The role of macrophage phenotype and age in spinal cord injury

巨噬细胞表型和年龄在脊髓损伤中的作用

• 批准号: 9532310
• 负责人: JOHN C GENSEL
• 金额: $ 32.66万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9532310
• 关键词: Acute; Affect; Age; Age Factors; Animals; Anti-inflammatory; Automobile Driving; Azithromycin; Biology; Cell Proliferation; Cells; Chronic; Clinical; Clinical Data; Data; Development; Dose; Effectiveness; Equilibrium; Estradiol; Female; Flow Cytometry; Genes; Genetically Engineered Mouse; Goals; Gonadal Steroid Hormones; Health Care Costs; Human; Immunomodulators; Impairment; In Vitro; Incidence; Individual; Inflammatory; Inflammatory Response; Intervention; Investigation; Knockout Mice; Knowledge; Macrolide Antibiotics; Macrophage Activation; Mediating; Modeling; Mus; Outcome Measure; Paralysed; Pathologic; Pathology; Patients; Pharmacology; Phenotype; Physiological; Process; Production; Progesterone; Publishing; Recovery; Recovery of Function; Research; Rodent; Role; Spinal Cord Contusions; Spinal cord injury; Techniques; Testing; Time; Tissues; United States; Work; Wound Healing; age effect; aged; arginase; axon growth; axon regeneration; base; clinical development; clinical practice; clinically relevant; functional disability; gain of function; immunomodulatory therapies; immunoregulation; improved; in vivo; injury and repair; innovation; loss of function; macrophage; male; middle age; mouse model; neuroinflammation; neuropathology; neuroprotection; neurotoxic; neurotoxicity; novel; pre-clinical; public health relevance; remyelination; repaired; response; sex; translational impact; treatment strategy

 DESCRIPTION (provided by applicant): Spinal cord injury (SCI) triggers a heterogeneous neuroinflammatory response consisting of macrophages with the potential to both aggravate tissue damage and promote wound healing and repair. These macrophages have been identified as pro-inflammatory, pathological "M1" macrophages or anti-inflammatory, alternatively activated, pro-reparative "M2" macrophages. There is published evidence that driving M2 macrophage activation improves SCI recovery. The mechanisms underlying the reparative effects of M2 macrophages, however, are not well understood. As a result, the development of clinically viable, pharmacological interventions that harness the reparative potential of activated macrophages remains a critical challenge that is compounded by a changing SCI demographic. The incidence of SCI among older individuals has increased in recent years with a more equal balance of SCI across sexes. The purpose of this proposal is to investigate the mechanisms of M2 macrophage-mediated SCI repair and determine the effects of age and sex on SCI macrophage activation. Aim 1 will determine the role of arginase in M2 macrophage-mediated SCI repair processes through the use of genetically engineered mice with macrophages that lack arginase-1 (Arg1) and a newly identified treatment that increases M2-mediated arginase production. Parallel in vivo and in vitro SCI models of neurotoxicity, axon growth/dieback, and remyelination will test the hypothesis that the effects of M2 macrophages are dependent upon Arg1 production. In Aim 2 mice of different ages and sex will be used to determine the effect of these physiological factors on the acute SCI macrophage response. The macrophage response over time will be evaluated using newly developed focused gene profiling and flow cytometry techniques. The hypothesis to be tested is that aged males will have impaired M2 macrophage activation. In Aim 3, the effect of age and sex on M2 macrophage-mediated SCI repair and recovery will be evaluated using a clinically relevant mouse SCI model and a newly developed immunomodulatory SCI treatment. Forms of M2 macrophage activation occur in most CNS pathologies; therefore the current work is significant because it is expected to have broad translational impact on a wide range of neuroinflammatory conditions. This project is both conceptually and technically innovative. It will employ creative use of Arg1 knockout mice and a novel immunomodulatory agent. The investigation of the effects of age and sex on the macrophage response to SCI using a comprehensive focused gene array approach is novel. Collectively, the completion of the proposed research will improve scientific knowledge regarding macrophage biology as it specifically relates to age and sex. This knowledge will improve clinical practice by leading to sophistication of treatment strategies that include sex and age as potential influences in the context of SCI treatment and recovery.

 描述（由适用提供）：脊髓损伤（SCI）触发了由巨噬细胞组成的异质神经炎症反应，其潜力既会加剧组织损伤并促进伤口愈合和修复。这些巨噬细胞已被确定为促炎性，病理性的“ M1”巨噬细胞或抗炎，替代激活的，依靠的“ M2”巨噬细胞。有证据表明，驱动M2巨噬细胞激活可改善SCI恢复。然而，尚不清楚M2巨噬细胞的修复作用的基础机制。结果，利用激活巨噬细胞的修复潜力的临床可行性，药物干预的发展仍然是一个关键的挑战，而SCI人群不断变化。近年来，老年人中SCI的事件有所增加，而性别的SCI平衡更加平等。该提案的目的是研究M2巨噬细胞介导的SCI修复的机制，并确定年龄和性别对科幻巨噬细胞激活的影响。 AIM 1将通过使用具有缺乏精氨酸酶-1（ARG1）的巨噬细胞的基因工程小鼠（ARG1）和一种新鉴定的治疗方法来确定精氨酸酶在M2巨噬细胞介导的SCI修复过程中的作用。平行于体内和体外SCI的神经毒性，轴突生长/死亡和雷梅尔化模型将检验以下假设：M2巨噬细胞的影响取决于ARG1的产生。在AIM 2小鼠中，不同年龄和性别将用于确定这些生理因素对急性SCI巨噬细胞反应的影响。随着时间的推移，巨噬细胞反应将使用新开发的聚焦基因分析和流式细胞仪技术评估。要检验的假设是，老年男性会损害M2巨噬细胞激活。在AIM 3中，将使用临床相关的小鼠SCI模型和新开发的免疫调节性SCI治疗评估年龄和性别对M2巨噬细胞介导的SCI修复和恢复的影响。 M2巨噬细胞激活的形式发生在大多数CNS病理中。因此，目前的工作很重要，因为预计它将对广泛的神经炎症条件产生广泛的翻译影响。该项目在概念上和技术上都是创新的。它将利用ARG1淘汰小鼠和一种新颖的免疫调节剂的创造性使用。使用全面的集中基因阵列方法对年龄和性别对SCI巨噬细胞反应的影响的投资是新颖的。总的来说，拟议的研究的完成将改善有关巨噬细胞生物学的科学知识，因为它与年龄和性别有关。这些知识将通过提出包括性别在内的复杂治疗策略来改善临床实践 在SCI治疗和恢复背景下，年龄是潜在影响。