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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

基本信息

批准号：
7555953
负责人：
Benedict J Alter
金额：
$ 2.77万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/7555953
关键词：
Address Afferent Neurons Behavior Behavioral Biochemistry Chronic Cyclic AMP-Responsive DNA-Binding Protein Data Developed Countries Developing Countries Development Electrophysiology (science)Embryo Extracellular Signal Regulated Kinases Formalin Freund&apos 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 combat 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5 neuronal excitability painful neuropathy prevent research study response sensory system tool treatment strategy unpublished works upstream kinase

项目摘要

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）：