NEUROTROPHINS IN OLFACTORY DEVELOPMENT

神经营养因子在嗅觉发育中的作用

基本信息

批准号：
6175951
负责人：
KATHLEEN M GUTHRIE
金额：
$ 10.53万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-08-01 至 2001-07-31
项目状态：
已结题

项目摘要

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.

描述：（改编自申请人的摘要）神经营养蛋白是已知会导致神经的关键发展过程系统。申请人的最新研究表明神经营养蛋白在发育中的哺乳动物嗅觉上皮中表达与发育的突触连接建立的时间前脑。目前，尾脑脑中的细胞表达适用于这些神经营养蛋白的适当酪氨酸激酶TRK受体和嗅球开始形成。空间和时间模式表达的假设是在嗅觉上皮前生运输特定的神经营养素反应敏感的前脑神经元的因素，从而有助于嗅球的开发。拟议研究的目标是检验该假设的方面。第一个具体目的是确定表达不同神经营养蛋白的特定细胞类型，它们的受体在上皮和灯泡中。特别是我们希望确定神经营养蛋白mRNA是否通过嗅觉表达神经元和神经营养蛋白是否位于嗅觉中神经预测。细胞类型将通过共定位来确定神经营养蛋白/受体mRNA和蛋白质具有表型标记的特异性对于嗅觉细胞的亚群，第二个目的是确定是否是否嗅觉神经直系神经从上皮到灯泡，如果有功能后果。研究将确定秋水仙碱治疗是否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末端。我们还将评估应用于嗅觉的放射性标记神经营养蛋白的重新分布上皮和测量灯泡TRK磷酸化的水平这样的治疗方法。第三个目的是确定早期神经营养是否早期因子剥夺导致形态或表型异常在灯泡中。这将通过评估嗅觉系统来完成在神经营养基因中携带靶向突变的小鼠的发育。神经营养蛋白的水平，分布和细胞定位 TRK表达和表型细胞标记将在正常和神经营养蛋白缺乏的嗅觉系统。差异前脑和鳞茎神经元形态中细胞死亡的模式也将被检查。最终目的是确定早期神经营养素是否通过评估，剥夺在该系统中具有功能后果鳞茎TRK磷酸化和气味刺激的C-FOS表达敲除小鼠和控制同窝仔。这些研究的结果将有助于我们对调节分子信号的理解哺乳动物的前脑发育。