Treatment for neuropathic pain targeting selective inhibition of MEK

选择性抑制 MEK 治疗神经性疼痛

基本信息

批准号：
8976229
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
项目类别：
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/8976229
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 small molecule inhibitor spared nerve spontaneous pain

项目摘要

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）：因当前可用的DRG Armamentarium而难以治疗神经系统慢性炎症和伤害引起的神经性疼痛。与神经性疼痛相关的治疗所导致的社会的年度超额财务成本估计为160亿美元，在收入损失和相关的无可估量的人类痛苦方面，其额外的财务成本为160亿美元。显然需要一种基于机制的新型神经性疼痛治疗方法。有丝分裂原活化的蛋白激酶（MAPK）是细胞内信号转导的分子，在将细胞外事件转换为细胞反应中起着至关重要的作用。据报道，背部根神经节（DRG）中的ERK1/2及其上游MAPK激酶（MEK1/2）在介导神经性疼痛的损伤的信号级联层中发挥了作用。我们希望检验以下假设：在背根神经节中对MEK1/2的选择性抑制作用将抑制神经性疼痛。通过3个特定的目的，我们建议通过小分子和病毒载体来研究MEK1/2的抑制作用，以表达显性阴性的MEK1作为基于机制的神经性疼痛的治疗方法。 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使用AAV2/8-DN-MEK1选择性抑制DRG中的该信号。我们采用艺术行为方法的状态，用于对三种具有强烈炎症（爪子福尔马林注射），神经性损伤（避免神经损伤）或混合（慢性狭窄损伤）病因的啮齿动物疼痛模型的有效性分析。传统评估疼痛（热痛觉过敏和机械性异常症）以及自发疼痛的行为测定（负重测试和有条件的位置偏好）。提出了由结合的自由能作为配体亲和力的量度的指导的配体对MEK的硅醇分子的合理化学修饰。研究小组由具有神经科学/疼痛研究，疼痛行为分析和化学合成方面的专业知识的高级研究人员组成，共同提供了执行该项目的所有必要技能。