Glial regulation of neuronal physiology in response to local injury

神经胶质对局部损伤的神经生理学调节

基本信息

批准号：
10255497
负责人：
Taylor Reagan Jay
金额：
$ 6.89万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-17 至 2022-09-17
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10255497
关键词：
ANXA5 gene Acute Address Affect Anterior Axon Axonal Transport Axotomy Cells Chronic Development Distant Drosophila genus Exhibits Fellowship Focal Brain Injuries Genetic Transcription Goals Impaired cognition Impairment Individual Injury Label Laboratories Lead Length Mediating Mediator of activation protein Mentorship Modeling Molecular Mutation Nerve Nervous system structure Neurobiology Neuroglia Neuronal Injury Neurons Pathway interactions Peripheral Nervous System Diseases Physiological Physiology Population Process Receptor Activation Recovery Regulation Research Research Personnel Sensory Severities Signal Pathway Signal Transduction Signaling Molecule Site Spinal nerve structure Stimulus Structure System Technical Expertise Testing Time Training Activity Traumatic Brain Injury Visualization Wing Work axon injury axonal degeneration base chronic pain cognitive change fly improved in vivo injured insight knock-down nerve injury neuronal circuitry neurophysiology neurotransmission novel strategies painful neuropathy prevent programs receptor response response to injury sensory stimulus skills success targeted treatment therapeutic target tool

项目摘要

Localized damage to the nervous system can lead to far-reaching alterations in neurophysiology, even in uninjured neurons distant from the site of injury. Surprisingly, it is these changes in the physiology of uninjured neurons, rather than damage to injured neurons themselves, that is responsible for the chronic pain associated with peripheral neuropathy after nerve injury. These changes have also been observed in uninjured neurons following traumatic brain injury, and it has been posited that physiological changes in uninjured neurons could be responsible for the widespread cognitive changes that result from even focal brain injuries. Despite their involvement in these important processes, the mechanisms by which injury signals spread across the nervous system are poorly defined. We have recently developed a model in which neurons within a single nerve can be sparsely labeled and individual injured and uninjured neurons definitively identified after axotomy. Using this model of axotomy in the anterior nerve of the Drosophila wing, we found that uninjured neurons within the nerve undergo stalling of axon transport and exhibit reduced activity in response to sensory stimuli. Interestingly, we found that these effects require glial signaling, demonstrating that glia act as mediators between injured and uninjured neurons to drive changes in physiology. This proposal will focus on understanding how glia sense that neurons have been injured, and how and why these cells then change the physiology of surrounding neurons. In Aim 1, I will assess what type of injury glia recognize as sufficient to modulate neuronal physiology and will test whether these signaling pathways are distinct from those required for injured axon degeneration. We have already identified that the Draper receptor is required in glia to sense injury. In Aim 2, I will perform a structure function analysis of the Draper receptor to determine which functional domains are required for signaling downstream of receptor activation and test whether the associated signaling molecules are required for glial modulation of uninjured neuron signaling. In Aim 3, I will determine why glia might cause these change in uninjured neurons by blocking uninjured neuron signaling and assessing long-term recovery of neuronal physiology and survival within the nerve. Together, these studies will provide insight into the mechanisms by which injury signals spread across the nervous system and identify the cellular and molecular pathways responsible for this unknown but important phenomenon. These mechanisms could then be targeted therapeutically to maintain beneficial responses of glia in clearing axonal debris after injury, but prevent signaling that leads to detrimental changes in uninjured neuronal physiology. This would be a completely novel approach to targeting neuropathic pain and cognitive dysfunction after injury. In addition, performing this work will allow me to develop the new technical skills and intellectual approaches I will need to use Drosophila to address fundamental neurobiological questions in my own laboratory. The additional training activities proposed in this fellowship will also enhance my quantitative and analytical skills, improve my ability to communicate my work, and engage in mentorship, preparing me for success as an independent investigator.

神经系统的局部损伤可能会导致神经生理学发生深远的改变，即使是远离损伤部位的未受伤神经元也是如此。令人惊讶的是，正是未受伤神经元生理学的这些变化，而不是受伤神经元本身的损伤，才是神经损伤后与周围神经病相关的慢性疼痛的原因。在创伤性脑损伤后未受伤的神经元中也观察到了这些变化，并且推测未受伤神经元的生理变化可能是由局灶性脑损伤引起的广泛认知变化的原因。尽管它们参与了这些重要过程，但损伤信号在神经系统中传播的机制尚不清楚。我们最近开发了一种模型，可以对单个神经内的神经元进行稀疏标记，并在轴突切除后明确识别单个受伤和未受伤的神经元。使用果蝇翅膀前神经的轴切开模型，我们发现神经内未受伤的神经元经历轴突运输的停滞，并表现出对感觉刺激的反应活性降低。有趣的是，我们发现这些效应需要神经胶质信号传导，这证明神经胶质细胞充当受伤和未受伤神经元之间的中介，以驱动生理变化。该提案将重点了解神经胶质细胞如何感知神经元已受伤，以及这些细胞如何以及为何改变周围神经元的生理机能。在目标 1 中，我将评估神经胶质细胞识别哪种类型的损伤足以调节神经元生理学，并将测试这些信号传导途径是否与受伤的轴突变性所需的信号传导途径不同。我们已经确定，神经胶质细胞需要 Draper 受体来感知损伤。在目标 2 中，我将对 Draper 受体进行结构功能分析，以确定受体激活下游信号传导所需的功能域，并测试未损伤神经元信号传导的胶质细胞调节是否需要相关信号传导分子。在目标 3 中，我将通过阻断未受伤的神经元信号传导并评估神经元生理学的长期恢复和神经内的存活来确定为什么神经胶质细胞可能会导致未受伤的神经元发生这些变化。总之，这些研究将深入了解损伤信号在神经系统中传播的机制，并确定导致这种未知但重要现象的细胞和分子途径。然后可以针对这些机制进行治疗，以维持神经胶质细胞在损伤后清除轴突碎片的有益反应，但防止导致未受伤神经元生理学发生有害变化的信号传导。这将是一种针对损伤后神经性疼痛和认知功能障碍的全新方法。此外，执行这项工作将使我能够发展新的技术技能和智力方法，我将需要使用果蝇在我自己的实验室中解决基本的神经生物学问题。该奖学金中提出的额外培训活动还将增强我的定量和分析技能，提高我交流工作的能力，并参与指导，为我作为一名独立调查员的成功做好准备。