The role of the glial engulfment receptor Jedi1 in regulating sensory neuron function

胶质吞噬受体Jedi1在调节感觉神经元功能中的作用

• 批准号: 10392877
• 负责人: Bruce D Carter
• 金额: $ 33.8万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10392877
• 关键词: Action Potentials; Acute; Adult; Afferent Neurons; Aging; Apoptosis; Apoptosis Regulation Gene; Apoptotic; Astrocytes; Buffers; Capsaicin; Cells; Clinical; Collection; Communication; Defect; Development; Disease; Embryonic Development; Excision; Exhibits; Foundations; Genes; Glutamates; Hyperalgesia; Hypersensitivity; Impairment; In Vitro; Injections; Ion Channel; Knock-out; Knockout Mice; Lead; Measures; Mediating; Modality; Mus; Nerve Degeneration; Neuroglia; Neurons; Nociception; Nociceptors; Pain; Perception; Perinatal; Peripheral; Phagocytes; Phagocytosis; Phenotype; Population; Predisposition; Property; Proprioception; Role; Sensory; Signal Transduction; Spinal Ganglia; Stimulus; Temperature; Testing; allodynia; base; chronic pain; chronic pain management; excitotoxicity; in vivo; inflammatory pain; mechanical allodynia; nerve injury; neuron loss; novel; novel therapeutics; pain sensation; painful neuropathy; patch clamp; prevent; receptor; response

The dorsal root ganglia (DRG) are a diverse collection of sensory neurons that convey information such as proprioception, mechanosensation and temperature from the periphery to the CNS. Stimuli that activate specific DRG neurons (nociceptors) can trigger pain sensation. There is increasing evidence that satellite glial cells (SGCs), which surround the DRG neurons, modulate sensory processing, particularly for chronic pain. The overall objective of this project is to elucidate the mechanisms by which SGCs influence sensory neuron function; particularly, how the engulfment receptor Jedi1, expressed by SGCs, regulates nociceptive neurons. SGCs form a tight barrier around DRG neurons and buffer the local milieu, thereby regulating neuronal activity. In addition, we demonstrated that SGCs are the primary phagocytes that clear apoptotic neurons during development of the DRG and identified Jedi1 as a novel engulfment receptor expressed by these glia. To investigate the in vivo role of Jedi1, we generated jedi1-/- mice. In the DRG from null mice the removal of dead cells during development was impaired. Interestingly, despite Jedi1 expression only being detected in the glia and not the neurons, we found altered function of jedi1-/- sensory neurons. Electrical recording from perinatal jedi1-/- DRG neurons revealed a substantial increase in excitability; most wild type neurons only fired 1-2 action potentials in response to current injection, whereas most jedi-/- cells fired multiple action potentials. Such enhanced excitability is typical of DRG neurons in early development and following nerve injury. The hypersensitivity was accompanied by a 25% decrease in the number of DRG neurons in adult, but not perinatal jedi1-/- mice, suggesting there may be excitotoxic neurodegeneration. In addition, there was a 30% increase in the fraction of DRG neurons responsive to capsaicin, which was paralleled by enhanced capsaicin-induced allodynia in jedi1-/- mice relative to wild type. Enhanced excitability, a greater fraction of capsaicin responsive neurons and increased susceptibility to apoptosis, are all associated with DRG neurons in early development, suggesting defects in the normal maturation of jedi1-/- neurons. Therefore, we hypothesize that loss of Jedi1 in SGCs results in impaired sensory neuron maturation, which leads to altered nociception and excitotoxic neurodegeneration. To test this hypothesis, we will (1) determine which sensory modalities are altered in jedi1-/- mice, (2) determine if loss of Jedi1 selectively in SGCs during development leads to an altered sensory neuron phenotype, (3) identify the mechanism underlying the sensory neuron phenotype. These studies will reveal fundamental mechanisms by which glia regulate neuronal function and sensory perception, provide a foundation for understanding how dysfunctional signaling can lead to peripheral sensitization and disease, and potentially identify novel targets for the treatment of chronic pain.

