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

基本信息

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
项目类别：
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

项目摘要

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) 是感觉神经元的多样化集合，可传递信息，例如如从外周到中枢神经系统的本体感觉、机械感觉和温度。激活的刺激特定的 DRG 神经元（伤害感受器）可以触发疼痛感。越来越多的证据表明卫星胶质细胞围绕 DRG 神经元的细胞（SGC）调节感觉处理，尤其是慢性疼痛。该项目的总体目标是阐明 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屏障，缓冲局部环境，从而调节神经元活动。此外，我们证明 SGC 是清除凋亡神经元的主要吞噬细胞。 DRG 的发育，并确定 Jedi1 是这些神经胶质细胞表达的新型吞噬受体。到为了研究 Jedi1 的体内作用，我们生成了 jedi1-/- 小鼠。在来自无效小鼠的 DRG 中，去除死亡的细胞在发育过程中受到损害。有趣的是，尽管 Jedi1 表达仅在神经胶质细胞中检测到我们发现 jedi1-/- 感觉神经元的功能发生了改变，而不是神经元。围产期电记录 jedi1-/- DRG 神经元的兴奋性显着增加；大多数野生型神经元仅发射 1-2 次动作电位响应电流注射，而大多数 Jedi-/- 细胞会激发多个动作电位。这种增强的兴奋性是早期发育和神经损伤后 DRG 神经元的典型特征。这成人过敏症伴随着 DRG 神经元数量减少 25%，但围产期则不然 jedi1-/- 小鼠，表明可能存在兴奋毒性神经变性。此外，增长了30% DRG 神经元对辣椒素有反应的比例，这与增强辣椒素诱导的反应平行 jedi1-/- 小鼠相对于野生型的异常性疼痛。兴奋性增强，辣椒素反应性更大神经元和细胞凋亡敏感性增加，都与早期发育中的 DRG 神经元有关，表明 jedi1-/- 神经元的正常成熟存在缺陷。因此，我们假设 Jedi1 的损失 SGC 会导致感觉神经元成熟受损，从而导致伤害感受改变和兴奋性毒性神经变性。为了检验这个假设，我们将 (1) 确定哪些感觉方式是 Jedi1-/- 小鼠中发生改变，(2) 确定在发育过程中 SGC 中 Jedi1 选择性缺失是否会导致改变的感觉神经元表型，（3）确定感觉神经元表型的潜在机制。这些研究将揭示神经胶质细胞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如何导致外周敏化和疾病，并有可能确定治疗慢性疼痛的新靶点。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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：
发表时间：
2019
期刊：
影响因子：
0
作者：
Vanoye, Carlos G;Sakakura, Masayoshi;Follis, Rose M;Trevisan, Alexandra J;Narayan, Malathi;Li, Jun;Sanders, Charles R;Carter, Bruce D
通讯作者：
Carter, Bruce D

Neurotrophin Responsiveness of Sympathetic Neurons Is Regulated by Rapid Mobilization of the p75 Receptor to the Cell Surface through TrkA Activation of Arf6.

交感神经元的神经营养素反应性是通过 Arf6 的 TrkA 激活将 p75 受体快速动员到细胞表面来调节的。