PLASTICITY IN THE AGING OLFACTORY SYSTEM

老化嗅觉系统的可塑性

• 批准号: 7022280
• 负责人: Harriet D. Baker
• 金额: $ 42.54万
• 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 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7022280
• 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，调节成年人的基因表达是一个关键问题 在神经生物学中。了解多巴胺能神经元中的这些现象， 由于它们在黑质中的丢失， 帕金森病（PD）的丘脑腹外侧部。嗅球（OB）包含一个 肾小球周围（PG）DA神经元群体的特征，提供 两者都是理解DA表型表达调控的理想模型， 也是移植用细胞的潜在来源。OB DA神经元来源于 在整个生命过程中，来自室管膜下前区（SVZa）的干细胞， 在嘴侧洄游流中洄游到OB。来自转基因小鼠的数据 在我们的实验室生产，表达lacZ报告基因驱动的9 kb的 酪氨酸羟化酶（TH）启动子提示OB DA 前体在迁移到其最终位置之前是表型定型的。 在肾小球层的位置，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 测试这个假设。目标1将表征分子的表达 与发育和成年动物中DA表型分化相关 以及参与TH表达的信号通路。Aim 1还将使用 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。Aim 2将使用初级 从表达lacZ的转基因小鼠获得的新生OB培养物， 阐明DA分化所需的信号转导途径 神经元和TH表达的调节。Aim 2将使用一个新的特征 来源于表达SV 4 OT-抗原（ts）的小鼠的OB克隆细胞系， 9 kbTH启动子研究DA的分子机制 分化提出的目标将描绘分子机制 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 这是建立PD患者移植潜力的必要条件。