Extracellular mechanism regulating synaptic function and pain plasticity

调节突触功能和疼痛可塑性的细胞外机制

• 批准号: 10226181
• 负责人: Matthew B Dalva
• 金额: $ 51.11万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226181
• 关键词: Acute Pain; Address; Amino Acids; Analgesics; Area; Binding; Brain; Charge; Chemosensitization; Cortical Cord; Data; Development; EphB2 Receptor; Ephrin B Receptor; Ephrins; Event; Extracellular Protein; Fibronectins; Functional disorder; Generations; Hyperalgesia; Hypersensitivity; In Vitro; Injections; Ketamine; Knowledge; Link; Mass Spectrum Analysis; Mechanics; Mediating; Mental Depression; Molecular; Mus; N-Methyl-D-Aspartate Receptors; N-terminal; NMDA receptor A1; Neurologic Effect; Neuronal Plasticity; Neurons; Neuropathy; Nociception; Pain; Pattern; Peripheral nerve injury; Persistent pain; Phosphorylation; Phosphotransferases; Phylogeny; Play; Population; Post-Translational Protein Processing; Postoperative Pain; Protein Kinase; Protein Tyrosine Kinase; Proteins; Publishing; Receptor Protein-Tyrosine Kinases; Recombinants; Resistance; Role; Sequence Analysis; Spinal; Spinal Cord; Stimulus; Surface; Synapses; Synaptic Transmission; Synaptic plasticity; Tertiary Protein Structure; Testing; Work; allodynia; central sensitization; chronic pain; dorsal horn; effective therapy; extracellular; insight; molecular targeted therapies; mutant; nervous system disorder; neuron development; new therapeutic target; non-opioid analgesic; novel; novel therapeutic intervention; pain model; pain relief; pain signal; painful neuropathy; prevent; protein protein interaction; receptor; receptor function; release of sequestered calcium ion into cytoplasm; side effect; synaptic function; therapeutic target; tool

Abstract: As much as 20% of the population will suffer from chronic pain lasting for more than 6 months. Chronic pain and its underlying pathophysiology, can result in depression and other debilitating neurological effects and although there are effective treatments for acute pain chronic pain is resistant to most current treatments requiring the development of novel therapeutics that target molecular events underlying these pain states. Neuropathic and persistent post-surgical pain occurs, at least in part, due to long lasting changes in the function of excitatory synaptic transmission in the spinal dorsal horn resulting in enhanced pain signalling (hyperalgesia) and innocuous stimuli evoking pain (allodynia). These synaptic events share many features of neuronal plasticity that has been studied in higher CNS areas. Many of these changes are NMDAR dependent resulting in increased synaptic strength. One mechanism that has emerged underlying these changes in synaptic function is the potentiation of NMDAR function by a direct molecular interaction with the EphB receptor tyrosine kinase. Building on our published work, we will test the hypothesis that an EphB-NMDAR interaction is responsible for the development of a chronic pain state by directing NMDARs to synapses by expressing wild type or mutant EphB2 receptors in vitro and in mice. To test this hypothesis, we will determine the mechanism mediating the EphB-NDMAR interaction, characterize molecules and other tools to disrupt this interaction, and determine whether preventing the EphB-NMDAR interaction will alleviate chronic pain. To address these questions we will undertake three specific aims: 1. Determine the domain on the NMDAR responsible for the EphB-NMDAR interaction. 2. Test the hypothesis that VLK directs phosphorylation of Y504 on EphB2. 3. Determine the functional significance of VLK in pain plasticity. Collectively these aims will create a new knowledge that will provide a deeper understanding of the role of EphB-NMDAR interaction in pain and enable progress toward understanding the basic mechanisms behind chronic pain states.

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