PLASTICITY IN THE AGING OLFACTORY SYSTEM

老化嗅觉系统的可塑性

• 批准号: 6707544
• 负责人: Harriet D. Baker
• 金额: $ 36.3万
• 依托单位: WINIFRED MASTERSON BURKE MED RES INST
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-02-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6707544
• 关键词: DNA footprinting; Parkinson' s disease; aging; biological signal transduction; cell differentiation; cell migration; cell proliferation; dopamine; gamma aminobutyrate; gel mobility shift assay; genetically modified animals; immunocytochemistry; laboratory mouse; neural plasticity; neurogenetics; neurons; olfactory lobe; olfactory stimulus; phenotype; polymerase chain reaction; sensory deprivation; stem cells; substantia nigra; tissue /cell culture; transcription factor; tyrosine 3 monooxygenase

Elucidating the mechanisms that determine neuronal phenotype during development and that regulate gene expression in adults is a key issue in neurobiology. Understanding these phenomena in dopaminergic (DA) neurons has been the focus of much research because of their loss in the substantia nigra pars compacta in Parkinson's disease (PD). The olfactory bulb (OB) contains a population of periglomerular (PG) DA neurons with characteristics that provide both an ideal model for understanding regulation of DA phenotypic expression and a potential source of cells for transplantation. OB DA neurons are derived throughout life from stem cells in the anterior subventricular zone (SVZa) and migrate in the rostral migratory stream to the OB. Data from a transgenic mouse produced in our laboratory, expressing a lacZ reporter gene driven by a 9kb tyrosine hydroxylase (TH) promoter suggest the testable hypothesis that OB DA precursors are phenotypically committed before they migrate to their final position in the glomerular layer but that full DA expression requires environmental cues during progenitor cell migration. Two specific aims will test this hypothesis. Aim 1 will characterize expression of molecules associated with DA phenotypic differentiation in developing and adult animals as well as signaling pathways involved in TH expression. Aim 1 also will employ in vivo tracer injections and slice cultures to investigate mechanisms regulating proliferation and migration of DA neurons. Aim 2 will employ primary cultures of neonatal OB taken from the lacZ expressing transgenic mice to delineate signal transduction pathways required for differentiation of DA neurons and regulation of TH expression. Aim 2 will use a newly characterized OB clonal cell line derived from mice expressing SV4OT-antigen (ts) directed by the 9kb TH promoter to study molecular mechanisms involved in DA differentiation. The proposed aims will delineate the molecular mechanisms underlying differentiation of SVZa stem cells into DA neurons. Understanding pathways involved in differentiation and regulation of OB DA neurons is necessary to establishing their potential for transplants in PD patients.

阐明决定神经元表型的机制 在发育过程中以及调节成人基因表达是一个关键问题 在神经生物学中。了解多巴胺能 (DA) 神经元中的这些现象有助于 由于它们在黑质中的缺失而成为许多研究的焦点 帕金森病 (PD) 中的致密部。嗅球 (OB) 包含一个 肾小球周围 (PG) DA 神经元群体具有提供以下特性的特性： 两者都是了解 DA 表型表达调控的理想模型 以及移植细胞的潜在来源。 OB DA 神经元衍生 整个生命过程中来自前室下区 (SVZa) 的干细胞和 沿吻端迁徙流迁徙至 OB。来自转基因小鼠的数据 我们实验室生产的，表达由 9kb 驱动的 lacZ 报告基因 酪氨酸羟化酶 (TH) 启动子提出了可检验的假设 OB DA 前体在迁移到最终阶段之前就已表现出典型的特征 肾小球层中的位置，但完整的 DA 表达需要 祖细胞迁移过程中的环境线索。两个具体目标将 检验这个假设。目标 1 将表征分子的表达 与发育中和成年动物的 DA 表型分化相关 以及参与 TH 表达的信号通路。目标 1 还将采用 体内示踪剂注射和切片培养以研究机制 调节 DA 神经元的增殖和迁移。目标 2 将采用初级 取自表达 lacZ 的转基因小鼠的新生 OB 培养物 描绘 DA 分化所需的信号转导途径 神经元和 TH 表达的调节。目标 2 将使用新特征的 源自表达 SV4OT 抗原 (ts) 的小鼠的 OB 克隆细胞系 9kb TH 启动子用于研究 DA 涉及的分子机制 差异化。拟议的目标将描述分子机制 SVZa 干细胞向 DA 神经元的潜在分化。理解 参与 OB DA 神经元分化和调节的途径是 对于确定它们在帕金森病患者中进行移植的潜力是必要的。