中的受体亚型。 这 机械轴切开术和兴奋性病变的影响将是 在未成熟和成年动物中进行评估。 预计 拟议的实验将提供新颖而重要的基本科学 将有助于我们理解可能的信息 神经营养蛋白受体在成熟期间可能扮演的角色 中枢神经系统及其对伤害的反应。