Validation of Targeting Macrophage-Mediated Events in the DRG to Alleviate Chronic Spinal Cord Injury Pain

验证靶向 DRG 中巨噬细胞介导的事件以减轻慢性脊髓损伤疼痛

• 批准号: 9816362
• 负责人: MEGAN R DETLOFF
• 金额: $ 60.08万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9816362
• 关键词: Acute; Administrative Supplement; Affect; American; Animals; Biological; Cells; Chronic; Development; Event; Funding; Future; Generations; Healthcare Systems; Immune response; Impairment; Individual; Inflammation; Inflammatory Response; Injury; Institute of Medicine (U.S.); Intervention; Lesion; Locomotion; Measures; Mediating; Mediator of activation protein; Molecular; Neurons; Nociceptors; Pain; Peripheral; Phenotype; Reporting; Sensory; Series; Site; Spinal Cord; Spinal Ganglia; Spinal cord injury; Testing; Therapeutic; Time; Up-Regulation; Validation; Work; chemokine; chronic pain; cost; effective therapy; experimental study; functional outcomes; improved; inflammatory milieu; macrophage; monocyte; neuropathology; pain behavior; pain signal; painful neuropathy; recruit; response; sex; spasticity; spinal cord injury pain; transmission process; treatment optimization

PROJECT SUMMARY Spinal cord injury (SCI) impairs sensory transmission leads to chronic, debilitating neuropathic pain. Chronic pain afflicts over 100 million Americans and creates an enormous burden on US health care systems, costing over half a trillion dollars annually according to a recent report from the Institute of Medicine. While our understanding of the molecular basis underlying the development of chronic pain has improved, the available therapeutics provide limited relief. In the proposed administrative supplement, we will examine the peripheral immune and inflammatory response. Secondary inflammation in response to SCI is a series of temporally ordered events- an acute, transient upregulation of chemokines, followed by the recruitment of monocytes/ macrophages and generation of an inflammatory environment at the lesion site in the spinal cord, but also surrounding primary nociceptors in the dorsal root ganglia. These events precede neuropathic pain development. Work on our funded R01 has shown that at chronic time points after SCI, macrophage presence in the dorsal root ganglia correlates with neuropathic pain. We will extend the currently funded experiments by conducting experiments to better understand 1) whether the phenotype of macrophages that infiltrate the dorsal root ganglia is different than those that persist chronically after SCI and 2) how manipulation of macrophage phenotype affects nociceptor activity and pain development. Moreover, a large portion of this application is dedicated to rigorous validation of the potential of the macrophage as a target for future interventions. The proposed experiments include: 1) multiple species of animals, 2) inclusion of several tests for aberrant pain behavior, 3) consider and measure sex as a potential biological variable, and 4) attend to the potential of off-target effects of macrophage manipulation on other functional outcomes like locomotion and spasticity. Understanding the temporal response of these immune cells and how they affect nociceptor activity and pain behavior will guide future efforts to optimize the treatment of SCI-induced pain.

项目概要 脊髓损伤 (SCI) 损害感觉传递，导致慢性、衰弱性神经性疼痛。慢性的 疼痛折磨着超过 1 亿美国人，给美国医疗保健系统造成巨大负担，造成超过半数的损失 根据医学研究所最近的一份报告，每年价值数万亿美元。虽然我们的理解 慢性疼痛发展的分子基础已经改善，现有的治疗方法提供有限 宽慰。在拟议的行政补充中，我们将检查外周免疫和炎症反应。 SCI 引起的继发性炎症是一系列暂时有序的事件——急性、短暂的上调 趋化因子，然后是单核细胞/巨噬细胞的募集和炎症环境的产生 脊髓中的病变部位，而且还包括背根神经节中的初级伤害感受器周围。这些事件先于 神经性疼痛的发展。我们资助的 R01 的工作表明，在 SCI 后的长期时间点，巨噬细胞 背根神经节的存在与神经性疼痛相关。我们将通过以下方式扩展目前资助的实验 进行实验以更好地了解 1) 浸润背根的巨噬细胞的表型是否 神经节与 SCI 后长期存在的神经节不同，2）巨噬细胞表型的操纵如何影响 伤害感受器活动和疼痛发展。此外，该应用程序的很大一部分致力于严格的验证 巨噬细胞作为未来干预目标的潜力。建议的实验包括：1）多个 动物种类，2) 纳入多项针对异常疼痛行为的测试，3) 考虑并衡量性别作为潜在的疼痛行为 生物变量，4) 关注巨噬细胞操作对其他功能的潜在脱靶效应 结果如运动和痉挛。了解这些免疫细胞的时间反应及其影响 伤害感受器活动和疼痛行为将指导未来优化 SCI 引起的疼痛治疗的努力。