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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要虽然蛋白酶体通常被称为蛋白质降解机器，但现在人们认识到它具有神经系统中的一种尚不清楚但在治疗上很重要的作用。然而，蛋白酶体在周围神经系统（PNS）的疼痛调节中的关系。蛋白酶体活性对痛觉的影响是复杂且有些矛盾的：蛋白酶体抑制已被证实发现可以减轻疼痛或引起疼痛敏化和周围神经病变，具体取决于疼痛的持续时间最近的一项发现可能有助于深入了解这一监管。机制是我们实验室检测到一种与血浆结合的专门的、神经元特异性的蛋白酶体快速调节活性依赖性神经元钙的膜（NMP：神经元膜蛋白酶体）我们实验室的初步数据显示，通过释放细胞外信号肽来传递信号。证明 NMP 抑制可降低背根神经节伤害感受器活性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/疼痛中至关重要然而，关于 NMP 的许多基本问题仍然存在，包括它与细胞质有何不同。蛋白酶体以及神经元亚群中不同的 NMP 表达如何影响疼痛感觉。该提案的中心假设是 PNS NMP 在疼痛信号传导中发挥重要作用，并且 PNS 感觉神经元中 NMP 表达的特征，包括亚型特异性活动模式和膜定位模式，通过旁分泌的差异直接影响其对疼痛敏化的调节为了解决这个假设，我们提出了一系列的生化、分子、生理和信号传导。行为测定解决两个具体目标：目标 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这些目标的完成将阐明 PNS 的基本特性。 NMP 并深入了解其在疼痛感觉中的调节作用，确定可能的治疗途径疼痛调节并为未来研究 PNS NMP 在健康中的作用奠定基础和疾病。