Novel mechanisms regulating protein interaction and pain

项目摘要 多达20%的人口将遭受持续超过6个月的慢性疼痛。慢性疼痛 及其潜在的病理生理学，可导致抑郁和其他使人衰弱的神经效应， 尽管有有效的治疗急性疼痛的方法，但慢性疼痛对大多数当前的治疗方法都有抵抗力 需要开发靶向这些疼痛状态下的分子事件的新疗法。 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。 脊髓背角兴奋性突触传递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， 神经可塑性，已在更高的中枢神经系统领域的研究。这些变化中有许多是NMDAR依赖性的 导致突触强度增加。这些变化背后出现的一种机制是， 突触功能是通过与EphB的直接分子相互作用增强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EphB-NMDAR 这种相互作用通过将NMDAR引导至突触而导致慢性疼痛状态的发展， 在体外和小鼠中表达野生型或突变型EphB 2受体。为了验证这一假设，我们将确定 介导EphB-NDMAR相互作用的机制，表征分子和其他工具来破坏这种相互作用， 本发明还提供了用于预防EphB-NMDAR相互作用的方法，并确定预防EphB-NMDAR相互作用是否将减轻慢性疼痛。到 针对这些问题，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 的Y504对EphB 2。3.确定VLK在疼痛可塑性中的功能意义。统称 目标将创造一个新的知识，将提供更深入的了解EphB-NMDAR的作用 在疼痛中的相互作用，并使理解慢性疼痛背后的基本机制取得进展 states.

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.