Genetic and post-translational modifications of TRPV1 in craniofacial pain

项目总结 头面部病理中的疼痛管理是一项重大的临床挑战。透彻了解 颅面疼痛的分子机制应有助于开发更好的新策略 治疗。TRPV1是辣椒素和多种内源性刺激(如热和质子)的受体。在……里面 除了对热痛敏的众所周知的贡献外，TRPV1还整合了伤害性信号转导 在炎症和损伤下，并牵涉到各种头面部病理情况。虽然 TRPV1是颅面部抗痛觉过敏治疗的良好候选药物，拮抗剂可抑制TRPV1 功能可能完全不适用，因为严重的不良反应。因此，重要的是要 开发针对病理特异性TRPV1活性的治疗药物。基于文献和我们的初步研究 数据，我们假设TRPV1活性的改变是由翻译后修饰和 基因变异导致头面部病理性疼痛。为了检验这一假设，我们将执行一个 体外、体内和人体内的综合分析。我们将确定特定于医疗设备的基础 磷酸化诱导的TRPV1超敏反应(目标1)，检测PKC诱导的作用 体内TRPV1对感觉神经元和头面部疼痛的超敏反应的磷酸化(目标2)，以及 确定人类TRPV1基因座内的非同义变异是否会导致 体外经络功能和人类头面部疼痛表型(目标3)。如果成功，这个项目将 提供指导开发新的靶向病理学特异性残留的方法的信息 TRPV1和/或选择性患者亚组用于治疗头面部疼痛。

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.