Neuron Glial Interactions

描述(申请人提供)：影响嗅神经进行嗅觉感觉神经元轴突替换的能力的机制还不是很清楚。最近来自我们实验室和其他实验室的数据强调了神经中包裹轴突束的胶质细胞的作用，即嗅鞘细胞/胶质细胞(OECs)。我们之前展示了嗅鞘细胞支持轴突生长，描述了它们的一些基本分子特性，并证明了它们作为脊髓损伤的移植策略的有效性。在当前的应用中，我们提出了一系列研究来检查嗅鞘细胞之间以及轴突和嗅鞘细胞之间的通讯机制。神经系统其他部位所描述的神经胶质细胞与神经元的相互作用为协调和同步活动提供了一种机制。在嗅觉通路中，神经元-神经胶质细胞的相互作用可以提供一种策略来调控生长因子或其他分子的释放，这些分子可能有助于嗅鞘细胞对轴突延伸的营养效应。为了实现这一总体假设，我们提出了一系列3个目标。首先，我们将测试假设，谷氨酸机制，包括谷氨酸受体和/或转运体，是由嗅鞘细胞表达的。我们还将量化缝隙连接蛋白的表达及其在这一途径中的分布。最后，我们将研究轴突的同步丢失和替换对这些特性的影响。其次，嗅鞘细胞的基本生物物理特性及其对轴突释放的谷氨酸的反应尚未被研究。我们的初步数据表明，可能会发生动态相互作用，嗅鞘细胞可以支持瞬时膜电流对谷氨酸的反应。我们将继续这一发现，同时确定这些特性在退化/再生事件期间是否发生变化。第三，嗅鞘细胞增殖/更新的机制尚不清楚，但也可能受到嗅神经的影响；初步数据表明，嗅鞘细胞在轴突(再生)生成过程中可能会促进增殖，从而提出了嗅鞘细胞与轴突的比率可能是恢复的决定因素的假设。总之，这些研究将对我们理解嗅觉通路中细胞更新和轴突生长的机制产生重大影响；对于治疗嗅神经损伤患者以及将嗅鞘细胞作为脊髓损伤的治疗策略的建议至关重要的信息。

DESCRIPTION (provided by applicant): The mechanisms influencing the capacity of the olfactory nerve for ongoing replacement of olfactory sensory neuron axons is not well understood. Recent data, from our labs and others, emphasize the role of the glia that wrap axon fascicles in the nerve, the olfactory ensheathing cells/glia (OECs). We showed previously that OECs support axon outgrowth, described some of their basic molecular properties, and demonstrated their effectiveness as a transplant strategy in spinal cord injury. In the current application we propose a series of studies to examine mechanisms of communication among OECs and between the axons and OECs. Glia-neuron interactions being described elsewhere in the nervous system provide a mechanism for coordinating and synchronizing activity. In the olfactory pathway, neuron-glia interactions could provide a strategy for governing the release of growth factors or other molecules that may contribute to the trophic effect of OECs on axon extension. To pursue this overarching hypothesis we propose a series of 3 aims. First, we will test the hypothesis that glutamate mechanisms, including glutamate receptors and/or transporters, are expressed by the OECs. We will also quantify gap junction protein expression and their distribution in this pathway. Finally, the effects of synchronized loss and replacement of axons on these properties will be examined. Second, the basic biophysical properties of OECs and their response to glutamate released by axons has not been studied. Our preliminary data suggest a dynamic interaction may occur and that the OECs can support transient membrane currents in response to gluatamate. We will pursue this finding while also determining if these properties change during degenerative/regenerative events. Third, the mechanisms of OEC proliferation/turnover are unknown but may also be subject to influences from the olfactory nerve; there is preliminary data suggesting that OECs may increase proliferation during axon (re)generation raising the hypothesis that the ratio of OECs:axons may be a determinant of recovery. Collectively, these studies will have a significant impact on our understanding of the mechanisms of cell turnover and axon growth in the olfactory pathway; information critical to the treatment of patients with traumatic injury to the olfactory nerve as well as to the proposed use of OECs as a treatment strategy in spinal cord injury.