Treatment for neuropathic pain targeting selective inhibition of MEK

选择性抑制 MEK 治疗神经性疼痛

• 批准号: 8627282
• 负责人: JAY YANG
• 金额: $ 28.6万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8627282
• 关键词: Affinity; Animals; Arts; Behavior; Behavioral; Behavioral Assay; Binding; Biochemical; Biochemical Pathway; Biological Assay; Cardiovascular system; Chemical Structure; Chemicals; Chemistry; Chronic; Clinical; Clinical Pharmacology; Collaborations; Communities; Complex; Computer Simulation; Core Facility; Docking; Dominant-Negative Mutation; Effectiveness; Engineering; Environment; Etiology; Evaluation; Event; Financial cost; Flavonoids; Flavonols; Formalin; Free Energy; Healed; Human; Image; In Vitro; Inflammation; Inflammatory; Injection of therapeutic agent; Injury; Lead; Ligands; MAP2K1 gene; MAPK3 gene; MEK inhibition; MEKs; Measures; Mediating; Methods; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Modeling; Modification; Molecular; Molecular Bank; Nervous system structure; Neurons; Neuropathy; Neurosciences; Nociception; Pain; Pain Measurement; Pain Research; Pathogenesis; Pharmaceutical Preparations; Phosphotransferases; Plants; Play; Property; Psychiatry; Quercetin; Rattus; Reporting; Research; Research Personnel; Rodent; Role; Schools; Scientist; Signal Transduction; Signaling Molecule; Societies; Spinal Ganglia; Techniques; Testing; Thermal Hyperalgesias; Time; Training Programs; Translating; Universities; Viral; Viral Vector; Virus; Weight-Bearing state; Wisconsin; Work; Yang; base; chemical synthesis; chronic constriction injury; design; effective therapy; extracellular; gene therapy; healing; high throughput screening; in vivo; inhibitor/antagonist; innovation; mechanical allodynia; member; nerve injury; novel; painful neuropathy; preference; programs; public health relevance; receptor; research study; response; screening; skills; small molecule; spontaneous pain

Abstract: Neuropathic pain resulting from chronic inflammation and injury to the nervous system is particularly difficult to treat with the currently available drug armamentarium. Annual excess financial cost to the society resulting from neuropathic pain-related treatment is estimated to be $16 billion with much more in terms of lost revenue and associated immeasurable human suffering. A novel mechanism-based treatment for neuropathic pain is clearly needed. Mitogen activated protein kinases (MAPK) are intracellular signal transducing molecules that play a critical role in transducing extracellular events to cellular responses. ERK1/2 and its upstream MAPK kinases (MEK1/2) in the dorsal root ganglion (DRG) have been reported to play a role in the signaling cascade mediating injury to neuropathic pain. We wish to test the working hypothesis that: Selective inhibition of MEK1/2 in the dorsal root ganglion will suppress neuropathic pain. Through 3 specific aims, we propose to investigate inhibition of MEK1/2 by small molecules and a viral vector expressing a dominant-negative MEK1 as a mechanism-based treatment for neuropathic pain. The study involves assessment of anti-nociceptive effects of quercetin, a small molecule flavonol compound found to inhibit MEK1/2 by binding to a region of MEK overlapping the ATP- binding pocket, further high throughput search for other novel small molecule MEK1/2 inhibitor with anti-nociceptive properties, modification of the small molecule through in silico docking-guided rational chemistry, and the use of AAV2/8-DN-MEK1 to selectively inhibit this signaling in the DRG. We employ state of art behavioral methods for in vivo analysis of effectiveness against three rodent pain models with a strong inflammatory (paw pad formalin injection), neuropathic (spared nerve injury), or mixed (chronic constriction injury) etiology. Traditional assessment of pain (thermal hyperalgesia and mechanical allodynia) as well as behavioral assays for spontaneous pain (weight bearing test and conditional place preference) will be employed. Rational chemical modification of a lead flavonol molecule with extensive use of in silico docking of ligands to MEK guided by the free-energy of binding as a measure of ligand affinity is proposed. The research team consists of senior investigators with expertise in neuroscience/pain research, behavior assay of pain, and chemical synthesis, together providing all the necessary skills to execute this project.

摘要：由慢性炎症和神经系统受伤引起的神经性疼痛是 当前可用的药物武术特别难以治疗。年过剩 据估计，由神经性疼痛相关治疗引起的社会的经济成本估计为 160亿美元的收入损失和相关的人类苦难方面，更多。 显然需要一种基于机制的新型神经性疼痛治疗方法。有丝分裂原活化 蛋白激酶（MAPK）是细胞内信号转导的分子，在 将细胞外事件转化为细胞反应。 ERK1/2及其上游MAPK激酶 （MEK1/2）在背根神经节（DRG）中据报道在信号中发挥作用 级联介导神经性疼痛的损伤。我们希望检验以下工作的假设： 在背根神经节中对MEK1/2的选择性抑制作用会抑制神经性疼痛。通过 3特定的目的，我们建议通过小分子和病毒研究对MEK1/2的抑制作用 表达主要阴性MEK1的矢量是基于机制的神经性治疗方法 疼痛。该研究涉及评估槲皮素的抗伤害感受效应，这是一个小分子 黄酮醇化合物发现通过与ATP重叠的MEK区域结合来抑制MEK1/2 结合口袋，进一步的高吞吐量搜索其他新型小分子MEK1/2抑制剂 抗伤害性特性，在硅对接引导中修饰小分子 理性化学和使用AAV2/8-DN-MEK1在DRG中有选择地抑制此信号。 我们采用艺术状态行为方法来体内对三个的有效性分析 啮齿动物疼痛模型具有强烈的炎症性（爪子福尔马林注射），神经性疗法（保留 神经损伤）或混合（慢性狭窄损伤）病因。传统疼痛评估 （热痛觉和机械性异常性）以及自发的行为测定 将采用疼痛（负重测试和有条件的位置偏好）。理性化学 通过大量使用配体向MEK的硅二聚体对铅的修饰黄酮分子的修饰 提出了由结合的自由能作为配体亲和力的量度的指导。研究 团队由具有神经科学/疼痛研究专业知识的高级调查员组成 疼痛和化学合成，共同提供了执行该项目的所有必要技能。