Regulation of SCI-induced pain by macrophages and exercise

项目摘要 脊髓损伤（SCI）损害感觉传递并导致慢性的、使人衰弱的神经病理性损伤。 痛苦慢性疼痛困扰着超过1亿美国人，并给美国医疗保健带来了巨大的负担。 根据医学研究所最近的一份报告，这些系统每年的成本超过5000亿美元。 虽然我们对慢性疼痛发展的分子基础的理解有所提高， 可用的治疗剂提供有限的缓解。虽然我们的实验室和其他实验室已经表明， 可以防止疼痛的发展，由于多系统，人类SCI的早期康复可能是不可能的， 多处创伤性损伤的患者。因此，迫切需要一种辅助疗法来帮助 那些无法参加早期康复的人。神经性疼痛越来越被认为是一种 神经免疫紊乱虽然巨噬细胞被认为是慢性疼痛发展的关键调节因子，但它是 不清楚它们是否以炎症或修复的方式起作用。R01旨在更好地理解 巨噬细胞的激活状态如何或是否影响伤害性神经元兴奋性和疼痛发展 SCI之后我们将利用已建立的神经性疼痛发展和驱动的脊髓损伤模型， 通过损伤后康复、鞘内施用来源于Raw的外泌体来维持巨噬细胞活化状态 264.7体外刺激的巨噬细胞或通过聚合物纳米递送系统的磷酸二酯酶4抑制剂 专门针对巨噬细胞这项提案旨在了解巨噬细胞的作用， 脊髓损伤后，无论是在发展和维持脊髓背根神经节， 慢性神经性疼痛。

PROJECT SUMMARY Spinal cord injury (SCI) impairs sensory transmission and 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. While our lab and others have shown that early post-SCI rehab can prevent pain development, early rehab in human SCI may not be possible due to the multisystem, polytraumatic injuries individuals with SCI sustain. Thus, there is a critical need for an adjuvant therapy to aid those individuals who are unable to participate in early rehab. Neuropathic pain is increasingly recognized as a neuroimmune disorder. While macrophages are regarded as key regulators of chronic pain development, it is unclear whether they are acting in an inflammatory or reparative manner. This R01 seeks to better understand how or if the activation state of macrophages influences nociceptive neuron excitability and pain development after SCI. We will utilize an established spinal cord injury model of neuropathic pain development and drive macrophage activation state by post-injury rehab, intrathecal administration of exosomes derived from Raw 264.7 macrophages stimulated in vitro or a phosphodiesterase 4 inhibitor by a polymer nanodelivery system that specifically targets macrophages. This proposal seeks to understand the role of macrophages that infiltrate the dorsal root ganglia and persist there chronically after SCI both in the development and maintenance of chronic neuropathic pain.