背根神经节（DRG）是多种感官神经元的集合，传达了此类信息 作为本体感受，机械敏感和温度从周围到中枢神经系统。激活的刺激 特定的DRG神经元（伤害感受器）会触发疼痛感。有越来越多的证据表明卫星神经胶质 围绕DRG神经元的细胞（SGC）调节感觉处理，尤其是用于慢性疼痛。 该项目的总体目的是阐明SGC影响感觉神经元的机制 功能;特别是，SGC表达的吞噬受体JEDI1如何调节伤害性神经元。 SGC在DRG神经元周围形成紧密的障碍，并缓冲当地环境，从而调节神经元活动。 此外，我们证明了SGC是在前吞噬细胞的主要吞噬细胞 DRG的开发并确定了JEDI1是这些神经胶质表达的新型吞噬受体。到 研究JEDI1的体内作用，我们生成了JEDI1 - / - 小鼠。在无效老鼠的DRG中删除死亡 发育过程中的细胞受损。有趣的是，尽管JEDI1表达仅在神经胶质中检测到 而不是神经元，我们发现JEDI1 - / - 感觉神经元的功能改变了。围产期电气记录 JEDI1 - / - DRG神经元揭示了兴奋性的大幅增加。大多数野生型神经元仅发射1-2 动作电位响应当前注入，而大多数绝地武元 - / - 细胞发射了多个动作电位。 这种增强的兴奋性是DRG神经元在早期发育和神经损伤之后的典型特征。这 超敏反应伴随着成人的DRG神经元数量减少25％，但不会减少 JEDI1 - / - 小鼠，表明可能存在兴奋性神经退行性。此外，增加了30％ DRG神经元对辣椒素的反应的分数，与辣椒素诱导的增强相似 JEDI1 - / - 小鼠相对于野生型中的异常痛。增强的兴奋性，辣椒素反应率更大 神经元和对细胞凋亡的敏感性增加，都与早期发育中的DRG神经元有关， 表明JEDI1 - / - 神经元正常成熟的缺陷。因此，我们假设JEDI1的损失 在SGC中，导致感觉神经元成熟受损，从而导致伤害感受和 兴奋性神经变性。为了检验该假设，我们将（1）确定哪些感觉方式是 JEDI1 - / - 小鼠的改变，（2）确定在开发过程中SGC中JEDI1是否有选择性的损失导致 改变感觉神经元表型，（3）确定感觉神经元表型的基础机制。 这些研究将揭示基本机制调节神经元功能和感觉的基本机制 感知，为理解功能失调的信号传导提供基础 致敏和疾病，并有可能识别出治疗慢性疼痛的新靶标。

项目成果

Jedi-1 deficiency increases sensory neuron excitability through a non-cell autonomous mechanism.

Jedi-1 缺陷通过非细胞自主机制增加感觉神经元的兴奋性。

• DOI: 10.1038/s41598-020-57971-2
• 发表时间: 2020
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Trevisan,AlexandraJ;Bauer,MaryBeth;Brindley,RebeccaL;Currie,KevinPM;Carter,BruceD
• 通讯作者: Carter,BruceD

Peripheral myelin protein 22 modulates store-operated calcium channel activity, providing insights into Charcot-Marie-Tooth disease etiology.

外周髓鞘蛋白 22 调节钙池操纵的钙通道活性，为了解腓骨肌萎缩症病因学提供见解。

• DOI: 10.1074/jbc.ra118.006248
• 发表时间: 2019
• 期刊: The Journal of biological chemistry
• 作者: Vanoye,CarlosG;Sakakura,Masayoshi;Follis,RoseM;Trevisan,AlexandraJ;Narayan,Malathi;Li,Jun;Sanders,CharlesR;Carter,BruceD
• 通讯作者: Carter,BruceD