張文豪，李建軍，楊德剛，高品操，楊明亮，杜良杰，高峰，唐芳，

MicroRNA在脊髓損傷中的研究進(jìn)展①

張文豪1,2,3,4，李建軍1,2,3,4，楊德剛1,2,3,4，高品操5，楊明亮1,2,3,4，杜良杰1,2,3,4，高峰1,2,3,4，唐芳5，

劉長彬1,2,3,4，李大鵬1,2,3,4，張?chǎng)?,2,3,4，張潔1,2,3,4

microRNA是能夠調(diào)控靶基因表達(dá)的小分子RNA，在脊髓發(fā)育和脊髓損傷等過程的基因表達(dá)中具有重要作用，可能是促進(jìn)脊髓損傷后神經(jīng)再生和修復(fù)的治療性干預(yù)新靶點(diǎn)，是脊髓損傷潛在的生物學(xué)標(biāo)志物。本文從microRNA在脊髓損傷中的機(jī)制及熱點(diǎn)microRNA方面做一綜述。

脊髓損傷；microRNA；基因表達(dá)；轉(zhuǎn)錄調(diào)控；生物學(xué)標(biāo)記；新靶點(diǎn)；綜述

[本文著錄格式]張文豪，李建軍，楊德剛，等.MicroRNA在脊髓損傷中的研究進(jìn)展[J].中國康復(fù)理論與實(shí)踐,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.

脊髓損傷(spinal cord injury)是一種高發(fā)生率、高死亡率、高致殘率、高耗費(fèi)的中樞神經(jīng)系統(tǒng)疾病[1-3]，隨著現(xiàn)代經(jīng)濟(jì)社會(huì)和交通建筑事業(yè)的發(fā)展，其發(fā)病率逐年上升，在美國每年有1萬例新發(fā)患者[4]，我國每年新增病例超過6萬人，給患者以及社會(huì)帶來沉重的負(fù)擔(dān)[5-6]，故應(yīng)給予足夠的重視[7-9]。

脊髓損傷可分為原發(fā)性損傷和繼發(fā)性損傷。原發(fā)性損傷由受傷當(dāng)時(shí)所承受的扭轉(zhuǎn)力、壓縮力和神經(jīng)橫斷程度決定；而后期伴發(fā)的血脊髓屏障障礙、缺血水腫、炎癥反應(yīng)、脂質(zhì)過氧化作用、自由基生成、離子通路受損、軸突脫髓鞘作用、神經(jīng)細(xì)胞凋亡和瘢痕形成等繼發(fā)性損傷將進(jìn)一步加重病情[10-13]。由于外界暴力等因素引起原發(fā)性損傷在一定程度上決定了患者神經(jīng)病理學(xué)的等級(jí)，因此，治療脊髓損傷的策略主要在于對(duì)抗級(jí)聯(lián)發(fā)生的繼發(fā)性損傷，刺激軸突再生，阻止自發(fā)持續(xù)性的神經(jīng)元退化以及增加新生神經(jīng)元和膠質(zhì)細(xì)胞以填補(bǔ)并整合損傷區(qū)的存活神經(jīng)組織。

脊髓損傷的病理發(fā)展過程是一個(gè)大量分子參與的多因素、多步驟、多階段的網(wǎng)絡(luò)調(diào)控過程，目前臨床上仍缺乏明確有效的干預(yù)靶點(diǎn)。脊髓損傷后脊髓組織難以進(jìn)行修復(fù)[14]，而且功能重建也相對(duì)困難，這不僅與神經(jīng)元微弱的再生能力密切相關(guān)，還與脊髓損傷后出現(xiàn)的瘢痕形成有關(guān)。因此，脊髓損傷后修復(fù)和重建神經(jīng)功能是目前困擾醫(yī)學(xué)界的核心問題[14]。20世紀(jì)80年代，科學(xué)家發(fā)現(xiàn)在適當(dāng)?shù)臈l件下脊髓組織可出現(xiàn)神經(jīng)軸突的再生，這個(gè)開創(chuàng)性的發(fā)現(xiàn)開啟了脊髓損傷病理生理學(xué)治療發(fā)展之路。

