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：慢性炎症和神经系统损伤引起的神经病理性疼痛是 尤其难以用目前可用的药物医疗器械治疗。年度超额 神经性疼痛相关治疗对社会造成的经济成本估计为 160亿美元，还有更多的收入损失和相关的不可估量的人类痛苦。 显然需要一种新的基于机制的治疗神经病理性疼痛的方法。有丝分裂原激活 蛋白激酶(MAPK)是细胞内的信号转导分子，在 将细胞外事件传递给细胞反应。ERK1/2及其上游MAPK激酶 (MEK1/2)在背根节(DRG)中起信号转导作用 级联介导损伤为神经病理性疼痛。我们希望检验以下工作假设： 选择性抑制背根神经节中的MEK1/2将抑制神经病理性疼痛。穿过 3个特定目标，我们建议研究小分子和一种病毒对MEK1/2的抑制作用 表达显性-阴性MEK1的载体作为神经病机制治疗的基础 疼痛。这项研究包括评估小分子槲皮素的抗伤害性作用。 发现黄酮醇化合物通过与MEK区域重叠的ATP结合来抑制MEK1/2。 结合口袋，进一步高通量寻找其他新的小分子MEK1/2抑制剂 抗伤害性，通过硅胶对接引导的小分子修饰 合理的化学，并使用AAV2/8-dN-MEK1选择性地抑制DRG中的这一信号。 我们使用最先进的行为方法在体内分析对三个 大鼠疼痛模型具有较强的炎症性(爪垫福尔马林注射)、神经性(备用 神经损伤)或混合性(慢性缩窄性损伤)病因。传统的疼痛评估 (热痛觉过敏和机械性痛觉异常)以及自发的行为分析 将采用疼痛(负重测试和有条件的地点偏好)。合理的化学物质 黄酮醇铅分子的修饰及其在MEK电子对接中的广泛应用 在结合自由能的指导下，提出了配体亲和力的度量方法。这项研究 团队由具有神经科学/疼痛研究、行为分析专业知识的高级调查人员组成 疼痛和化学合成，共同提供了执行这一项目所需的所有技能。