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）：由慢性炎症和神经系统损伤引起的神经性疼痛用目前可用的药物治疗特别难以治疗。神经性疼痛相关治疗每年给社会造成的超额财务成本估计为 160 亿美元，其中收入损失和相关的无法估量的人类痛苦要多得多。显然需要一种新的基于机制的神经性疼痛治疗方法。丝裂原激活蛋白激酶 (MAPK) 是细胞内信号转导分子，在将细胞外事件转变成细胞反应方面发挥着关键作用。据报道，背根神经节 (DRG) 中的 ERK1/2 及其上游 MAPK 激酶 (MEK1/2) 在介导神经性疼痛损伤的信号级联中发挥作用。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 将抑制神经性疼痛。通过 3 个具体目标，我们建议研究小分子和表达显性失活 MEK1 的病毒载体对 MEK1/2 的抑制，作为基于机制的神经性疼痛治疗。该研究涉及评估槲皮素的抗伤害作用，槲皮素是一种小分子黄酮醇化合物，通过与与 ATP 结合袋重叠的 MEK 区域结合来抑制 MEK1/2，进一步高通量寻找其他新型小分子 MEK1/2 抑制剂具有抗伤害特性，通过计算机对接引导的合理化学修饰小分子，并使用 AAV2/8-DN-MEK1 选择性抑制该信号传导DRG。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，这些模型具有强炎症性（足垫福尔马林注射）、神经性（无神经损伤）或混合性（慢性压迫性损伤）病因。将采用传统的疼痛评估（热痛觉过敏和机械异常性疼痛）以及自发疼痛的行为测定（负重测试和条件位置偏好）。提出了对先导黄酮醇分子进行合理的化学修饰，广泛使用配体与 MEK 的计算机对接，以结合自由能为指导，作为配体亲和力的测量。研究团队由具有神经科学/疼痛研究、疼痛行为分析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。