最近20年來，臨床上新發(fā)現(xiàn)了一種基因表達(dá)調(diào)節(jié)因子，即microRNA。脊髓損傷后有大量的microRNA表達(dá)發(fā)生改變[13,15-18]。研究證明microRNA參與脊髓損傷后基因表達(dá)的調(diào)控，此類基因表達(dá)與脊髓缺血水腫、炎癥反應(yīng)、神經(jīng)元壞死等病理過程密切相關(guān)[13]。隨著分子生物學(xué)日新月異的發(fā)展和人類基因組計(jì)劃的完成，關(guān)于microRNA的研究越來越受到重視。研究表明，microRNA在脊髓發(fā)育、脊髓可塑性和脊髓損傷后的病理生理發(fā)生發(fā)展過程中均發(fā)揮重要的調(diào)節(jié)作用，一些microRNA可能成為脊髓損傷后治療性干預(yù)的有效靶點(diǎn)[13-14,19-21]。因此研究microRNA在脊髓損傷病理發(fā)展過程中的功能及作用，不僅能夠進(jìn)一步明確繼發(fā)性脊髓損傷的發(fā)病機(jī)制，而且給脊髓損傷的治療與康復(fù)提供新的治療靶點(diǎn)和干預(yù)策略。

1 microRNA機(jī)制

脊髓損傷后神經(jīng)元的再生與修復(fù)機(jī)制極其復(fù)雜，涉及神經(jīng)元所處的惡劣微環(huán)境以及復(fù)雜的細(xì)胞內(nèi)信號(hào)通路，因此加強(qiáng)脊髓損傷后脊髓組織的修復(fù)與重建研究具有重要的價(jià)值和意義[22]。脊髓損傷造成損傷節(jié)段兩側(cè)脊髓組織之間神經(jīng)纖維聯(lián)系的斷裂或損傷，軸突和樹突的修復(fù)與重建對(duì)于損傷區(qū)兩側(cè)殘存的神經(jīng)元實(shí)現(xiàn)信號(hào)傳導(dǎo)至關(guān)重要。轉(zhuǎn)錄因子、蛋白修飾、染色質(zhì)修飾、mRNA半衰期等多種方式調(diào)控基因表達(dá)。

研究表明，microRNA通過調(diào)控轉(zhuǎn)錄過程中的基因表達(dá)，影響神經(jīng)元的功能和狀態(tài)，其在脊髓損傷中具有的重要功能與作用已經(jīng)逐漸被人們所認(rèn)可[23]。microRNA作為一種長度約為22個(gè)核苷酸的內(nèi)源性、具有基因調(diào)控功能的非編碼RNA，近年來已成為國內(nèi)外研究的熱點(diǎn)，因此也發(fā)現(xiàn)microRNA的多種生物學(xué)功能，如參與調(diào)控生長發(fā)育、增殖分化、新陳代謝、炎癥反應(yīng)、腫瘤及細(xì)胞凋亡等許多病理生理過程[22,24-27]。1993年Lee等[28]在研究秀麗新小桿線蟲發(fā)育缺陷時(shí)最早發(fā)現(xiàn)microRNA；2000年Reinhart等[29]觀察到同樣現(xiàn)象。microRNA在正常細(xì)胞和組織中表達(dá)，且廣泛存在于動(dòng)植物中，截至目前microRNA數(shù)據(jù)庫(http://www.mirbase.org/)已收錄約15,000個(gè)microRNA序列，約占人類基因的1%～4%，這使microRNA成為人體內(nèi)功能與作用最廣泛的一類基因調(diào)控因子。microRNA對(duì)3′端非編碼區(qū)的保守性極高，它可以通過和靶基因mRNA部分或完全互補(bǔ)配對(duì)，調(diào)控下游靶基因，抑制mRNA翻譯或促使其降解，從而在轉(zhuǎn)錄翻譯水平上對(duì)靶基因mRNA表達(dá)起到很好的負(fù)向調(diào)控作用[30-33]。

