MicroRNA在脊髓损伤中的研究进展①

张文豪，李建军，杨德刚，高品操，杨明亮，杜良杰，高峰，唐芳，

MicroRNA在脊髓损伤中的研究进展①

张文豪1,2,3,4，李建军1,2,3,4，杨德刚1,2,3,4，高品操5，杨明亮1,2,3,4，杜良杰1,2,3,4，高峰1,2,3,4，唐芳5，

刘长彬1,2,3,4，李大鹏1,2,3,4，张鑫1,2,3,4，张洁1,2,3,4

microRNA是能够调控靶基因表达的小分子RNA，在脊髓发育和脊髓损伤等过程的基因表达中具有重要作用，可能是促进脊髓损伤后神经再生和修复的治疗性干预新靶点，是脊髓损伤潜在的生物学标志物。本文从microRNA在脊髓损伤中的机制及热点microRNA方面做一综述。

脊髓损伤；microRNA；基因表达；转录调控；生物学标记；新靶点；综述

[本文著录格式]张文豪，李建军，杨德刚，等.MicroRNA在脊髓损伤中的研究进展[J].中国康复理论与实践,2017,23(6): 649-653.

CITED AS:Zhang WH,Li JJ,Yang DG,et al.Research progress of microRNAin spinal cord injury(review)[J].Zhongguo Kangfu Lilun Yu Shijian,2017,23(6):649-653.

脊髓损伤(spinal cord injury)是一种高发生率、高死亡率、高致残率、高耗费的中枢神经系统疾病[1-3]，随着现代经济社会和交通建筑事业的发展，其发病率逐年上升，在美国每年有1万例新发患者[4]，我国每年新增病例超过6万人，给患者以及社会带来沉重的负担[5-6]，故应给予足够的重视[7-9]。

脊髓损伤可分为原发性损伤和继发性损伤。原发性损伤由受伤当时所承受的扭转力、压缩力和神经横断程度决定；而后期伴发的血脊髓屏障障碍、缺血水肿、炎症反应、脂质过氧化作用、自由基生成、离子通路受损、轴突脱髓鞘作用、神经细胞凋亡和瘢痕形成等继发性损伤将进一步加重病情[10-13]。由于外界暴力等因素引起原发性损伤在一定程度上决定了患者神经病理学的等级，因此，治疗脊髓损伤的策略主要在于对抗级联发生的继发性损伤，刺激轴突再生，阻止自发持续性的神经元退化以及增加新生神经元和胶质细胞以填补并整合损伤区的存活神经组织。

脊髓损伤的病理发展过程是一个大量分子参与的多因素、多步骤、多阶段的网络调控过程，目前临床上仍缺乏明确有效的干预靶点。脊髓损伤后脊髓组织难以进行修复[14]，而且功能重建也相对困难，这不仅与神经元微弱的再生能力密切相关，还与脊髓损伤后出现的瘢痕形成有关。因此，脊髓损伤后修复和重建神经功能是目前困扰医学界的核心问题[14]。20世纪80年代，科学家发现在适当的条件下脊髓组织可出现神经轴突的再生，这个开创性的发现开启了脊髓损伤病理生理学治疗发展之路。

最近20年来，临床上新发现了一种基因表达调节因子，即microRNA。脊髓损伤后有大量的microRNA表达发生改变[13,15-18]。研究证明microRNA参与脊髓损伤后基因表达的调控，此类基因表达与脊髓缺血水肿、炎症反应、神经元坏死等病理过程密切相关[13]。随着分子生物学日新月异的发展和人类基因组计划的完成，关于microRNA的研究越来越受到重视。研究表明，microRNA在脊髓发育、脊髓可塑性和脊髓损伤后的病理生理发生发展过程中均发挥重要的调节作用，一些microRNA可能成为脊髓损伤后治疗性干预的有效靶点[13-14,19-21]。因此研究microRNA在脊髓损伤病理发展过程中的功能及作用，不仅能够进一步明确继发性脊髓损伤的发病机制，而且给脊髓损伤的治疗与康复提供新的治疗靶点和干预策略。

1 microRNA机制

脊髓损伤后神经元的再生与修复机制极其复杂，涉及神经元所处的恶劣微环境以及复杂的细胞内信号通路，因此加强脊髓损伤后脊髓组织的修复与重建研究具有重要的价值和意义[22]。脊髓损伤造成损伤节段两侧脊髓组织之间神经纤维联系的断裂或损伤，轴突和树突的修复与重建对于损伤区两侧残存的神经元实现信号传导至关重要。转录因子、蛋白修饰、染色质修饰、mRNA半衰期等多种方式调控基因表达。

