CYCLIC-NUCLEOTIDE CHANNELS IN OLFACTORY DEVELOPMENT

描述（逐字从申请人的摘要）：该项目的目的是 阐明环核苷酸激活的离子通道在神经元 连通性和差异化。我们将使用哺乳动物模型系统 到遗传操作来研究神经元祖细胞的命运， 第二信使信号特异性缺陷的嗅觉神经元 途径。我们将调查的作用，活动依赖的过程中， 神经元前体细胞的增殖，感觉神经元的初始投射 以及神经元连接的稳定性。分子 生物学、遗传学、生物化学和电生理学方法将被 用于了解OcNC-1和OcNC-2离子通道亚基的作用 在嗅觉神经元分化和建立投射到 嗅球嗅觉神经元缺乏突触输入导致 OcNC-1和OcNC-2亚基提供了启动 在发展和随后的气味转导活动依赖的过程。 OcNC-1蛋白的功能，至少部分，是将环核苷酸 增加进入钙内流并启动膜去极化。在 平行，我们将测试假设，第二个嗅觉神经元周期性 核苷酸通道，OcNC-2，在介导的关键阶段具有独特的作用， 神经元分化具体而言，应用程序将（1）表征 OcNC-1和OcNC-2通道亚单位对正常人的 嗅上皮的发育。我们将检验这个假设， 嗅觉环核苷酸激活通道有助于发展 嗅觉系统和适当连接的成熟。(2)审查 正常和OcNC-1缺陷神经元之间的竞争的影响， 神经元活性在细胞分化和建立中的作用， 保持连通性。这些研究将纳入一个独特的系统， 产生具有嗅觉上皮的小鼠，所述嗅觉上皮由野生的嵌合体组成， 型和OcNc-1缺陷的感觉神经元。(3)测试假设， OcNC-2亚基有助于环状结构的功能性质， 成熟嗅觉神经元中核苷酸介导的信号转导通路。这 应用程序将利用嗅觉系统的特殊性质， 阐明活动依赖过程在正常和 神经细胞的异常发育。

DESCRIPTION (Verbatim From the Applicant's Abstract): This project aims to elucidate the role of cyclic nucleotide-activated ion channels in neuronal connectivity and differentiation. We will use a mammalian model system amenable to genetic manipulation to study the fate of neuronal progenitors and mature olfactory sensory neurons with specific defects in second messenger signaling pathways. We will investigate the role of activity dependent processes in the proliferation of neuronal precursors, the initial projection of sensory neurons to their target and the stabilization of neuronal connections. Molecular biological, genetic, biochemical and electrophysiological methods will be utilized to understand the role of the OcNC-1 and OcNC-2 ion channel subunits in olfactory neuronal differentiation and establishment of projections to the olfactory bulb. The absence of synaptic input to olfactory neurons results in the OcNC-1 and OcNC-2 subunits providing a central mechanism for initiating activity-dependent processes in development and subsequent odor transduction. The OcNC-1 protein functions, at least in part, to convert cyclic nucleotide increases into calcium influx and initiate membrane depolarization. In parallel, we will test the hypothesis that a second olfactory neuronal cyclic nucleotide channel, OcNC-2, has a distinct role in mediating critical stages of neuronal differentiation. Specifically, the application will (1) Characterize the contributions of the OcNC-1 and OcNC-2 channel subunits to the normal development of the olfactory epithelium. We will test the hypothesis that olfactory cyclic nucleotide-activated channels contribute to the development of the olfactory system and the maturation of appropriate connections. (2) Examine the effects of competition between normal and OcNC-1 deficient neurons and the role of neuronal activity in cellular differentiation and the establishment and maintenance of connectivity. These studies will incorporate a unique system to generate mice possessing an olfactory epithelium comprised of a mosaic of wild type and OcNc-1-deficient sensory neurons. (3) Test the hypothesis that the OcNC-2 subunit contributes to the functional properties of the cyclic nucleotide-mediated transduction pathway in mature olfactory neurons. This application will utilize the special properties of the olfactory system to elucidate the contribution of activity dependent processes in the normal and abnormal development of neuronal cells.