Modulating microglial phenotype to prevent SCI-induced central neuropathic pain

调节小胶质细胞表型预防 SCI 引起的中枢神经病理性疼痛

• 批准号: 10371015
• 负责人: Mousumi Ghosh
• 金额: --
• 依托单位: MIAMI VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371015
• 关键词: Address; Animals; Anti-Inflammatory Agents; Attenuated; Cell Death; Cells; Chronic; Clinical; Contusions; Development; Esthesia; Evolution; Exhibits; Female; Frequencies; Gender; Immune response; Immunomodulators; Individual; Inflammation; Inflammatory; Injury; Innate Immune System; Investigation; Laboratories; Lesion; Light; Lumbar spinal cord structure; Microglia; Multiple Sclerosis; Neuraxis; Neurologic; Nociception; Pain; Pathologic; Patients; Phenotype; Physiological; Play; Population Dynamics; Posterior Horn Cells; Prevalence; Process; Production; Protocols documentation; Refractory; Role; Severities; Signal Transduction; Spinal cord injury; Stroke; System; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Touch sensation; Traumatic Brain Injury; Work; angiogenesis; axon growth; axon regeneration; base; clinically relevant; experimental study; innovation; insight; macrophage; male; neuron loss; neurotransmission; novel; novel therapeutics; pain behavior; painful neuropathy; prevent; relating to nervous system; remyelination; response; somatosensory; therapeutic target

A significant percentage (40-50%) of individuals with spinal cord injury (SCI) exhibit central neuropathic pain (CNP), a condition of persistent discomfort involving often unbearable burning, pricking, shooting and/or evoked types of pain in response to light touch. CNP appears more frequently in females, who also exhibit a greater sensitivity to pain than males. CNP develops in response to a dysregulation of somatosensory signaling and is largely refractory to conventional therapeutic interventions with only 40-60% of people achieving partial relief. Therefore CNP remains a major unmet clinical challenge, not only for SCI but numerous other neurological conditions, including Multiple Sclerosis, stroke and traumatic brain injury where its prevalence has been observed. Though the activation of cells comprising the innate immune system, microglia and macrophages, has been identified as key effector in the development and persistence of CNP, through their production of a repertoire of pain and plasticity modulating factors, the immunophenotypical identity of these cells remains poorly characterized in SCI under conditions in which there is the presence or absence of CNP. Recent work has highlighted the importance of the classically-activated M1 microglia-macrophage phenotype in the deleterious processes associated with injury including inflammation, cell death and abortive axon regeneration, while the alternatively-activated M2 form, which functionally promotes tissue remodeling, angiogenesis, axon growth and remyelination, is largely absent from chronic lesions. The phenotypic identity of activated microglia and macrophages within regions of the neural axis outside of the immediate injury, such as the lumbar spinal cord, where physiological changes in nociceptive and anti-nociceptive system processing occurs, including increased hyperexcitability of dorsal horn neurons and the loss/inhibition of GABAnergic neurotransmission, however, is unknown. Furthermore, the characterization of microglia and macrophage phenotype after SCI in animals where there is an absence or presence of CNP has not been investigated nor has the therapeutic targeting of M1 to M2 phenotypic conversion as an approach to preventing CNP development or persistence been evaluated. The proposed investigation will employ a clinically-relevant contusion paradigm to study temporally and spatially M1 and M2 population dynamics in SCI animals in which CNP is present and absent as evidenced by pain behaviors (Specific Aim 1). This paradigm will allow us to begin to understand the involvement of specific microglia phenotypes in the development and persistence of CNP as well as the influence of gender on these responses. Subsequently, through the use of a novel and potent M1 to M2 conversion protocols established in our laboratory, we will further address this question by examining if the conversion of M1 microglia to a M2a or M2c phenotype can either prevent the development of CNP or reduce its severity (Specific Aim 2). Collectively these studies will provide novel insight into the role specific phenotypic forms of microglia and macrophages play in CNP, how gender influences these immune responses and the development of CNP as well as offer a putative therapeutic direction for attenuating CNP after SCI.

很大比例 (40-50%) 的脊髓损伤 (SCI) 患者表现出中枢神经性疼痛 (CNP)，一种持续不适的状况，通常涉及难以忍受的灼烧感、刺痛感、射击感和/或诱发感 轻触反应的疼痛类型。 CNP 在女性中出现得更频繁，而且女性也表现出更大的 对疼痛的敏感性高于男性。 CNP 的发展是为了响应体感信号传导失调，并且是 传统治疗干预措施在很大程度上难以缓解，只有 40-60% 的人获得部分缓解。 因此，CNP 仍然是一个重大的未满足的临床挑战，不仅对于 SCI，而且对于许多其他神经系统疾病也是如此。 疾病，包括多发性硬化症、中风和创伤性脑损伤，其患病率一直在 观察到。尽管先天免疫系统、小胶质细胞和巨噬细胞等细胞的激活已 通过产生一种 疼痛和可塑性调节因子的全部成分，这些细胞的免疫表型特征仍然很差 在存在或不存在 CNP 的条件下进行 SCI 表征。最近的工作有 强调了经典激活的 M1 小胶质细胞-巨噬细胞表型在有害物质中的重要性 与损伤相关的过程，包括炎症、细胞死亡和轴突再生失败，而 替代激活的 M2 形式，在功能上促进组织重塑、血管生成、轴突生长和 髓鞘再生，慢性病变基本上不存在。活化的小胶质细胞的表型特征和 直接损伤之外的神经轴区域内的巨噬细胞，例如腰脊髓， 伤害性和抗伤害性系统处理发生生理变化的地方，包括增加 然而，背角神经元的过度兴奋和 GABA 能神经传递的丧失/抑制是 未知。此外，动物 SCI 后小胶质细胞和巨噬细胞表型的表征 尚未研究 CNP 的缺失或存在，也未研究 M1 的治疗靶向 M2 表型转换作为预防 CNP 发展或持续存在的方法进行了评估。 拟议的研究将采用临床相关的挫伤范式来研究时间和 SCI 动物中存在和不存在 CNP 的空间 M1 和 M2 种群动态，如 疼痛行为（具体目标 1）。这个范式将使我们开始理解特定的参与 小胶质细胞表型在 CNP 的发展和持续过程中以及性别对这些的影响 回应。随后，通过使用一种新颖且有效的 M1 到 M2 转换协议， 我们的实验室，我们将通过检查 M1 小胶质细胞是否转化为 M2a 或 M2c 表型可以预防 CNP 的发展或减轻其严重程度（具体目标 2）。集体 这些研究将为小胶质细胞和巨噬细胞的特定表型形式的作用提供新的见解 在 CNP 中，性别如何影响这些免疫反应和 CNP 的发展，并提供了一个假定的 SCI后减轻CNP的治疗方向。