NEUROTROPHINS IN OLFACTORY DEVELOPMENT

描述：(改编自申请者摘要)神经营养素 已知对神经细胞的关键发育过程有贡献 系统。申请人最近的研究表明，神经营养素 在发育中的哺乳动物嗅觉上皮细胞中表达 突触连接建立的时间与发育 前脑。此时，吻侧端脑中的细胞表达 这些神经营养因子的适当酪氨酸激酶trk受体和 嗅球开始形成。空间和时间模式 表达的结果表明，在大脑中发育的感觉神经元 嗅上皮顺行运输特异性神经营养因子 与反应灵敏的前脑神经元有关的因素，从而有助于 嗅球的发育。拟议研究的目标 是为了检验这一假说的各个方面。第一个具体目标是 确定表达不同神经营养因子的特定细胞类型和 它们在上皮和鳞茎中的受体。我们尤其希望 确定神经营养因子mRNAs是否通过嗅觉表达 神经元和神经营养因子蛋白是否定位于嗅觉 神经投射。单元格类型将通过以下方式确定 具有表型特异性标志物的神经营养因子/受体mRNA和蛋白 对于嗅觉细胞亚群，第二个目标是确定 嗅神经顺行运输神经营养因子。 如果这有功能后果的话。 研究将确定秋水仙碱治疗是否会增加神经营养素 感觉神经元的免疫反应性同时降低免疫反应性 在嗅觉轴突和终末。我们还将评估 放射性标记神经营养因子在嗅觉中的再分布 上皮细胞，并检测鳞状细胞trk磷酸化水平 这样的待遇。第三个目标是确定早期神经营养是否 因子剥夺导致形态或表型异常 在灯泡里。这将通过评估嗅觉系统来实现 携带神经营养因子基因靶向突变的小鼠的发育。 神经营养因子和神经营养因子的水平、分布和细胞定位 Trk的表达，以及表型细胞标记，将在 正常和神经营养因子剥夺的嗅觉系统。差异在于 前脑和延髓神经元的细胞死亡模式也将 接受检查。最终目标是确定早期神经营养因子 通过评估，剥夺在这个系统中具有功能性后果 灯泡Trk磷酸化和气味刺激的c-fos表达 基因敲除小鼠和对照窝产仔。这些研究的结果将 有助于我们理解调控的分子信号 哺乳动物的前脑发育。

DESCRIPTION: (Adapted From The Applicant's Abstract) Neurotrophins are known to contribute to critical developmental processes in the nervous system. Recent studies by the applicant have shown that neurotrophins are expressed in the developing mammalian olfactory epithelium during the time that synaptic connections are being made with the developing forebrain. At this time, cells in the rostral telencephalon express the appropriate tyrosine kinase trk receptors for these neurotrophins and the olfactory bulbs begin to form. The spatial and temporal patterns of expression suggest the hypothesis that developing sensory neurons in the olfactory epithelium anterogradely transport specific neurotrophin factors to responsive forebrain neurons and thereby contribute to development of the olfactory bulb. The goals of the proposed research are to test aspects of this hypothesis. The first specific aim is to identify the specific cell types expressing different neurotrophins and their receptors in the epithelium and bulb. In particular we wish to determine if neurotrophin mRNAs are expressed by olfactory sensory neurons and if neurotrophin proteins are localized within olfactory nerve projections. Cell types will be identified by colocalization of neurotrophin/receptor mRNA and protein with phenotypic markers specific for subpopulations of olfactory cells The second aim is to determine if the olfactory nerve anterogradely transports neurotrophins from the epithelium to the bulb, and if this has functional consequences. Studies will determine if colchicine treatment increases neurotrophin immunoreactivity in sensory neurons while decreasing immunoreactivity in olfactory axons and terminals. We will also evaluate the redistribution of radiolabeled neurotrophins applied to the olfactory epithelium, and measure levels of bulb trk phosphorylation following such treatment. The third aim is to determine if early neurotrophic factor deprivation leads to morphological or phenotypic abnormalities in the bulb. This will be accomplished by evaluating olfactory system development in mice carrying targeted mutations in neurotrophin genes. The levels, distribution and cellular localization of neurotrophin and trk expression, and of phenotypic cell markers, will be examined in the normal and neurotrophin-deprived olfactory system. Differences in patterns of cell death in forebrain and bulb neuron morphology will also be examined. The final aim is to determine if early neurotrophin deprivation has functional consequences in this system by evaluating bulb trk phosphorylation and odor-stimulated c-fos expression in knockout mice and control littermates. Results of these studies will contribute to our understanding of the molecular signals that regulate mammalian forebrain development.