Protease Activated Receptor Type 2 Targeting for Migraine Pain

蛋白酶激活受体 2 型靶向治疗偏头痛

• 批准号: 10161867
• 负责人: Scott Boitano
• 金额: $ 48.11万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10161867
• 关键词: Adult; Afferent Neurons; Agonist; Antibodies; Area; Attenuated; Binding; Biological Assay; Cell Degranulation; Chemicals; Data; Development; Digit structure; Disease; Dura Mater; Electrophysiology (science); Europium; Functional disorder; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Genetic; Goals; Human; Inflammation Mediators; Knock-out; Knockout Mice; Label; Laboratories; Lead; Ligands; Link; LoxP-flanked allele; Mediating; Meningeal; Meninges; Migraine; Modeling; Molecular; Morbidity - disease rate; Mus; Nociception; Nociceptors; PAR-2 Receptor; Pain; Pathogenesis; Pathology; Pathway interactions; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacology; Physiological; Physiology; Planet Earth; Play; Population; Positioning Attribute; Price; Property; Protease Inhibitor; Proteinase-Activated Receptors; Research; Rodent Model; Role; Signal Pathway; Specificity; Sumatriptan; System; Testing; Time; Transgenic Mice; Trigeminal System; Validation; Work; cancer pain; cell analyzer; cell type; design; drug discovery; effective therapy; high throughput screening; improved; inflammatory pain; innovation; mast cell; mouse genetics; mouse model; nervous system disorder; next generation; novel; novel therapeutics; pain behavior; paracrine; peptidomimetics; pre-clinical; programs; public health relevance; tool

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.

蛋白酶激活受体 2 型靶向治疗偏头痛 PI：Theodore Price、Gregory Dussor、Josef Vagner 和 Scott Boitano 抽象的 偏头痛是最常见的神经系统疾病，是地球上第三大最常见疾病，也是第八大最常见疾病 禁用。目前可用的治疗方法无法有效控制大多数患者的偏头痛。发展 新疗法进展缓慢，很大程度上是由于对潜在病理学的了解不足 偏头痛。内源性蛋白酶由常驻肥大细胞在脑膜中释放，已被提议作为 通过对蛋白酶激活受体 2 (PAR2) 的作用，可能导致偏头痛。不幸的是 该机制的证据依赖于不精确的药理学工具，并且缺乏遗传验证。中央 该多 PI 研究计划的假设是 PAR2 在投射到脑膜的伤害感受器中表达 通过将脑膜蛋白酶的释放与偏头痛的敏化联系起来，在偏头痛的发病机制中发挥关键作用 三叉神经伤害感受系统。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 作为偏头痛目标，并使用小鼠遗传学来识别 PAR2 表达在脑膜投射伤害感受器对偏头痛的具体作用。我们的首要目标是 利用我们已建立的 PAR2 开发管道来设计新的 PAR2 拮抗剂，并具有改进的类药性 在偏头痛小鼠模型中探测 PAR2 功能的特性。我们的第二个目标将使用 新型小鼠偏头痛模型中的药理学工具，以进一步了解 PAR2 在治疗中的潜在作用 偏头痛和 PAR2 参与的信号通路引起硬脑膜疼痛。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 PAR2 拮抗剂； 2）制定创新的新目标 偏头痛； 3) 首次对 PAR2 在疼痛中的细胞类型特异性作用进行基因验证 途径。总而言之，成功的研究将为进一步的开发和提供临床前理论依据。 测试 PAR2 配体治疗偏头痛和其他形式的疼痛。

项目成果

Transient Photoinactivation of Cell Membrane Protein Activity without Genetic Modification by Molecular Hyperthermia.

细胞膜蛋白活性的瞬时光失活，无需通过分子热疗进行基因修饰。

• 发表时间: 2019
• 影响因子: 17.1
• 作者: Kang, Peiyuan;Li, Xiaoqing;Liu, Yaning;Shiers, Stephanie I;Xiong, Hejian;Giannotta, Monica;Dejana, Elisabetta;Price, Theodore John;Randrianalisoa, Jaona;Nielsen, Steven O;Qin, Zhenpeng
• 通讯作者: Qin, Zhenpeng