研究表明，microRNA通过调控转录过程中的基因表达，影响神经元的功能和状态，其在脊髓损伤中具有的重要功能与作用已经逐渐被人们所认可[23]。microRNA作为一种长度约为22个核苷酸的内源性、具有基因调控功能的非编码RNA，近年来已成为国内外研究的热点，因此也发现microRNA的多种生物学功能，如参与调控生长发育、增殖分化、新陈代谢、炎症反应、肿瘤及细胞凋亡等许多病理生理过程[22,24-27]。1993年Lee等[28]在研究秀丽新小杆线虫发育缺陷时最早发现microRNA；2000年Reinhart等[29]观察到同样现象。microRNA在正常细胞和组织中表达，且广泛存在于动植物中，截至目前microRNA数据库(http://www.mirbase.org/)已收录约15,000个microRNA序列，约占人类基因的1%～4%，这使microRNA成为人体内功能与作用最广泛的一类基因调控因子。microRNA对3′端非编码区的保守性极高，它可以通过和靶基因mRNA部分或完全互补配对，调控下游靶基因，抑制mRNA翻译或促使其降解，从而在转录翻译水平上对靶基因mRNA表达起到很好的负向调控作用[30-33]。

脊髓损伤多由外伤等暴力因素引起，并引起深静脉血栓、性功能障碍等严重并发症[34-35]，往往导致损伤节段以下肢体功能的严重障碍，造成患者严重身心伤害[36]。虽然有关脊髓损伤的microRNA研究起步较晚，但目前却已引起研究者的广泛关注，并呈Moore律增长。多数研究表明[23,37-40]，脊髓损伤后脊髓组织中的microRNA的水平发生变化，其变化水平可分为以下三种情况：①上调；②下调；③早期(4 h)上调，后期(1～7 d)下调。生物信息学分析表明，脊髓损伤后发生变化的microRNA，其靶基因可能包括编码炎症、氧化应激和细胞凋亡等过程的基因，这些过程被认为在脊髓损伤病理机制中具有重要作用。microRNA分子受到其他生物学分子基因的调控，它也调控着它们下游的靶基因，一个miRNA可能调控着数十个甚至上百个靶基因[41]，但本身又有可能受数个基因的调控，在分子生物学基因-microRNA-靶基因-机体功能等方面构成纷繁复杂的信号通路网络，调节着机体病理生理等方面的功能与作用。另有研究表明，microRNA能够调控多个靶基因，但是在不同细胞类型或不同应激状态下其调控的靶基因可能会有差异。脊髓损伤伴随着其特异性microRNA基因表达的改变，但相关机制有待进一步阐明[19]。

2 热点microRNA

尽管microRNA在人类疾病中的功能与作用尚需要进一步阐明，但是越来越多的研究表明，microRNA可以作为一种全新的药物靶点。本部分重点阐述脊髓损伤研究领域的热点microRNA及其可能的分子机制。

2.1 microRNA-124(miR-124)

中枢神经系统特异性表达最为丰富的是miR-124。miR-124具有3种亚型，其中以miR-124a最为常见。在细胞的增殖分化过程中，miR124a的表达水平可发生较大的变化[40,42-44]。目前，学者对中枢神经中miR-124基因表达情况的研究多集中在果蝇、小鼠的中枢神经系统。Chen等[45]研究发现，阻断中枢神经系统中miR-124a的表达后，神经再生出现明显的延迟。赵宇[42]研究发现脊髓损伤后miR-124低表达。上述研究均表明，miR-124a在中枢神经系统损伤的机制中发挥着重要作用，可作为中枢神经系统损伤的有效干预性治疗靶点。但有些学者的报道尚存在一定的争议[40,46]，这可能是由于选用的动物种类、损伤模型以及检测时间点的不同引起，故尚需更多的实验来加以验证。

2.2 microRNA-152(miR-152)

