The role of macrophage phenotype and age in spinal cord injury

 描述（由申请人提供）：脊髓损伤（SCI）引发由巨噬细胞组成的异质性神经炎症反应，可能会加重组织损伤并促进伤口愈合和修复。这些巨噬细胞已被鉴定为促炎性、病理性“M1”巨噬细胞或抗炎性、替代性活化的促修复性“M2”巨噬细胞。有已发表的证据表明，驱动M2巨噬细胞活化可改善SCI恢复。然而，M2巨噬细胞的修复作用的机制还没有很好地理解。因此，开发临床上可行的药理学干预措施，利用活化的巨噬细胞的修复潜力仍然是一个关键的挑战，这是由不断变化的SCI人口。近年来，老年人中SCI的发病率有所增加，性别之间SCI的比例更加平衡。本研究的目的是探讨M2巨噬细胞介导的SCI修复机制，并确定年龄和性别对SCI巨噬细胞活化的影响。目的1将通过使用基因工程小鼠和缺乏精氨酸酶-1（Arg 1）的巨噬细胞以及新发现的增加M2介导的精氨酸酶产生的治疗来确定精氨酸酶在M2巨噬细胞介导的SCI修复过程中的作用。平行的体内和体外SCI模型的神经毒性，轴突生长/死亡，和髓鞘再生将测试的假设，M2巨噬细胞的影响是依赖于Arg 1的生产。在目的2中，将使用不同年龄和性别的小鼠来确定这些生理因素对急性SCI巨噬细胞反应的影响。将使用新开发的聚焦基因分析和流式细胞术技术评价巨噬细胞随时间的反应。待检验的假设是老年男性M2巨噬细胞活化受损。在目标3中，将使用临床相关的小鼠SCI模型和新开发的免疫调节SCI治疗来评估年龄和性别对M2巨噬细胞介导的SCI修复和恢复的影响。M2巨噬细胞活化的形式发生在大多数CNS病理中;因此，目前的工作是重要的，因为预计它对广泛的神经炎性疾病具有广泛的翻译影响。该项目在概念和技术上都具有创新性。它将采用Arg 1基因敲除小鼠和一种新的免疫调节剂的创造性使用。使用综合聚焦基因阵列方法研究年龄和性别对巨噬细胞对SCI反应的影响是新颖的。总的来说，拟议研究的完成将提高有关巨噬细胞生物学的科学知识，因为它特别涉及年龄和性别。这些知识将通过导致包括性别和年龄在内的治疗策略的复杂性来改善临床实践。 年龄是SCI治疗和恢复的潜在影响因素。

 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.