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

• 批准号: 10394054
• 负责人: Taylor Reagan Jay
• 金额: $ 0.25万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-16 至 2022-09-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394054
• 关键词: ANXA5 gene; Acute; Address; Affect; Anterior; Axon; Axonal Transport; Axotomy; Brain; Cells; Chronic; Development; Distant; Drosophila genus; Exhibits; Focal Brain Injuries; Gene Expression; Genetic Transcription; Goals; Impaired cognition; Impairment; Individual; Injury; Label; Lead; Length; Mediating; Mediator of activation protein; Modeling; Molecular; Mutation; Nerve; Nervous system structure; Neuroglia; Neuronal Dysfunction; Neuronal Injury; Neurons; Neuropathy; Pathway interactions; Peripheral Nervous System Diseases; Physiological; Physiology; Population; Process; Receptor Activation; Recovery; Regulation; Research; Sensory; Severities; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Spinal nerve structure; Stimulus; Structure; System; Testing; Time; Traumatic Brain Injury; Visualization; Wing; axon injury; axonal degeneration; base; chronic pain; cognitive change; fly; in vivo; injured; insight; knock-down; nerve injury; nerve transection; neuronal circuitry; neurophysiology; neurotransmission; novel strategies; painful neuropathy; prevent; programs; receptor; response; response to injury; targeted treatment; tool; ANXA5 gene; Acute; Address; Affect; Anterior; Axon; Axonal Transport; Axotomy; Brain; Cells; Chronic; Development; Distant; Drosophila genus; Exhibits; Focal Brain Injuries; Gene Expression; Genetic Transcription; Goals; Impaired cognition; Impairment; Individual; Injury; Label; Lead; Length; Mediating; Mediator of activation protein; Modeling; Molecular; Mutation; Nerve; Nervous system structure; Neuroglia; Neuronal Dysfunction; Neuronal Injury; Neurons; Neuropathy; Pathway interactions; Peripheral Nervous System Diseases; Physiological; Physiology; Population; Process; Receptor Activation; Recovery; Regulation; Research; Sensory; Severities; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Spinal nerve structure; Stimulus; Structure; System; Testing; Time; Traumatic Brain Injury; Visualization; Wing; axon injury; axonal degeneration; base; chronic pain; cognitive change; fly; in vivo; injured; insight; knock-down; nerve injury; nerve transection; neuronal circuitry; neurophysiology; neurotransmission; novel strategies; painful neuropathy; prevent; programs; receptor; response; response to injury; targeted treatment; tool

Project Summary Localized damage to the nervous system can lead to far-reaching alterations in neurophysiology, even in uninjured neurons far 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 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 stimuli. Interestingly, these effects were shown to require glial signaling, demonstrating that glia are required mediators between injured neurons and the uninjured neurons in which physiology is altered. 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 signaling broadly within the circuit. I will also 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 these injury responses. 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 signaling components downstream of those domains are required for glial modulation of uninjured neuron signaling. TRAPseq on glia after injury will be used to identify additional factors that glia use to communicate with uninjured neurons. 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.

项目摘要 神经系统的局部损害可能导致神经生理学的深远改变，即使在未受伤中 神经元远离受伤部位。令人惊讶的是，正是这些变化是未受伤的神经元的生理学的变化，而不是 对受伤的神经元本身的损害，这是导致与周围神经病有关的慢性疼痛 神经损伤后。创伤性脑损伤后，在未受伤的神经元中也观察到了这些变化，并且 人们被认为，未受伤的神经元的生理变化可能导致广泛的认知能力 甚至局灶性脑损伤导致的变化。尽管他们参与了这些重要过程，但 损伤信号传播在神经系统中的机制的定义很差。 我们最近开发了一个模型，在该模型中，神经内神经元可以被稀疏标记和受伤，并且 轴突切开术后明确鉴定出未受伤的神经元。在该模型的前神经中使用这种轴切开术 果蝇翼，我们发现神经内的未受伤的神经元经历了轴突运输和展览的停滞 响应刺激的活性减少。有趣的是，这些效果表明需要神经胶质信号传导，证明 该神经胶质是受伤的神经元和生理改变的未受伤神经元之间的介体。这 提案将集中于了解神经胶质对神经元受伤的感觉，以及这些细胞如何以及为什么 改变周围神经元的生理学。 在AIM 1中，我将评估哪种类型的损伤胶质识别足以在电路中广泛调节信号。我会 还测试这些信号通路是否与受伤的轴突变性所需的信号通路不同。我们有 已经确定在神经胶质中需要draper受体才能感觉到这些损伤反应。在AIM 2中，我将执行 Draper受体的结构功能分析以确定信号需要哪些功能域 受体激活的下游并测试这些域下游的信号传导成分是否为 未受伤的神经元信号传导的神经胶质调制所需。受伤后神经胶质的Trapseq将用于识别 神经胶质用于与未受伤的神经元通信的其他因素。在AIM 3中，我将确定为什么神经胶质可能导致 通过阻断未受伤的神经元信号传导并评估神经元的长期恢复，这些变化在未受伤的神经元中发生变化 神经内的生理和生存。 这些研究将共同​​洞悉损伤信号在神经上传播的机制 系统并确定负责这种未知但重要现象的细胞和分子途径。 然后可以将这些机制靶向治疗，以保持神经胶质的有益反应清除轴突 受伤后的碎片，但可以防止信号导致未受害神经元生理的有害变化。这会 成为靶向神经性疼痛和损伤后认知功能障碍的一种新颖的方法。