14-3-3 gamma regulation of peripheral kappa opioid receptor function

14-3-3 外周κ阿片受体功能的γ调节

• 批准号: 10606163
• 负责人: Michael Joaquin Wedemeyer
• 金额: $ 7.09万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10606163
• 关键词: 14-3-3 Family; Advisory Committees; Afferent Neurons; Analgesics; Animals; Behavior; Behavioral; Behavioral Assay; Binding; Binding Sites; Biological Assay; Bioluminescence; Biosensor; Brain; Cell physiology; Central Nervous System; Chinese Hamster Ovary Cell; Co-Immunoprecipitations; Communication; Complex; Computer Models; Coupled; Cyclic AMP; Dangerousness; Data; Effectiveness; Ensure; Family; Fellowship; Foundations; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Hypersensitivity; Local Anesthetics; Mass Spectrum Analysis; Mediating; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Motor Neurons; Mutation; Neurons; Nociception; Nociceptors; Opioid; Opioid Analgesics; Opioid Receptor; Opioid agonist; Pain; Pain management; Pathway interactions; Peripheral; Peripheral Nervous System; Persons; Pharmacology; Phenotype; Physiological; Population; Postdoctoral Fellow; Production; Proteins; Publishing; Rattus; Receptor Activation; Receptor Signaling; Regulation; Research; Research Personnel; Rodent; Role; Scaffolding Protein; Sedation procedure; Signal Pathway; Signal Transduction; Signaling Protein; Spinal Cord; Stimulus; System; Techniques; Testing; Training; Treatment Efficacy; United States; Ventilatory Depression; Work; addiction; antinociception; beta-arrestin; career; chronic pain; delta opioid receptor; design; effective therapy; human disease; improved; in vitro Assay; in vivo; innovation; insight; kappa opioid receptors; nociceptive response; novel; opioid epidemic; opioid mortality; pain relief; peripheral pain; predictive modeling; receptor function; receptor-mediated signaling; recruit; side effect; transmission process

ABSTRACT Nearly one third of the population of the United States suffers from chronic pain. This pain causes major activity restrictions in nearly 11 million people. Opioids are used for the treatment of pain, but have many negative effects such as respiratory depression, addiction, and sedation. As these negative effects are mediated by the central nervous system, a promising approach for the safe and effective treatment of pain is to target the peripheral nervous system. Signals are sent by the peripheral nervous system to the brain and are interpreted as pain. By specifically inhibiting the transmission of these signals, pain can be alleviated. The value of this approach is illustrated by the pronounced analgesic effectiveness of local anesthetics. Peripherally restricted opioids can target peripheral neurons and overcome the limitations of local anesthetics, such as motor neuron inhibition. However, opioid receptors in the periphery are uniquely regulated, and poorly understood mechanisms of long-term inhibition reduce the effectiveness of peripherally restricted opioids. This study has preliminary evidence that the regulatory molecule 14-3-3γ mediates long-term inhibition of antinociception through the kappa opioid receptor (KOR). Further, 14-3-3γ appears to bias KOR signaling towards the pronociceptive mitogen-activated protein kinase (MAPK) pathways. This fellowship will: (1) establish that 14-3-3γ directly interacts with KOR, (2) identify KOR signaling pathways mediated by 14-3-3γ, and (3) evaluate the changes in KOR nociceptive signaling in vivo. These proposed studies will elucidate the role of 14-3-3γ in regulating KOR-mediated antinociception in peripheral sensory neurons. As a result, these studies will have significant impact on the use of peripherally restricted opioids for the safe and effective treatment of pain. Additionally, these studies will serve as an outstanding training vehicle for the applicant. The innovative research approach combines a heterologous expression system, rat primary neuronal culture, and behavioral nociception assays, which will ensure comprehensive training in the fields of pharmacology, cellular signaling, and rodent behavior. With the guidance of the applicant’s postdoctoral advisory committee, the training goals of developing new techniques, expanding understanding in a new field, refining communications, and producing research products will be realized. Ultimately, this fellowship will lay the foundation for a successful career as an independent investigator studying opioid receptor signaling in human disease.

摘要 美国近三分之一的人口患有慢性疼痛。这种疼痛导致 近1100万人的重大活动限制。阿片类药物用于治疗疼痛，但有许多 负面影响，如呼吸抑制、成瘾和镇静。由于这些负面影响是 通过中枢神经系统介导，安全有效治疗疼痛的一种有前途的方法是 瞄准周围神经系统信号由周围神经系统发送到大脑， 解释为疼痛。通过特异性抑制这些信号的传递，疼痛可以减轻。的 局部麻醉剂的显著镇痛效果说明了这种方法的价值。 外周限制性阿片类药物可以靶向外周神经元并克服局部麻醉剂的局限性， 例如运动神经元抑制。然而，外周的阿片受体受到独特的调节， 长期抑制的已知机制降低了外周限制的阿片类药物的有效性。这 这项研究有初步证据表明，调节分子14-3-3γ介导了长期抑制 通过κ阿片受体（KOR）的抗伤害感受。此外，14-3-3γ似乎偏向KOR信号传导， 有丝分裂原活化蛋白激酶（MAPK）通路。该奖学金将：（1） 确定14-3-3γ与KOR直接相互作用，（2）鉴定14-3-3γ介导KOR信号通路， （3）评价体内KOR伤害性信号的变化。这些拟议的研究将阐明 14-3-3γ在调节外周感觉神经元KOR介导的抗伤害感受中的作用结果这些 研究将对使用外周限制阿片类药物安全有效地 治疗疼痛。 此外，这些研究将作为申请人的优秀培训工具。创新 研究方法结合了异源表达系统，大鼠原代神经元培养和行为学。 伤害感受试验，这将确保在药理学，细胞信号传导， 和啮齿动物的行为在申请人博士后咨询委员会的指导下，培养目标 开发新技术，扩大对新领域的理解，改进通信， 研究产品的生产将得以实现。最终，这项奖学金将为成功的 职业生涯作为一个独立的研究人员研究阿片受体信号在人类疾病。