脊髓損傷多由外傷等暴力因素引起，并引起深靜脈血栓、性功能障礙等嚴(yán)重并發(fā)癥[34-35]，往往導(dǎo)致?lián)p傷節(jié)段以下肢體功能的嚴(yán)重障礙，造成患者嚴(yán)重身心傷害[36]。雖然有關(guān)脊髓損傷的microRNA研究起步較晚，但目前卻已引起研究者的廣泛關(guān)注，并呈Moore律增長。多數(shù)研究表明[23,37-40]，脊髓損傷后脊髓組織中的microRNA的水平發(fā)生變化，其變化水平可分為以下三種情況：①上調(diào)；②下調(diào)；③早期(4 h)上調(diào)，后期(1～7 d)下調(diào)。生物信息學(xué)分析表明，脊髓損傷后發(fā)生變化的microRNA，其靶基因可能包括編碼炎癥、氧化應(yīng)激和細(xì)胞凋亡等過程的基因，這些過程被認(rèn)為在脊髓損傷病理機(jī)制中具有重要作用。microRNA分子受到其他生物學(xué)分子基因的調(diào)控，它也調(diào)控著它們下游的靶基因，一個(gè)miRNA可能調(diào)控著數(shù)十個(gè)甚至上百個(gè)靶基因[41]，但本身又有可能受數(shù)個(gè)基因的調(diào)控，在分子生物學(xué)基因-microRNA-靶基因-機(jī)體功能等方面構(gòu)成紛繁復(fù)雜的信號(hào)通路網(wǎng)絡(luò)，調(diào)節(jié)著機(jī)體病理生理等方面的功能與作用。另有研究表明，microRNA能夠調(diào)控多個(gè)靶基因，但是在不同細(xì)胞類型或不同應(yīng)激狀態(tài)下其調(diào)控的靶基因可能會(huì)有差異。脊髓損傷伴隨著其特異性microRNA基因表達(dá)的改變，但相關(guān)機(jī)制有待進(jìn)一步闡明[19]。

2 熱點(diǎn)microRNA

盡管microRNA在人類疾病中的功能與作用尚需要進(jìn)一步闡明，但是越來越多的研究表明，microRNA可以作為一種全新的藥物靶點(diǎn)。本部分重點(diǎn)闡述脊髓損傷研究領(lǐng)域的熱點(diǎn)microRNA及其可能的分子機(jī)制。

2.1 microRNA-124(miR-124)

中樞神經(jīng)系統(tǒng)特異性表達(dá)最為豐富的是miR-124。miR-124具有3種亞型，其中以miR-124a最為常見。在細(xì)胞的增殖分化過程中，miR124a的表達(dá)水平可發(fā)生較大的變化[40,42-44]。目前，學(xué)者對(duì)中樞神經(jīng)中miR-124基因表達(dá)情況的研究多集中在果蠅、小鼠的中樞神經(jīng)系統(tǒng)。Chen等[45]研究發(fā)現(xiàn)，阻斷中樞神經(jīng)系統(tǒng)中miR-124a的表達(dá)后，神經(jīng)再生出現(xiàn)明顯的延遲。趙宇[42]研究發(fā)現(xiàn)脊髓損傷后miR-124低表達(dá)。上述研究均表明，miR-124a在中樞神經(jīng)系統(tǒng)損傷的機(jī)制中發(fā)揮著重要作用，可作為中樞神經(jīng)系統(tǒng)損傷的有效干預(yù)性治療靶點(diǎn)。但有些學(xué)者的報(bào)道尚存在一定的爭議[40,46]，這可能是由于選用的動(dòng)物種類、損傷模型以及檢測(cè)時(shí)間點(diǎn)的不同引起，故尚需更多的實(shí)驗(yàn)來加以驗(yàn)證。

2.2 microRNA-152(miR-152)

中樞神經(jīng)系統(tǒng)發(fā)育過程中，miR-152在大腦皮層和脊髓組織中，自胚胎9.5 d至出生后表達(dá)水平逐漸升高。研究表明[47-48]，自脊髓損傷早期至晚期miR-152表達(dá)水平持續(xù)上調(diào)，提示其在中樞神經(jīng)系統(tǒng)生長發(fā)育和病理過程中發(fā)揮重要作用。武昊[47]通過實(shí)驗(yàn)證實(shí)，脊髓損傷后miR-152的表達(dá)上調(diào)，并且進(jìn)一步驗(yàn)證機(jī)械性損傷或炎性環(huán)境導(dǎo)致miR-152的表達(dá)上調(diào)，而上調(diào)的miR-152靶向抑制N端α乙?；D(zhuǎn)移酶15(Naa15)基因的表達(dá)，影響N端乙?；D(zhuǎn)移酶的活性，阻礙微管的組裝，最終抑制神經(jīng)元樹突的生長。陳琨[48]雖然同樣發(fā)現(xiàn)小鼠脊髓損傷后miR-152的表達(dá)水平升高，但其通過實(shí)驗(yàn)證明Hu antigen D (HuD)基因在脊髓損傷后表達(dá)水平下降，且與miR-152的表達(dá)水平基本呈相反趨勢(shì)，并通過雙熒光素酶報(bào)告系統(tǒng)及Western boltting技術(shù)進(jìn)一步證實(shí)HuD基因可能是miR-152的靶基因；其研究還發(fā)現(xiàn)miR-152過表達(dá)后可以顯著促進(jìn)PC12細(xì)胞的增殖，并與miR-152具有依賴性且其作用具有細(xì)胞類型選擇性有關(guān)，猜測(cè)這種現(xiàn)象可能是miR-152通過抑制周期素依賴性蛋白激酶19(cyclin dependent kinase 19,CDK19)的基因表達(dá)所導(dǎo)致。2.3 microRNA-223(miR-223)

