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.

翻译后摘要：神经病理性疼痛造成的慢性炎症和损伤的神经系统是 特别难以用目前可用的药物治疗。每年超额 据估计，神经性疼痛相关治疗对社会造成的经济成本为 160亿美元，在收入损失和相关的不可估量的人类痛苦方面要多得多。 显然需要一种新的基于机制的神经性疼痛治疗方法。丝裂原活化 蛋白激酶（MAPK）是细胞内信号转导分子， 将细胞外事件转换为细胞反应。ERK 1/2及其上游MAPK激酶 (MEK1背根神经节（DRG）中的1/2）在信号传导中起作用 级联介导损伤神经性疼痛。我们希望检验以下工作假设： 选择性抑制背根神经节中的MEK 1/2将抑制神经性疼痛。通过 3个具体目标，我们建议研究小分子和病毒对MEK 1/2的抑制作用。 表达显性阴性MEK 1的载体作为神经病的基于机制的治疗 痛苦这项研究涉及评估槲皮素的抗伤害作用， 黄酮醇化合物，发现通过结合与ATP重叠的MEK区域来抑制MEK 1/2， 结合口袋，进一步高通量寻找其他新的小分子MEK 1/2抑制剂， 抗伤害性，通过计算机对接引导的小分子修饰 合理的化学，以及使用AAV 2/8-DN-MEK 1选择性抑制DRG中的这种信号传导。 我们采用最先进的行为方法进行体内分析， 啮齿类动物疼痛模型具有强烈的炎症（爪垫福尔马林注射）、神经性（备用 神经损伤）或混合（慢性压迫性损伤）病因学。传统的疼痛评估 （热痛觉过敏和机械异常性疼痛）以及自发性痛觉过敏的行为测定。 将采用疼痛（负重测试和条件性位置偏好）。理性化学 广泛使用MEK配体的计算机对接修饰黄酮醇先导分子 提出了以结合自由能为指导来衡量配体亲和力。研究 团队由具有神经科学/疼痛研究、行为测定和神经行为学等专业知识的高级研究人员组成。 疼痛和化学合成，一起提供执行这个项目所需的所有技能。