CYCLIC-NUCLEOTIDE CHANNELS IN OLFACTORY DEVELOPMENT

描述(逐字摘自申请者摘要)：本项目旨在 阐明环核苷酸激活的离子通道在神经元中的作用 互联互通、差异化。我们将使用一个哺乳动物模型系统 以基因操作研究神经前体细胞的命运和成熟 嗅觉感觉神经元在第二信使信号中的特定缺陷 小路。我们将研究依赖于活动的过程在 神经元前体的增殖--感觉神经元的初始投射 他们的目标和神经元连接的稳定。分子 生物、遗传、生化和电生理方法将是 用来理解OcNC-1和OcNC-2离子通道亚基的作用 在嗅神经细胞分化和向 嗅球。缺乏对嗅觉神经元的突触输入导致 OcNC-1和OcNC-2亚基提供启动的中央机制 发育和随后的气味转导中依赖活动的过程。 OcNC-1蛋白至少部分地起到转化环核苷酸的作用 增加钙离子内流，启动膜去极化。在……里面 同时，我们将测试第二个嗅觉神经元循环 核苷酸通道OcnC-2在介导骨质疏松症的关键阶段发挥着独特的作用。 神经元分化。具体地说，应用程序将(1)表征 OcNC-1和OcNC-2通道亚基对正常的贡献 嗅觉上皮的发育。我们将检验这一假设 嗅觉环核苷酸激活通道参与脑血管疾病的发生 嗅觉系统和适当连接的成熟。(二)审查 正常神经元和OcNC-1缺陷神经元之间的竞争效应及 神经元活动在细胞分化中的作用及其建立和发展 保持连通性。这些研究将纳入一个独特的系统，以 产生拥有由野生马赛克组成的嗅觉上皮的小鼠 类型和OcNc-1缺乏的感觉神经元。(3)检验假设 OcNC-2亚基对环的功能性质有贡献 成熟嗅觉神经元中的核苷酸介导的转导通路。这 应用程序将利用嗅觉系统的特殊属性来 阐明活动依赖的过程在正常和 神经细胞发育异常。

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.