Protease Activated Receptor Type 2 Targeting for Migraine Pain

蛋白酶激活受体2靶向治疗偏头痛 PI：西奥多价格，格雷戈里杜索尔，约瑟夫瓦格纳和斯科特博伊塔诺 摘要 偏头痛是最常见的神经系统疾病，是地球上第三大最常见的疾病，也是第八大最常见的疾病。 禁用。目前可用的治疗方法不能有效地管理大多数患者的偏头痛。发展 新的治疗方法进展缓慢，这在很大程度上是由于对潜在的病理学缺乏了解。 偏头痛由驻留的肥大细胞在脑膜中释放的内源性蛋白酶已经被提出作为一种免疫调节剂。 通过作用于蛋白酶激活受体2型（PAR 2）而成为偏头痛的潜在驱动因素。不幸的是 这一机制的证据依赖于不精确的药理学工具，缺乏遗传学验证。中央 该多PI研究计划假设是PAR 2在投射到脑膜的伤害感受器中的表达 在偏头痛的发病机制中起着关键作用，通过将脑膜蛋白酶释放与 三叉神经伤害感受系统该提案的主要目标是开发下一代PAR 2 拮抗剂，使用这些工具来验证PAR 2作为偏头痛的靶点，并使用小鼠遗传学来鉴定 PAR 2表达在偏头痛脑膜投射伤害感受器中的特殊作用。我们的首要目标是 利用我们已建立的PAR 2开发管道设计新的PAR 2拮抗剂， 在偏头痛的小鼠模型的背景下探测PAR 2功能的性质。我们的第二个目标将使用 在一种新的小鼠偏头痛模型中使用药理学工具，以进一步了解PAR 2在 偏头痛和PAR 2参与的信号通路引起硬脑膜疼痛。我们的最终目标将使用鼠标 研究PAR 2在偏头痛中的细胞类型特异性作用。我们的工作将导致：1）发现和 PAR 2的新型高效拮抗剂的开发; 2）PAR 2的创新性新靶点的开发; 偏头痛;和3）提供PAR 2在疼痛中的细胞类型特异性作用的第一次遗传验证 通路总之，成功的研究将为进一步开发提供临床前依据， 测试PAR 2配体用于治疗偏头痛和其他形式的疼痛。

Protease Activated Receptor Type 2 Targeting for Migraine Pain PIs: Theodore Price, Gregory Dussor, Josef Vagner and Scott Boitano ABSTRACT Migraine is the most common neurological disorder, the 3rd most common disease on earth, and the 8th most disabling. Currently available treatments fail to effectively manage migraine in most patients. Development of new therapeutics has been slow due in large part to a poor understanding of the underlying pathology of migraine. Endogenous proteases, released in the meninges by resident mast cells, have been proposed as a potential driver of migraine pain via an action on protease activated receptor type 2 (PAR2). Unfortunately the evidence for this mechanism relies on imprecise pharmacological tools and lacks genetic validation. The central hypothesis of this multi-PI research program is that PAR2 expression in nociceptors that project to the meninges plays a key role in the pathogenesis of migraine pain by linking meningeal protease release to sensitization of the trigeminal nociceptive system. The primary objectives of this proposal are to develop next generation PAR2 antagonists, to use these tools to validate PAR2 as a migraine pain target and to use mouse genetics to identify the specific role of PAR2 expression in meningeal projecting nociceptors to migraine pain. Our first aim will be to use our established PAR2 development pipeline to design new PAR2 antagonists with improved drug-like properties to probe PAR2 function in the context of a mouse model of migraine pain. Our second aim will use pharmacological tools in a novel mouse migraine model to further understand the potential role of PAR2 in migraine and signaling pathways engaged by PAR2 to evoke pain from the dura. Our final aim will use mouse genetics to study the cell type-specific role of PAR2 in migraine pain. Our work will result in: 1) the discovery and development of novel high potency antagonists for PAR2; 2) the development of an innovative new target for migraine pain; and 3) provide the first genetic verification of the cell type-specific action of PAR2 in the pain pathway. Taken together, successful studies will provide a preclinical rationale for the further development and testing of PAR2 ligands for the treatment of migraine and other forms of pain.