miR-223是一種骨髓特異性的microRNA。研究顯示脊髓組織miR-223在脊髓損傷后6 h、12 h、3 d表達(dá)均升高，且在損傷部位表達(dá)。研究還表明脊髓損傷后中性粒細(xì)胞表達(dá)顯著升高，且與miR-223的表達(dá)存在時(shí)間依賴性，這提示miR-223可能參與脊髓損傷后中性粒細(xì)胞的調(diào)控[40,49]。Izumi等[49]發(fā)現(xiàn)miR-223在小鼠脊髓損傷區(qū)域頭端及尾端2 mm內(nèi)大量表達(dá)，同時(shí)炎癥因子白細(xì)胞介素(interleukin,IL)-1β、IL-6及腫瘤壞死因子(tumor necrosis factor,TNF)-α在相同區(qū)域表達(dá)亦顯著提高。這些研究表明，脊髓損傷后miR-223可能參與中性粒細(xì)胞介導(dǎo)的炎癥反應(yīng)，從而介導(dǎo)繼發(fā)性脊髓損傷的過程。孫煒俊[50]研究表明，脊髓損傷后miR-223基因表達(dá)顯著升高，RhoB基因的表達(dá)亦同步明顯上調(diào)，且二者呈顯著正相關(guān)，由此進(jìn)一步推測(cè)RhoB基因的表達(dá)可能受miR-223的調(diào)控。近些年研究發(fā)現(xiàn)，RhoB/ROCK信號(hào)通路在脊髓損傷的病理過程中發(fā)揮著重要作用，抑制RhoB/ROCK通路可能促進(jìn)中樞神經(jīng)損傷后的修復(fù)與重建。

2.4 microRNA-210(miR-210)

miR-210具有廣泛的生理作用，參與細(xì)胞增殖分化、血管生成、新陳代謝、DNA修復(fù)、細(xì)胞周期等的調(diào)控[51-53]，并可以作為一些癌癥的腫瘤標(biāo)志物[54-55]。研究表明miR-210能夠在缺血缺氧的情況下，參與低氧反應(yīng)、氧化應(yīng)激以及細(xì)胞凋亡的調(diào)控[56-57]。邵建立等[58]通過實(shí)驗(yàn)證實(shí)H2O2能夠刺激鼠脊髓神經(jīng)元內(nèi)miR-210表達(dá)的上調(diào)，而降低miR-210的表達(dá)能夠降低細(xì)胞內(nèi)NADPH氧化酶2(NADPH oxidase 2,NOX2)和活性氧(reactive oxygen species,ROS)的表達(dá)，進(jìn)而抑制NOX2/ROS通路，從而減緩H2O2對(duì)大鼠背脊髓神經(jīng)元細(xì)胞造成的損傷。Ujigo等[59]通過實(shí)驗(yàn)驗(yàn)證miR-210可能通過抑制蛋白酪氨酸磷酸酶1B的生成，從而促進(jìn)血管生成，進(jìn)而促進(jìn)脊髓損傷的修復(fù)。這些研究表明[58-59]，miR-210過表達(dá)和繼發(fā)性脊髓損傷存在一定的關(guān)系，miR-210在繼發(fā)性脊髓損傷中可能發(fā)揮重要的作用，從而推測(cè)miR-210可以作為脊髓損傷的治療靶點(diǎn)。

2.5 microRNA-21(miR-21)

