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: 8787120
• 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/8787120
• 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; Health; 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; receptor; research study; response; screening; skills; small molecule; spared nerve; spontaneous pain

DESCRIPTION (provided by applicant): Neuropathic pain resulting from chronic inflammation and injury to the nervous system is particularly difficult to treat with the currently available drg 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.

描述（由申请人提供）：由慢性炎症和神经系统损伤引起的神经性疼痛特别难以用目前可用的drg医疗设备治疗。据估计，神经性疼痛相关治疗给社会造成的年度超额财务成本为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，在将细胞外事件转导为细胞反应中起关键作用。ERK 1/2及其上游MAPK激酶（MEK 1/2）在背根神经节（DRG）中参与了神经病理性疼痛损伤的信号级联反应。我们希望测试工作假设：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个具体的目标，我们建议研究小分子和表达显性阴性MEK 1的病毒载体对MEK 1/2的抑制，作为神经性疼痛的基于机制的治疗。该研究涉及评估槲皮素的抗伤害感受作用，槲皮素是一种小分子黄酮醇化合物，被发现通过结合与ATP结合口袋重叠的MEK区域来抑制MEK 1/2，进一步高通量寻找具有抗伤害感受性质的其他新型小分子MEK 1/2抑制剂，通过计算机对接引导的合理化学修饰小分子，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对三种啮齿动物疼痛模型的有效性进行体内分析，这些模型具有强烈的炎症性（爪垫福尔马林注射）、神经性（备用神经损伤）或混合性（慢性压迫性损伤）病因。将采用传统的疼痛评估（热痛觉过敏和机械性异常性疼痛）以及自发性疼痛的行为测定（负重试验和条件性位置偏爱）。合理的化学修饰的一个铅黄酮醇分子与广泛使用的计算机对接的配体MEK指导的自由能结合作为配体亲和力的措施提出。研究团队由具有神经科学/疼痛研究，疼痛行为测定和化学合成专业知识的高级研究人员组成，共同提供执行该项目所需的所有必要技能。