Dynamic changes in Olfactory Ensheathing Cell properties after neuronal loss

描述(申请人提供)：嗅觉有助于提高生活质量，并对环境中存在的危险发出警告。损害这种感官形态的疾病和伤害会降低对外部世界的认识，并将一个人的生命置于危险之中。嗅觉上皮(OE)直接暴露在环境侮辱中，因此发展了一种非凡的能力，经历了广泛的再生。即使在正常情况下，嗅觉神经元(OSN)也会进行持续的再生。虽然OSNs的特性在正常和再生的上皮中已经得到了广泛的研究，但在非神经元嗅觉细胞中与之相关的动态细胞和分子变化在很大程度上还没有被探索。在这项提案中，我将研究嗅鞘细胞(OEC)的特性。嗅鞘细胞是一种特殊的神经胶质细胞群，专门存在于嗅觉系统中。当OSNs从鼻腔的嗅觉上皮细胞投射到大脑前部的嗅球时，它们包裹着OSNs的轴突束。它们存在于嗅觉上皮和大脑中，使嗅鞘细胞成为一种独特的神经胶质细胞，从周围神经系统到中枢神经系统都有投射。它们的分子和细胞特性反映了这种混合作用。嗅鞘细胞据称具有促进再生的能力，这使其成为治疗脊髓损伤、中风和帕金森病的有吸引力的治疗剂。嗅鞘细胞在体外促进轴突再生长，并被报道在脊髓损伤模型中促进功能恢复。然而，嗅鞘细胞在OSN再生过程中的变化的性质和动力学还没有被研究。因此，本研究的目标是研究嗅鞘细胞在OSN损伤、丢失和再生过程中体内发生的分子和细胞变化。这一提议的中心假设是，嗅觉感觉神经元的死亡导致嗅鞘细胞发生关键的分子和细胞变化，从而促进感觉神经元及其轴突的成功重新生长。因此，在这个方案中，我将通过监测基因表达的变化来表征嗅鞘细胞在OSN损伤和再生过程中的分子和细胞反应。此外，我还将描述由于嗅鞘细胞丢失而引起的嗅鞘细胞的分子和细胞反应。为验证这一假说而进行的实验结果将为我们提供对嗅鞘细胞生物学的新见解，这将有助于提高嗅鞘细胞作为修复神经元损伤的治疗剂的水平。 公共卫生相关性：在嗅觉系统中，感觉神经元与一种称为嗅鞘细胞(OECs)的细胞类型密切相关。嗅鞘细胞是神经系统中一种特殊的神经胶质细胞，可以促进某些受损神经元的再生。因此，这项建议的主要目的是对嗅鞘细胞的生物学有新的认识，以便改进嗅鞘细胞作为修复中风、身体损伤和帕金森病等引起的神经元损伤的治疗剂。

DESCRIPTION (provided by applicant): The sense of smell contributes to quality of life and warns of dangers present in the environment. Disease and injury that compromise this sensory modality decreases awareness of the outside world and puts one's life at risk. The olfactory epithelium (OE) is directly exposed to environmental insults and, as a result, developed a remarkable ability to undergo extensive regeneration. Even under normal circumstances, olfactory sensory neurons (OSN) undergo ongoing and continual regeneration. While the properties of OSNs have been extensively studied in normal and regenerating epithelium, the associated dynamic cellular and molecular changes in non-neuronal olfactory cells are largely unexplored. In this proposal, I will examine the properties of olfactory ensheathing cells (OEC). OECs are a special population of glial cells found exclusively in the olfactory system. They ensheath the axon bundles of OSNs as they project from the olfactory epithelium in the nasal cavity into the olfactory bulb at the front of the brain. Their presence in the olfactory epitheliu and the brain makes OECs a unique type of glial cell that span projections from the peripheral nervous system to the CNS. Their molecular and cellular properties reflect this hybrid role. The purported ability of OECs to promote regeneration has made OECs an attractive therapeutic agent for treating spinal cord injury, stroke, and Parkinson's disease. OECs promote axonal re-growth in vitro and are reported to enhance functional recovery in spinal cord injury models. However, the nature and dynamics of OECs change in response to OSN regeneration has not been studied. Therefore, the goal of this proposal is to study molecular and cellular changes that take place in vivo in OECs during OSN injury, loss, and regeneration. The central hypothesis of this proposal is that the death of olfactory sensory neurons causes critical molecular and cellular changes in olfactory ensheathing cells that encourage successful re- growth of sensory neurons and their axons. Therefore, in this proposal, I will characterize the molecular and cellular responses of OECs during OSN injury and regeneration by monitoring changes in gene expression. Moreover, I will characterize molecular and cellular responses of OSNs due to loss of OECs. The results of the experiments proposed to test this hypothesis will provide us with new insights on the OEC biology, which will lead to improvement of OECs as therapeutic agents for repairing neuronal injury. PUBLIC HEALTH RELEVANCE: In the olfactory system, sensory neurons are closely associated with a cell type called olfactory ensheathing cells (OECs). OECs are a special population of glial cells in the nervous system shown to promote re-growth of certain injured neurons. Therefore, the main aim of this proposal is to gain new insights on the biology of OEC, in order to make improvements to OECs as therapeutic agents for repairing neuronal injury caused by, for example, stroke, physical injury, and Parkinson's disease.