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.

有很大比例(40-50%)的脊髓损伤患者表现出中枢神经性疼痛。 (CNP)，一种持续的不适状态，通常包括无法忍受的灼烧、刺痛、射击和/或引起的 轻触后产生的疼痛类型。CNP在女性中出现的频率更高，她们也表现出更大的 对疼痛的敏感度高于男性。CNP的发生是对躯体感觉信号的失调和IS的反应 对传统的治疗干预措施很难奏效，只有40%-60%的人得到部分缓解。 因此，cnp仍然是一个重大的临床挑战，不仅对脊髓损伤，而且对许多其他神经病学。 疾病，包括多发性硬化症、中风和创伤性脑损伤，这些疾病的发病率一直很高 观察到的。尽管组成先天免疫系统的细胞、小胶质细胞和巨噬细胞的激活 已被确定为CNP发展和持续的关键效应者，通过他们生产的 作为一系列疼痛和可塑性调节因子，这些细胞的免疫表型一致性仍然很差。 在有或没有CNP的条件下以SCI为特征的。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 与损伤相关的过程包括炎症、细胞死亡和流产的轴突再生，而 交替激活的M2形式，它在功能上促进组织重塑、血管生成、轴突生长和 再髓鞘形成，在慢性皮损中基本不存在。活化的小胶质细胞和小胶质细胞的表型鉴定 直接损伤以外的神经轴区域内的巨噬细胞，如腰髓， 在伤害性和反伤害性系统的处理过程中发生生理变化的地方，包括增加 然而，背角神经元的超兴奋性和GABA能神经传递的丧失/抑制是 未知。此外，脊髓损伤后小胶质细胞和巨噬细胞表型的特征 尚未对CNP的缺失或存在进行调查，也未对M1的治疗靶点进行调查 对M2表型转换作为预防CNP发展或持续性的方法进行了评估。 拟议的研究将采用与临床相关的挫伤范例来研究暂时性和 脊髓损伤动物中存在和不存在CNP的M1和M2种群的空间动态 疼痛行为(特定目标1)。这一范式将使我们能够开始理解特定的 CNP发生、持续过程中的小胶质细胞表型及性别对其影响 回应。随后，通过使用新的和有效的M1到M2转换协议， 我们的实验室，我们将通过检查M1小胶质细胞到M2a或M2a的转换来进一步解决这个问题 M2c表型可以阻止CNP的发展或减轻其严重程度(特定目标2)。集体地 这些研究将为特定表型的小胶质细胞和巨噬细胞所起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，以及提供一个推定的 减轻脊髓损伤后CNP的治疗方向。