PLASTICITY IN THE AGING OLFACTORY SYSTEM

阐明决定神经元发育表型和调控基因的机制 成人的表达是神经生物学中的一个关键问题。了解多巴胺能(DA)中的这些现象 神经元一直是许多研究的焦点，因为它们在黑质致密部丢失。 帕金森氏病(PD)。嗅球(OB)含有一群球周(PG)DA神经元， 这些特征为理解DA表型表达的调控提供了理想的模型，也为 潜在的移植细胞来源。OB DA神经元在整个生命过程中都来自于 前脑室下区(SVZa)，并在吻端迁移流中迁移到OB。来自转基因生物的数据 本实验室生产的小鼠，表达由9kb酪氨酸羟化酶(TH)驱动的lacZ报告基因 启动子提出了可检验的假说，即OB DA前体在迁移之前是表型承诺的 到它们在肾小球层的最终位置，但这种完整的DA表达需要在 祖细胞迁移。有两个具体目标将检验这一假设。目标1将描述 与发育和成年动物DA表型分化相关的分子及其信号转导 参与TH表达的通路。AIM 1还将采用体内示踪剂注射和切片培养 探讨DA神经元增殖和迁移的调控机制。目标2将采用原代培养 从表达LacZ的转基因小鼠中提取新生OB以描述所需的信号转导途径 用于DA神经元的分化和TH表达的调节。Aim 2将使用一个新的OB角色 9kb TH启动子引导表达SV40T抗原(Ts)的小鼠克隆细胞系的研究 DA分化的分子机制。提议的目标将描绘出分子 SVZa干细胞分化为DA神经元的机制。了解所涉及的途径 OB DA神经元的分化和调控是建立其在帕金森病中移植潜能所必需的 病人。

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 lacZreporter 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 1will 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 SV40T-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.