Novel mechanisms regulating protein interaction and pain

调节蛋白质相互作用和疼痛的新机制

基本信息

批准号：
10350573
负责人：
Matthew B Dalva
金额：
$ 51.41万
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：
2019-12-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10350573
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 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

Project 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 signaling (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.

项目摘要多达 20% 的人口会遭受持续超过 6 个月的慢性疼痛。慢性疼痛及其潜在的病理生理学，可能导致抑郁症和其他使人衰弱的神经系统影响尽管有针对急性疼痛的有效治疗方法，但慢性疼痛对大多数现有治疗方法具有抵抗力需要开发针对这些疼痛状态背后的分子事件的新型疗法。神经性和持续性术后疼痛的发生，至少部分是由于神经系统的长期持续变化所致。脊髓背角兴奋性突触传递的功能导致疼痛信号增强（痛觉过敏）和引起疼痛的无害刺激（异常性疼痛）。这些突触事件有许多共同的特征神经元可塑性已在高级中枢神经系统区域进行了研究。其中许多变化都依赖于 NMDAR 导致突触强度增加。这些变化背后出现的一种机制突触功能是通过与 EphB 的直接分子相互作用来增强 NMDAR 功能受体酪氨酸激酶。基于我们已发表的工作，我们将测试以下假设：EphB-NMDAR 相互作用通过将 NMDAR 引导至突触而导致慢性疼痛状态的发展在体外和小鼠体内表达野生型或突变型 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相互作用，并确定阻止 EphB-NMDAR 相互作用是否会减轻慢性疼痛。到为了解决这些问题，我们将实现三个具体目标： 1. 确定 NMDAR 上的域负责 EphB-NMDAR 相互作用。 2.检验VLK指导磷酸化的假设 EphB2 上的 Y504。 3.确定VLK在疼痛可塑性中的功能意义。统称为这些目标将创造新的知识，使人们更深入地了解 EphB-NMDAR 的作用疼痛中的相互作用，有助于理解慢性疼痛背后的基本机制州。