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

基本信息

批准号：
10675034
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-01-08
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10675034
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 Evolution 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 Vertebral column Work allodynia antagonist 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

项目摘要

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.

抽象的：多达 20% 的人口将遭受持续 6 年以上的慢性疼痛几个月。慢性疼痛及其潜在的病理生理学可能导致抑郁和其他使人衰弱的神经系统影响，尽管有有效的治疗方法急性疼痛慢性疼痛对大多数目前的治疗方法有抵抗力，需要开发针对这些疼痛背后的分子事件的新型疗法州。神经性和持续性术后疼痛的发生，至少部分是由于长期的脊髓背侧兴奋性突触传递功能的持久变化喇叭导致疼痛信号增强（痛觉过敏）和无害刺激唤起疼痛（异常性疼痛）。这些突触事件具有神经元可塑性的许多特征已在高等中枢神经系统领域进行了研究。其中许多变化都依赖于 NMDAR 导致突触强度增加。已经出现的一种潜在机制突触功能的这些变化是 NMDAR 功能通过直接作用的增强与 EphB 受体酪氨酸激酶的分子相互作用。以我们发布的工作中，我们将检验以下假设：EphB-NMDAR 相互作用负责通过表达将 NMDAR 引导至突触来形成慢性疼痛状态体外和小鼠体内的野生型或突变型 EphB2 受体。为了检验这个假设，我们将确定介导 EphB-NDMAR 相互作用的机制，表征分子和其他工具来破坏这种相互作用，并确定是否阻止 EphB-NMDAR 相互作用将减轻慢性疼痛。为了解决这些问题我们将实现三个具体目标： 1. 确定 NMDAR 的域负责 EphB-NMDAR 相互作用。 2. 检验 VLK 的假设指导 EphB2 上 Y504 的磷酸化。 3.确定功能 VLK 在疼痛可塑性中的意义。这些目标共同将创造一个新的有助于更深入地了解 EphB-NMDAR 作用的知识疼痛中的相互作用并有助于理解基本机制慢性疼痛状态背后。