Protease Activated Receptor Type 2 Targeting for Migraine Pain

蛋白酶激活的2型受体靶向治疗偏头痛 PIS：西奥多·普莱斯、格雷戈里·杜莎、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，是地球上第三大常见病，也是第八大常见病 正在禁用。目前可用的治疗方法未能有效地控制大多数患者的偏头痛。发展中的 新的治疗方法进展缓慢，很大程度上是因为对其潜在的病理机制了解不深。 偏头痛。由常驻肥大细胞在脑膜中释放的内源性蛋白水解酶被认为是一种 通过对蛋白酶激活的2型受体(PAR2)的作用，可能是偏头痛的驱动因素。不幸的是， 这种机制的证据依赖于不精确的药理学工具，缺乏基因验证。中环 这个多PI研究项目的假设是PAR2在投射到脑膜的伤害性感受器中的表达 在偏头痛的发病机制中起着关键作用，它通过将脑膜蛋白水解酶的释放与脑膜蛋白的敏化联系起来。 三叉神经伤害性感受系统。该提案的主要目标是开发下一代PAR2 拮抗剂，使用这些工具来验证PAR2作为偏头痛疼痛的靶点，并使用小鼠遗传学来识别 PAR2表达在偏头痛的脑膜投射伤害性感受器中的特殊作用。我们的首要目标是 利用我们建立的PAR2开发流水线设计具有改进的类药物的新的PAR2拮抗剂 在偏头痛小鼠模型的背景下探索PAR2功能的性质。我们的第二个目标将使用 新的小鼠偏头痛模型的药理学工具进一步了解PAR2在偏头痛中的潜在作用 偏头痛和PAR2参与的信号通路从硬脑膜唤起疼痛。我们的最终目标是使用鼠标 遗传学研究PAR2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 开发新型高效的PAR2拮抗剂；2)开发一种创新的靶点 以及3)首次对PAR2在疼痛中的细胞类型特异性作用进行了遗传学验证 路径。综上所述，成功的研究将为进一步的发展和 测试PAR2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.