Olfactory ensheathing cells and microglia contributions to axon removal in the olfactory system.

嗅觉感觉神经元的神经发生是一个持续的过程，从早期开始 在成人中继续发育，并要求新生成的轴突成功 穿过固有层，穿过筛板，进入中枢神经 系统。与此同时，死亡神经元上的轴突碎片也需要清除。这个 这项建议的目的是通过研究嗅觉上皮细胞的再生能力 了解嗅觉感觉神经元轴突碎片、嗅觉 在再生过程中包裹神经胶质细胞和小胶质细胞。尽管人们对再生很感兴趣 这些神经元的加工过程对于其潜在的治疗用途，最基本的特征 与损伤相关的轴突生长仍不清楚。嗅觉也是如此。 包裹神经胶质细胞，使轴突长出。一个重要的事件，允许 新轴突是将嗅觉神经元胞体后的旧轴突移除。 死了。在此过程中，嗅神经层中没有任何小胶质细胞渗透的迹象。 嗅球。我们将开始使用化学烧蚀方法来解决这些问题。 再加上我们最近开发的基因命运图谱策略。用这只转基因小鼠， 轴突可以非常精确地被追踪。会对嗅觉上皮造成损伤 一次注射他巴唑。他巴唑是一种常用的药物，用于治疗 人类甲状腺功能亢进症，其副作用包括暂时丧失嗅觉。在……里面 小鼠，他巴唑导致嗅觉上皮细胞丢失，只留下干细胞 使丢失的神经元再生。首先，我们将比较神经胶质细胞与 单核吞噬细胞吞噬退化的轴突。因为我们的初步数据显示没有 单核巨噬细胞浸润增加，但其形态变化 观察到，在本提案的第二部分中，我们将分析它们的区别 吞噬细胞。最后，我们将研究区分单核细胞的信号分子。 吞噬细胞而不产生炎症反应。用这种方法得到的结果 建议将被证明是理解再生过程的关键，并将是 普遍感兴趣的是了解中枢神经系统损伤的反应如何 进行最低限度的炎症反应。

Neurogenesis of olfactory sensory neurons is an ongoing process that starts early in development, continues in adults, and requires that newly generated axons successfully navigate through the lamina propria, cross the cribriform plate and enter the central nervous system. At the same time axonal debris from the neurons that die needs to be removed. The goal of this proposal is by studying the regenerative capacity of the olfactory epithelium to understand what are the interactions between olfactory sensory neuron axonal debris, olfactory ensheathing glia, and microglia during regeneration. Despite the interest in the regeneration process of these neurons for its potential therapeutic use, the most fundamental features of injury-related axon growth remain unknown. The same can be said about the olfactory ensheathing glia that allows this axonal outgrowth. An important event to allow the growing of new axons is the removal of the old ones after the cell body of the olfactory sensory neuron died. This is done without any signs of infiltration of microglia in the olfactory nerve layer of the olfactory bulb. We will begin addressing these questions by using a chemical ablation approach together with our recently developed genetic fate mapping strategy. With this transgenic mouse, axons can be tracked with extraordinary precision. Injury to the olfactory epithelium will be done by a single injection of methimazole. Methimazole is a drug commonly used to treat hyperthyroidism in humans with side effects that include temporal loss of the sense of smell. In mice, methimazole induces loss of the olfactory epithelium leaving only stem cells that regenerate the lost neurons. First, we will compare the ability of ensheathing glial cells versus mononuclear phagocytes to engulf degenerating axons. Because our preliminary data shows no increase in the infiltration of mononuclear phagocytes, but changes in their morphology were observed, in the second part of this proposal we will analyze the differentiation of these phagocytes. Finally, we will look into the signaling molecules that differentiate mononuclear phagocytes without producing an inflammatory response. The results obtained with this proposal will prove to be critical in understanding the regeneration process and will be of general interest to understand how a response to an injury in the central nervous system can proceed with a minimal inflammatory response.