The Role of the Neuronal Membrane Proteasome in the Peripheral Nervous System and Pain Sensation

神经膜蛋白酶体在周围神经系统和痛觉中的作用

• 批准号: 10751515
• 负责人: Taylor Renne Church
• 金额: $ 4.77万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751515
• 关键词: Acute; Address; Affect; Afferent Neurons; Attenuated; Axon; Axonal Transport; Behavioral Assay; Binding; Biochemical; Biological Assay; Bortezomib; Calcium Signaling; Cell Cycle Arrest; Cell membrane; Cells; Central Nervous System; Characteristics; Collaborations; Communication; Complex; Confocal Microscopy; Cryoelectron Microscopy; Data; Defect; Dendrites; Detection; Development; Disease; Dose; Electron Microscopy; Electrophysiology (science); Extracellular Space; Fiber; Foundations; Freezing; Future; Glycoproteins; Goals; Grant; Health; Image; Immunofluorescence Immunologic; Individual; Investigation; Knock-out; Label; Laboratories; Length; Limb structure; Long-Term Potentiation; MG132; Macromolecular Complexes; Mechanics; Membrane; Modality; Modeling; Molecular; Molecular Structure; Multiple Myeloma; Mus; Nervous System; Neurons; Neuropathy; Nociception; Nociceptors; Numbness; Outcome; Pain; Paracrine Communication; Pathway interactions; Patients; Pattern; Peptide Signal Sequences; Peptides; Peripheral Nervous System; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Physiological; Play; Prevention; Production; Property; Proprioception; Proteasome Binding; Proteasome Inhibition; Proteasome Inhibitor; Proteins; Regulation; Reporter; Research; Role; Sensory; Series; Signal Transduction; Skin Tissue; Spinal Ganglia; Structure; Synapses; Techniques; Testing; Therapeutic; Thinness; Work; chemotherapy; experimental study; extracellular; in vivo calcium imaging; inflammatory pain; inhibitor; insight; light microscopy; mechanical allodynia; multicatalytic endopeptidase complex; myelination; neuronal cell body; neuronal patterning; neurotoxicity; novel; pain reduction; pain sensation; pain sensitivity; pain signal; painful neuropathy; protein complex; protein degradation; side effect; somatosensory; therapeutic target; ultra high resolution

PROJECT SUMMARY While the proteasome is typically known as protein degradation machinery, it is now recognized to have additional signaling functions in the nervous system. One poorly understood but therapeutically important role for the proteasome is in pain regulation in the peripheral nervous system (PNS). However, the relationship of proteasome activity to pain sensation is complex and somewhat paradoxical: proteasome inhibition has been found to either reduce pain or to cause pain sensitization and peripheral neuropathies depending on length of inhibition, type of inhibitor, and inhibitor dose. A recent discovery that may grant insight into this regulatory mechanism is our laboratory’s detection of a specialized, neuron-specific proteasome bound to the plasma membrane (NMP: neuronal membrane proteasome) that rapidly modulates activity-dependent neuronal calcium signaling through the release of extracellular signaling peptides. Preliminary data from our laboratory has demonstrated that NMP inhibition reduces dorsal root ganglion nociceptor activity and mechanical pain sensitivity, indicating that this novel neuronal communication pathway may be critical in proteasome/pain signaling. However, many fundamental questions about the NMP remain, including how it differs from cytosolic proteasomes and how variable NMP expression across neuronal sub-populations affects pain sensation. The central hypothesis of this proposal is that the PNS NMP plays an important role in pain signaling and that characteristics of NMP expression in PNS sensory neurons, including subtype-specific activity patterns and membrane localization patterns, directly affect its modulation of pain sensitization via differences in paracrine signaling. To address this hypothesis, we propose a series of biochemical, molecular, physiological, and behavioral assays addressing two specific aims: Aim 1. To determine the distribution and structure of the NMP in PNS neuronal membranes; and Aim 2. To investigate the role of the PNS NMP in diverse neuronal subtypes relevant to pain sensation. The completion of these aims will elucidate fundamental properties about the PNS NMP and provide insight into its regulatory role in pain sensation, identifying possible therapeutic avenues for pain modulation and laying the foundation for future investigations examining the role of the PNS NMP in health and disease.

项目总结 虽然蛋白酶体通常被称为蛋白质降解机制，但现在它被认为具有 神经系统中的附加信号功能。一个知之甚少但在治疗上很重要的角色 因为蛋白酶体在外周神经系统(PNS)中参与疼痛调节。然而，两国之间的关系 蛋白酶体对痛觉的活性是复杂的，而且有些矛盾：蛋白酶体抑制一直是 可以减轻疼痛或导致疼痛敏感化和周围神经病变，具体取决于 抑制作用、抑制物类型和抑制物剂量。最近的一项发现可能会让我们深入了解这一监管 机制是我们实验室检测到一种特殊的、神经元特异性的蛋白酶体与血浆结合 快速调节活性依赖性神经细胞钙的膜(NMP：神经细胞膜蛋白酶体) 通过释放细胞外信号肽来传递信号。我们实验室的初步数据显示 NMP抑制可降低背根神经节伤害性感受器活动和机械性疼痛 敏感性，表明这种新的神经元通讯途径可能在蛋白酶体/疼痛中起关键作用 发信号。然而，关于NMP的许多基本问题仍然存在，包括它与胞质有何不同 蛋白酶体以及不同神经元亚群的NMP表达如何影响痛觉。这个 这一提议的中心假设是，三叉神经核NMP在疼痛信号中发挥重要作用，并且 NMP在三叉神经节感觉神经元的表达特征，包括亚型特异性活动模式和 膜定位模式，通过旁分泌的不同直接影响其对痛敏的调控 发信号。为了解决这一假设，我们提出了一系列生化、分子、生理和 针对两个特定目标的行为分析：目的1.确定NMP的分布和结构 目的2.研究PNS NMP在不同神经元亚型中的作用 与痛感相关的。这些目标的实现将阐明PNS的基本属性 NMP并提供对其在痛觉中的调节作用的洞察，确定可能的治疗途径 为进一步研究三七总皂甙NMP在健康中的作用奠定基础 和疾病。