Stress and Survival of Olfactory Sensory Neurons

描述(由申请人提供)：嗅觉系统对生存至关重要，在人类中，随着衰老、损伤或退行性疾病而出现的感觉能力减弱危及健康和生活质量。嗅觉神经元(OSNs)是嗅觉的起始部位，因此它们的存活对嗅觉功能至关重要。虽然在OSN中调节气味检测的机制已经取得了进展，但对OSN生存的关键因素知之甚少。我们的研究表明，除了气味检测的快速信号外，感觉刺激还可以诱导可能支持神经元存活的长期反应。我们最近的数据表明，气味检测和感觉刺激驱动的生存是平行的。此外，我们发现感觉刺激会引起细胞应激，当感觉刺激激活的通路被抑制时，这种应激会加剧。我们的总体假设是，感觉刺激激活了与刺激检测平行的多个信号转导级联，以促进神经元存活和对活动诱导的细胞应激做出反应。对感觉刺激的这些反应的丧失会加剧与活动相关的应激，导致进行性细胞损伤，最终导致神经元死亡。这项提议的总体目标是描绘介导感觉刺激驱动的生存和应激反应的信号转导通路。我们使用分子和细胞生物学方法，使用体外和体内模型来研究可检验的假说。目的1将利用体外培养、体内感觉刺激和剥夺模型以及生化和遗传学方法来描述MEK/Erk和PI3K/Akt信号通路促进感觉刺激依赖型OSN存活的机制。目的2将使用这些模型来研究气味检测途径的分歧和依赖活动的OSN生存。目的3将利用感觉刺激和剥夺的体外和体内模型，以及生化和遗传学方法来研究感觉诱导应激对OSN生存的影响及其涉及的途径。这些研究的理论基础是，了解调节OSNs生存的因素对于旨在保护嗅觉功能的策略至关重要。这些发现有可能为开发治疗策略提供基础，以挽救损伤后死亡的神经元，从而保护嗅觉功能。

DESCRIPTION (provided by applicant): The olfactory system is critical for survival, and in humans, diminished sensory capacity seen with aging, injury, or degenerative diseases compromises health and the quality of life. Olfactory sensory neurons (OSNs) are the initial site of odorant detection, and thus their survival is critical for olfactory function. While progress has been made regarding the mechanisms that mediate odorant detection in OSNs, less is known about the factors that are critical for OSN survival. Our studies demonstrate that, in addition to the rapid signaling for odor detection, sensory stimulation induces long-term responses that may support neuronal survival. Our recent data suggest that odorant detection and sensory stimulation-driven survival proceed by parallel pathways. Furthermore, we found that sensory stimulation evokes cellular stress, which is exacerbated when sensory stimulation-activated pathways are inhibited. Our overall hypothesis is that sensory stimulation activates multiple signal transduction cascades in parallel to those that serve stimulus detection to promote neuronal survival and to respond to activity-induced cellular stress. Loss of these responses to sensory stimulation exacerbates activity- related stress, leading to progressive cell damage and ultimately neuronal death. The overall goal of this proposal is to delineate the signal transduction pathways that mediate sensory stimulation driven survival and stress responses. We employ molecular and cell biological approaches using in vitro and in vivo models to investigate testable hypotheses. Aim 1 will utilize in vitro cultures, in vivo sensory stimulation and deprivation models, and biochemical and genetic approaches to delineate the mechanisms of the MEK/Erk and PI3K/Akt signaling pathways that contribute to sensory stimulus-dependent OSN survival. Aim 2 will use these models to study the divergence of odorant detection pathways and activity-dependent OSN survival. Aim 3 will utilize in vitro and in vivo models of sensory stimulation and deprivation, and biochemical and genetic approaches to study the effects of sensory-induced stress on OSN survival and the pathways that are involved. The rationale for these studies is that understanding the factors that regulate the survival of OSNs is essential for strategies aimed at preserving olfactory function. These findings have the potential to provide a basis for the development of therapeutic strategies to rescue neurons from death in response to injury and thus preserve olfactory function.