PLASTICITY IN THE AGING OLFACTORY SYSTEM

阐明决定神经元表型的机制 在发育过程中，调节成人的基因表达是一个关键问题 在神经生物学方面。了解多巴胺(DA)能神经元中的这些现象 一直是许多研究的焦点，因为它们在黑质中丢失 帕金森病(PD)致密部。嗅球(OB)含有一个 小球周围(PG)DA神经元群体的特征是 两者都是了解DA表型表达调控的理想模型 也是移植细胞的潜在来源。OB-DA神经元是由 来自前脑室下区(SVZa)干细胞的整个生命过程 在嘴上的迁徙溪流中迁徙到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)启动子提示OB DA的可验证性假说 前体在迁移到最终的 位于肾小球层，但这种完整的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 检验这一假设。目标1将描述分子的表达 与发育中和成年动物的DA表型分化有关 以及参与TH表达的信号通路。AIM 1还将聘用 体内示踪剂注射和切片培养研究机制 调节DA神经元的增殖和迁移。目标2将采用主要 从表达LacZ的转基因小鼠中分离的新生OB的培养 DA分化所需的信号转导通路 神经元和TH表达的调节。《目标2》将使用一个新的角色 表达SV4OT抗原(Ts)的小鼠OB克隆性细胞株 9kb启动子用于研究DA的分子机制 差异化。提出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神经元分化和调控的通路 对于确定其在帕金森病患者中的移植潜力是必要的。

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.