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.

抽象的 美国近三分之一的人口患有慢性疼痛。这种疼痛会导致 近1100万人的重大活动限制。阿片类药物用于治疗疼痛，但有很多 负面影响，例如呼吸抑郁，成瘾和镇静。因为这些负面影响是 由中枢神经系统介导的安全有效治疗疼痛的有前途的方法是 针对周围神经系统。信号由周围神经系统发送到大脑，并且是 被解释为痛苦。通过特别抑制这些信号的传播，可以缓解疼痛。这 这种方法的价值通过局部麻醉剂的明显镇痛有效性说明了。 外围受限的阿片类药物可以靶向外围神经元并克服局部麻醉剂的局限性， 例如运动神经元抑制。但是，外周种中的阿片类药物受体受到唯一调节，较差 了解长期抑制的机制降低了外周限制阿片类药物的有效性。这 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Kappa阿片受体（Kor）的抗伤害感受。此外，14-3-3γ似乎会偏向kor信号传导 朝向促丝分裂原激活的蛋白激酶（MAPK）途径。该奖学金将：（1） 确定14-3-3γ与Kor直接相互作用，（2）确定由14-3-3γ介导的KOR信号通路 （3）评估体内Kor伤害感受信号传导的变化。这些提出的研究将阐明 14-3-3γ在调节周围感觉神经元中的KOR介导的抗伤害感受。结果，这些 研究将对使用外周限制阿片类药物的使用有重大影响 治疗疼痛。 此外，这些研究将是该应用程序的出色训练工具。创新 研究方法结合了异源表达系统，大鼠原发性神经元培养和行为 伤害性测定将确保在药理学，细胞信号传导领域进行全面训练 和啮齿动物行为。在申请人博士后咨询委员会的指导下，培训目标 开发新技术，扩大新领域的理解，提炼通讯和 生产研究产品将被实现。最终，该奖学金将为成功奠定基础 作为独立研究者，研究人类疾病中阿片受体信号传导的职业。