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.

这项研究的主要目的是调查的作用 酪氨酸激酶受体的trk家族，已经被 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）与神经元之间的相互作用 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。 免疫组织化学方法，免疫沉淀试验，原位 杂交技术和RNA酶保护试验将用于 实现四个具体目标。 第一个目标是确定 在成熟星形胶质细胞中存在的神经营养因子受体。 这些 研究将视神经作为体内实验准备， 为了鉴定哪种trk受体亚型存在于成熟的 星形胶质细胞和表征其响应于NGF的磷酸化， BDNF和NT-3。 在第二个具体目标中， 神经营养素受体将在神经元和 神经胶质细胞和这些细胞群的分布将是 与成人CNS中观察到的相比。 这些实验将 确定哪种受体亚型（trkA、trkB或trkC）存在于 一种特殊的神经元表型 目标三将研究 脑室内和脑实质内注射NGF、BDNF和NT- TRK受体3例。 拟议的研究将集中于评估 营养因子-受体相互作用发生在隔海马 和黑质纹状体系统 剂量反应和时间进程的 通过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中测定。 在另外的实验中， 将使用神经营养素的引发剂量来评估是否 特定营养因子的施用改变了其 受体的 具体目标四的实验将集中在 评估损伤诱导的不同trk表达的变化 隔海马和黑质纹状体系统中的受体亚型。 的 机械性轴突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价。 预计该 拟议的实验将提供新的和重要的基础科学 这些信息将有助于我们了解可能的 神经营养因子受体在神经细胞成熟过程中可能发挥的作用 CNS及其对损伤的反应。