Genetic and post-translational modifications of TRPV1 in craniofacial pain

项目摘要 颅面病理学中的疼痛管理是一个主要的临床挑战。透彻理解 颅面疼痛的分子机制应该有助于开发新的策略， 治疗TRPV 1是辣椒素和多种内源性刺激如热和质子的受体。在 TRPV 1除了对热痛觉过敏有众所周知的作用外，还整合了伤害性信号 在炎症和损伤下，并且与各种颅面病理学状况有关。虽然 TRPV 1是颅面抗痛觉过敏治疗的良好候选者，抑制TRPV 1的拮抗剂 功能完全可能不适用，由于严重的不良副作用。因此，重要的是 开发靶向病理特异性TRPV 1活性的治疗剂。根据文献和我们的初步研究， 数据，我们假设TRPV 1活性的改变由翻译后修饰介导， 遗传变异导致颅面病理性疼痛。为了验证这个假设，我们将执行一个 在体外、体内和人体内进行全面分析。我们将确定特定模式的基础， 磷酸化诱导的TRPV 1超敏反应（目的1），检查PKC诱导的TRPV 1超敏反应的贡献。 TRPV 1磷酸化对感觉神经元中的超敏反应和对体内颅面疼痛的超敏反应（Aim 2），和 确定人TRPV 1基因座内的非同义变异是否诱导以下的偶联改变： 体外通道功能和人类颅面疼痛表型（Aim 3）。如果成功，该项目将 提供了指导开发靶向肿瘤病理特异性残基的新方法的信息， TRPV 1和/或选择性患者亚组用于治疗颅面疼痛。

PROJECT SUMMARY Pain management in craniofacial pathology is a major clinical challenge. Thorough understanding of the molecular mechanisms underlying craniofacial pain should help the development of novel strategies for better treatment. TRPV1 is a receptor for capsaicin and multiple endogenous stimuli such as heat and proton. In addition to its well-known contribution to thermal hyperalgesia, TRPV1 also integrates nociceptive signaling under inflammation and injury, and is implicated in various craniofacial pathological conditions. Although TRPV1 is a good candidate for craniofacial anti-hyperalgesic therapy, antagonists that suppress TRPV1 function completely may not be applicable due to serious adverse side effects. Therefore, it will be important to develop therapeutics targeting pathology-specific TRPV1 activity. Based on the literature and our preliminary data, we hypothesize that alteration in activity of TRPV1 mediated by post-translational modification and genetic variations contributes to craniofacial pathological pain. To test this hypothesis, we will perform a comprehensive analysis in vitro, in vivo and in humans. We will determine modality-specific basis for the phosphorylation-induced hypersensitivity of TRPV1 (Aim 1), examine the contribution of PKC-induced phosphorylation of TRPV1 to hypersensitivity in sensory neurons and to craniofacial pain in vivo (Aim 2), and determine whether nonsynonymous variations within the human TRPV1 locus induce coupled alterations of channel functions in vitro and craniofacial pain phenotypes in humans (Aim 3). If successful, this project will provide information that guides development of novel approaches for targeting pathology-specific residues of TRPV1 and/or selective patient subgroups for treating craniofacial pain.