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