Isoform-specific Roles of Extracelluar-signal Regulated Kinases in Pain

细胞外信号调节激酶在疼痛中的异构体特异性作用

• 批准号: 7409313
• 负责人: Benedict J Alter
• 金额: $ 2.72万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7409313
• 关键词: Address; Afferent Neurons; Behavior; Behavioral; Biochemistry; Chromosome Pairing; Chronic; Cyclic AMP-Responsive DNA-Binding Protein; Data; Developed Countries; Developing Countries; Development; Electrophysiology (science); Embryo; Extracellular Signal Regulated Kinases; Formalin; Freund' s Adjuvant; Functional disorder; Future; GRM5 gene; Genetic; Glean; Goals; Individual; Inflammation; Inflammatory; Injury; Knock-out; Knockout Mice; Laboratories; MAPK1 gene; MAPK3 gene; Measures; Mediating; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Biology; Mus; Neuraxis; Neurons; Neuropathy; Nociception; Nociceptors; Pain; Peripheral; Pharmaceutical Preparations; Phosphotransferases; Play; Posterior Horn Cells; Potassium; Process; Protein Isoforms; Public Health; Rodent Model; Role; Signal Transduction; Spinal Cord; Spinal Cord Plasticity; Spinal cord posterior horn; Stimulus; Synapses; Testing; Tissues; Transcriptional Regulation; behavior test; behavioral sensitization; central sensitization; chronic pain; computerized data processing; experience; inflammatory neuropathic pain; inflammatory pain; inhibitor/antagonist; insight; metabotropic glutamate receptor 5; neuronal excitability; painful neuropathy; prevent; research study; response; sensory system; tool; unpublished works; upstream kinase

DESCRIPTION (provided by applicant): The long-term goal for this project is to elucidate the specific molecular and cellular mechanisms that underlie chronic pain. Understanding these mechanisms will guide the development of new drugs and treatment strategies to better treat this pervasive public health burden. This proposal tests the hypothesis that closely related extracellular-signal regulated kinase (ERK) isoforms, ERK1 and ERK2, play distinct functional roles in chronic pain. Pharmacological experiments indicate that ERK1 and/or ERK2 are necessary for behaviors observed in well-characterized rodent models of pathological pain. To test if ERK1 is necessary for behavioral sensitization in these models, I will compare the behavioral responses of conventional ERK1 knockout mice with wildtype littermates. Unfortunately, conventional ERK2 knockout mice die during development, preventing their use in behavioral experiments. Nevertheless, the behavioral analysis of mice lacking ERK1 will provide valuable information about the function of ERK2, since we know from pharmacological studies that ERK1 and/or ERK2 is involved. Studies using the same pharmacological tools indicate that ERK1/2 is necessary for the sensitization of spinal cord dorsal horn neurons, which is likely to contribute to behavioral sensitization in pain models. To test the necessity of each individual isoform in these cellular changes, I will eliminate either isoform in spinal cord dorsal horn primary cultures. I will then determine whether cellular plasticity changes associated with sensitization occur in these neurons. Sensitization also occurs elsewhere in the pain neuraxis. Nociceptors, which transduce peripheral noxious stimuli, are sensitized in pain models, and ERK1 and/or ERK2 have been implicated in this process. Preliminary results indicate that ERK1 knockout mice show responses similar to those of wildtype littermates in inflammatory pain models, which partially depend on nociceptor sensitization. To test the hypothesis that ERK2 is necessary for nociceptor sensitization, I will create a conditional nociceptor-specific ERK2 knockout and test the behavioral responses of this mouse in models of inflammatory pain. These experiments will be the first to address the isoform-specific roles of ERK1 and ERK2 in pain. Results from this proposal will provide insight into the cellular and molecular mechanisms of chronic pain.

描述（由申请人提供）： 该项目的长期目标是阐明慢性疼痛构成的特定分子和细胞机制。了解这些机制将指导新药和治疗策略的发展，以更好地治疗这种普遍的公共卫生负担。该建议检验了以下假设：密切相关的细胞外信号调节激酶（ERK）同工型ERK1和ERK2在慢性疼痛中起着不同的功能作用。药理学实验表明，在特征良好的病理疼痛模型中观察到的ERK1和/或ERK2是必需的。为了测试这些模型中的行为敏化是否需要，我将比较常规ERK1基因敲除小鼠的行为响应与野生型同窝仔。不幸的是，常规的ERK2敲除小鼠在发育过程中死亡，从而阻止了它们在行为实验中的使用。然而，缺乏ERK1的小鼠的行为分析将提供有关ERK2功能的有价值的信息，因为我们从药理学研究中知道ERK1和/或ERK2涉及。使用相同药理工具的研究表明，ERK1/2对于脊髓背角神经元的敏化是必不可少的，这很可能有助于疼痛模型中的行为敏化。为了在这些细胞变化中测试每个同工型的必要性，我将消除脊髓背角原发性培养物中的同工型。然后，我将确定这些神经元中是否发生了与敏化相关的细胞塑性变化。敏化也发生在疼痛神经上的其他地方。传递外围有害刺激的伤害感受器在疼痛模型中敏感，ERK1和/或ERK2与此过程有关。初步结果表明，ERK1基因敲除小鼠在炎症性疼痛模型中显示出类似于野生型同窝窝的反应，这些反应部分依赖于伤害感受器的敏感性。为了检验ERK2对于伤害感受器敏化所必需的假设，我将创建一个有条件的伤害感受器特异性ERK2敲除，并在炎症性疼痛的模型中测试该小鼠的行为反应。这些实验将是第一个解决ERK1和ERK2在疼痛中的同工型特异性作用的实验。该提案的结果将洞悉慢性疼痛的细胞和分子机制。