中枢神经系统发育过程中，miR-152在大脑皮层和脊髓组织中，自胚胎9.5 d至出生后表达水平逐渐升高。研究表明[47-48]，自脊髓损伤早期至晚期miR-152表达水平持续上调，提示其在中枢神经系统生长发育和病理过程中发挥重要作用。武昊[47]通过实验证实，脊髓损伤后miR-152的表达上调，并且进一步验证机械性损伤或炎性环境导致miR-152的表达上调，而上调的miR-152靶向抑制N端α乙酰基转移酶15(Naa15)基因的表达，影响N端乙酰基转移酶的活性，阻碍微管的组装，最终抑制神经元树突的生长。陈琨[48]虽然同样发现小鼠脊髓损伤后miR-152的表达水平升高，但其通过实验证明Hu antigen D (HuD)基因在脊髓损伤后表达水平下降，且与miR-152的表达水平基本呈相反趋势，并通过双荧光素酶报告系统及Western boltting技术进一步证实HuD基因可能是miR-152的靶基因；其研究还发现miR-152过表达后可以显著促进PC12细胞的增殖，并与miR-152具有依赖性且其作用具有细胞类型选择性有关，猜测这种现象可能是miR-152通过抑制周期素依赖性蛋白激酶19(cyclin dependent kinase 19,CDK19)的基因表达所导致。2.3 microRNA-223(miR-223)

miR-223是一种骨髓特异性的microRNA。研究显示脊髓组织miR-223在脊髓损伤后6 h、12 h、3 d表达均升高，且在损伤部位表达。研究还表明脊髓损伤后中性粒细胞表达显著升高，且与miR-223的表达存在时间依赖性，这提示miR-223可能参与脊髓损伤后中性粒细胞的调控[40,49]。Izumi等[49]发现miR-223在小鼠脊髓损伤区域头端及尾端2 mm内大量表达，同时炎症因子白细胞介素(interleukin,IL)-1β、IL-6及肿瘤坏死因子(tumor necrosis factor,TNF)-α在相同区域表达亦显著提高。这些研究表明，脊髓损伤后miR-223可能参与中性粒细胞介导的炎症反应，从而介导继发性脊髓损伤的过程。孙炜俊[50]研究表明，脊髓损伤后miR-223基因表达显著升高，RhoB基因的表达亦同步明显上调，且二者呈显著正相关，由此进一步推测RhoB基因的表达可能受miR-223的调控。近些年研究发现，RhoB/ROCK信号通路在脊髓损伤的病理过程中发挥着重要作用，抑制RhoB/ROCK通路可能促进中枢神经损伤后的修复与重建。

2.4 microRNA-210(miR-210)

miR-210具有广泛的生理作用，参与细胞增殖分化、血管生成、新陈代谢、DNA修复、细胞周期等的调控[51-53]，并可以作为一些癌症的肿瘤标志物[54-55]。研究表明miR-210能够在缺血缺氧的情况下，参与低氧反应、氧化应激以及细胞凋亡的调控[56-57]。邵建立等[58]通过实验证实H2O2能够刺激鼠脊髓神经元内miR-210表达的上调，而降低miR-210的表达能够降低细胞内NADPH氧化酶2(NADPH oxidase 2,NOX2)和活性氧(reactive oxygen species,ROS)的表达，进而抑制NOX2/ROS通路，从而减缓H2O2对大鼠背脊髓神经元细胞造成的损伤。Ujigo等[59]通过实验验证miR-210可能通过抑制蛋白酪氨酸磷酸酶1B的生成，从而促进血管生成，进而促进脊髓损伤的修复。这些研究表明[58-59]，miR-210过表达和继发性脊髓损伤存在一定的关系，miR-210在继发性脊髓损伤中可能发挥重要的作用，从而推测miR-210可以作为脊髓损伤的治疗靶点。

2.5 microRNA-21(miR-21)

研究发现小鼠脊髓损伤组织中miR-21的表达水平与正常脊髓组织相比显著升高[60]，通过生物信息学检索预测，其靶基因可能包括程序性细胞死亡因子4(programmed cell death, PDCD4)。研究表明[61-63]，PDCD4是一类细胞凋亡的相关基因，降低其表达可以抑制细胞凋亡的发生，从而对细胞起保护效应。佘飞等[64]通过实验验证小鼠脊髓损伤中高表达的miR-21直接作用于PDCD4，从而在mRNA和蛋白水平抑制PDCD4的表达，进而推测miR-21可能在脊髓损伤过程中具有重要的保护作用，这和多种损伤模型中miR-21通过抑制PDCD4的表达从而发挥保护效应的研究结果基本一致[63,65-66]。

