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: 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
• 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

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％的人口将遭受慢性疼痛持续超过6 月份。慢性疼痛及其潜在的病理生理学，可能导致抑郁症和 其他令人衰弱的神经系统作用，尽管有有效的治疗方法 急性疼痛慢性疼痛对大多数当前治疗都有抗性 开发针对这些疼痛的分子事件的新型治疗剂 国家。神经性疗法和持续性后手术后疼痛至少部分发生 脊柱背兴兴奋性突触传播功能的持久变化 喇叭导致疼痛信号（Hypergersia）增强和无害刺激 疼痛（异常性）。这些突触事件具有许多神经元可塑性的特征 已在CNS较高的地区进行了研究。这些更改中有许多是依赖NMDAR 导致突触强度提高。出现的一种机制 突触功能的这些变化是直接的NMDAR功能增强 与EPHB受体酪氨酸激酶的分子相互作用。建立在我们出版的基础上 工作，我们将检验以下假设：EPHB-NMDAR相互作用负责 通过指示NMDAR表达突触来开发慢性疼痛状态 野生型或突变体EPHB2受体在体外和小鼠中。为了检验这一假设，我们将 确定介导EPHB-NDMAR相互作用的机制，表征 分子和其他破坏这种相互作用的工具，并确定是否防止 EPHB-NMDAR相互作用将减轻慢性疼痛。为了解决这些问题 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的假设 指导Y504在EPHB2上的磷酸化。 3。确定功能 VLK在疼痛可塑性中的重要性。这些目标共同创造一个新的 知识将对EPHB-NMDAR的作用有更深入的了解 疼痛中的相互作用，并使进步能够理解基本机制 慢性疼痛状态的背后。