研究發(fā)現(xiàn)小鼠脊髓損傷組織中miR-21的表達(dá)水平與正常脊髓組織相比顯著升高[60]，通過生物信息學(xué)檢索預(yù)測(cè)，其靶基因可能包括程序性細(xì)胞死亡因子4(programmed cell death, PDCD4)。研究表明[61-63]，PDCD4是一類細(xì)胞凋亡的相關(guān)基因，降低其表達(dá)可以抑制細(xì)胞凋亡的發(fā)生，從而對(duì)細(xì)胞起保護(hù)效應(yīng)。佘飛等[64]通過實(shí)驗(yàn)驗(yàn)證小鼠脊髓損傷中高表達(dá)的miR-21直接作用于PDCD4，從而在mRNA和蛋白水平抑制PDCD4的表達(dá)，進(jìn)而推測(cè)miR-21可能在脊髓損傷過程中具有重要的保護(hù)作用，這和多種損傷模型中miR-21通過抑制PDCD4的表達(dá)從而發(fā)揮保護(hù)效應(yīng)的研究結(jié)果基本一致[63,65-66]。

3 總結(jié)與展望

在過去20多年里，關(guān)于microRNA的基礎(chǔ)研究迅速增加，研究結(jié)果有力地證實(shí)了microRNA應(yīng)用于臨床脊髓損傷治療的潛力。大量研究發(fā)現(xiàn)microRNA可能是脊髓損傷后神經(jīng)細(xì)胞死亡的一個(gè)潛在標(biāo)記物，可能成為干預(yù)脊髓損傷的有效靶點(diǎn)[13,19,21,23,37,67-70]，也為脊髓損傷患者神經(jīng)功能的恢復(fù)與重建提供了新思路、新方法與新技術(shù)，部分基于microRNA的研究已處于臨床試驗(yàn)階段。

迄今為止microRNA在脊髓損傷研究領(lǐng)域的報(bào)道仍然比較有限，仍有一些問題需要解決，例如脊髓損傷后microRNA研究的資料較少并且零散，研究內(nèi)容不夠深入，缺乏分子機(jī)制之間的相互聯(lián)系，目前僅知microRNA可能與脊髓損傷后的炎癥反應(yīng)、氧化應(yīng)激和神經(jīng)元壞死的調(diào)控有關(guān)。該研究領(lǐng)域下一步的發(fā)展方向可能是如何分離純化microRNA分子，microRNA與靶mRNA之間的關(guān)系，microRNA是否可以調(diào)節(jié)其他microRNA等。通過對(duì)特定microRNA作用分子機(jī)制的詳細(xì)研究，對(duì)特定microRNA分子調(diào)控的上下游分子及所涉及的信號(hào)通路做深入研究，進(jìn)而揭示相關(guān)microRNA在脊髓損傷中的調(diào)控網(wǎng)絡(luò)與調(diào)控模式。

隨著基因芯片、原位雜交、微陣列數(shù)據(jù)、實(shí)時(shí)定量反轉(zhuǎn)錄聚合酶鏈反應(yīng)(real-time quantitative polymerase chain reaction, RT-qPCR)檢測(cè)等技術(shù)手段的飛速發(fā)展與廣泛應(yīng)用，人們將進(jìn)一步理解microRNA在生物發(fā)展中的功能與作用，并利用microRNA進(jìn)行臨床診斷和治療，這將提高人們對(duì)脊髓損傷后microRNA調(diào)控作用的認(rèn)知水平，并促進(jìn)基于microRNA調(diào)控的脊髓損傷治療措施的研究。該研究有望找到基因調(diào)控階段修復(fù)與重建脊髓損傷的新途徑，為臨床治療尋找新靶點(diǎn)。

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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.國家自然科學(xué)基金面上項(xiàng)目(No.81272164)；2.中央級(jí)公益性科研院所基本科研業(yè)務(wù)費(fèi)專項(xiàng)資金項(xiàng)目(No.2015CZ-6)。

1.首都醫(yī)科大學(xué)康復(fù)醫(yī)學(xué)院，北京市100068；2.中國康復(fù)研究中心北京博愛醫(yī)院脊柱脊髓神經(jīng)功能重建科，北京市100068；3.北京腦重大疾病研究院神經(jīng)損傷與修復(fù)研究所，北京市100068；4.北京市神經(jīng)損傷與康復(fù)重點(diǎn)實(shí)驗(yàn)室，北京市100068；5.湖南醫(yī)藥學(xué)院，湖南懷化市418000。作者簡介：張文豪(1991-)，男，漢族，河南柘城縣人，碩士研究生，主要研究方向：脊柱脊髓損傷的康復(fù)與治療。通訊作者：李建軍(1962-)，男，漢族，教授，主任醫(yī)師，博士、博士后導(dǎo)師，主要研究方向：骨科及脊柱脊髓損傷的康復(fù)與治療。E-mail:crrc100@163.com。