3 总结与展望

在过去20多年里，关于microRNA的基础研究迅速增加，研究结果有力地证实了microRNA应用于临床脊髓损伤治疗的潜力。大量研究发现microRNA可能是脊髓损伤后神经细胞死亡的一个潜在标记物，可能成为干预脊髓损伤的有效靶点[13,19,21,23,37,67-70]，也为脊髓损伤患者神经功能的恢复与重建提供了新思路、新方法与新技术，部分基于microRNA的研究已处于临床试验阶段。

迄今为止microRNA在脊髓损伤研究领域的报道仍然比较有限，仍有一些问题需要解决，例如脊髓损伤后microRNA研究的资料较少并且零散，研究内容不够深入，缺乏分子机制之间的相互联系，目前仅知microRNA可能与脊髓损伤后的炎症反应、氧化应激和神经元坏死的调控有关。该研究领域下一步的发展方向可能是如何分离纯化microRNA分子，microRNA与靶mRNA之间的关系，microRNA是否可以调节其他microRNA等。通过对特定microRNA作用分子机制的详细研究，对特定microRNA分子调控的上下游分子及所涉及的信号通路做深入研究，进而揭示相关microRNA在脊髓损伤中的调控网络与调控模式。

随着基因芯片、原位杂交、微阵列数据、实时定量反转录聚合酶链反应(real-time quantitative polymerase chain reaction, RT-qPCR)检测等技术手段的飞速发展与广泛应用，人们将进一步理解microRNA在生物发展中的功能与作用，并利用microRNA进行临床诊断和治疗，这将提高人们对脊髓损伤后microRNA调控作用的认知水平，并促进基于microRNA调控的脊髓损伤治疗措施的研究。该研究有望找到基因调控阶段修复与重建脊髓损伤的新途径，为临床治疗寻找新靶点。

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Research Progress of MicroRNAin Spinal Cord Injury(review)

ZHANG Wen-hao1,2,3,4,LI Jian-jun1,2,3,4,YANG De-gang1,2,3,4,GAO Pin-cao5,YANG Ming-liang1,2,3,4,DU Liang-jie1,2,3,4, GAO Feng1,2,3,4,TANG Fang5,LIU Chang-bin1,2,3,4,LI Da-peng1,2,3,4,ZHANG Xin1,2,3,4,ZHANG Jie1,2,3,4
1.Capital Medical University School of Rehabilitation Medicine,Beijing 100068,China;2.Department of Spinal and Neural Function Reconstruction,Beijing Bo'ai Hospital,China Rehabilitation Research Center,Beijing 100068,China;3.Center of Neural Injury and Repair,Beijing Institute for Brain Disorders,Beijing 100068,China;4.Beijing Key Laboratory of Neural Injury and Rehabilitation,Beijing 100068,China;5.Hunan Medical University,Huaihua,Hunan 418000,China

LI Jian-jun.E-mail:crrc100@163.com

MicroRNAs are short non-coding RNAs that regulate and control the translation of target genes,and play an important role in gene expression involved in the development of spinal cord and spinal cord injury,which constitute novel targets for therapeutic intervention to promote repair and regeneration of the spinal cord,also they are the potential biomarkers of spinal cord injury.This article reviewed the mechanism of microRNAs and listed several microRNAs in spinal cord injury area.

spinal cord injury;microRNA;gene expression;transcriptional regulation;biological markers;novel targets;review

R651.2

A

1006-9771(2017)06-0649-05

2016-11-01

2016-11-18)

10.3969/j.issn.1006-9771.2017.06.006

1.国家自然科学基金面上项目(No.81272164)；2.中央级公益性科研院所基本科研业务费专项资金项目(No.2015CZ-6)。

1.首都医科大学康复医学院，北京市100068；2.中国康复研究中心北京博爱医院脊柱脊髓神经功能重建科，北京市100068；3.北京脑重大疾病研究院神经损伤与修复研究所，北京市100068；4.北京市神经损伤与康复重点实验室，北京市100068；5.湖南医药学院，湖南怀化市418000。作者简介：张文豪(1991-)，男，汉族，河南柘城县人，硕士研究生，主要研究方向：脊柱脊髓损伤的康复与治疗。通讯作者：李建军(1962-)，男，汉族，教授，主任医师，博士、博士后导师，主要研究方向：骨科及脊柱脊髓损伤的康复与治疗。E-mail:crrc100@163.com。