組學(xué)在轉(zhuǎn)化醫(yī)學(xué)中的應(yīng)用進(jìn)展

金利泰

（溫州醫(yī)科大學(xué)藥學(xué)院，溫州 325035）

組學(xué)在轉(zhuǎn)化醫(yī)學(xué)中的應(yīng)用進(jìn)展

金利泰

（溫州醫(yī)科大學(xué)藥學(xué)院，溫州 325035）

金利泰，教授，博士生導(dǎo)師。主要研究領(lǐng)域包括蛋白質(zhì)組學(xué)，慢性疾病及皮膚創(chuàng)傷等發(fā)病機(jī)制研究，生物大分子檢測技術(shù)的開發(fā)及其機(jī)理研究。以蛋白質(zhì)組學(xué)平臺(tái)為基礎(chǔ)，對(duì)心肌病、糖尿病和皮膚創(chuàng)傷等發(fā)病機(jī)理及FGF對(duì)相關(guān)疾病治療機(jī)制展開了深入的研究，并開發(fā)了多種DNA和蛋白質(zhì)等大分子檢測技術(shù)。

E-mail:jin-li-tai@163.com

作為當(dāng)前醫(yī)學(xué)科學(xué)研究領(lǐng)域的熱點(diǎn)方向，轉(zhuǎn)化醫(yī)學(xué)（translational medicine）是指以患者為中心，從臨床應(yīng)用的實(shí)際需求出發(fā)，將基礎(chǔ)研究成果快速有效地轉(zhuǎn)化為臨床技術(shù)的過程，并通過臨床數(shù)據(jù)的深入分析進(jìn)一步指導(dǎo)基礎(chǔ)研究，以循環(huán)的方式不斷高效促成醫(yī)療水平的提升與完善，從而更好地服務(wù)于人類健康。作為轉(zhuǎn)化醫(yī)學(xué)的重要研究手段，基因組學(xué)、轉(zhuǎn)錄組學(xué)、蛋白組學(xué)和代謝組學(xué)等技術(shù)平臺(tái)為其高速發(fā)展提供了強(qiáng)勁的動(dòng)力。文章對(duì)轉(zhuǎn)化醫(yī)學(xué)及其相關(guān)組學(xué)平臺(tái)的應(yīng)用進(jìn)行了闡述，并對(duì)其發(fā)展趨勢進(jìn)行了探討。

傳統(tǒng)的基礎(chǔ)研究和臨床應(yīng)用之間相互獨(dú)立，缺少必要的溝通和聯(lián)系，具有局限性、盲目性和滯后性等不足，迫使醫(yī)學(xué)研究一度陷入了發(fā)展的瓶頸。轉(zhuǎn)化醫(yī)學(xué)的產(chǎn)生為現(xiàn)代醫(yī)學(xué)發(fā)展提供了革命性的理念，其概念的內(nèi)涵也在不斷的延伸、發(fā)展和完善。Sung將轉(zhuǎn)化醫(yī)學(xué)定義為“從實(shí)驗(yàn)臺(tái)到臨床”單向通道的概念，其主要目標(biāo)是將基礎(chǔ)研究的成果轉(zhuǎn)化為實(shí)用技術(shù)，應(yīng)用于臨床的治療，即基礎(chǔ)醫(yī)學(xué)研究-人類實(shí)驗(yàn)轉(zhuǎn)化-臨床科學(xué)知識(shí)-臨床實(shí)踐應(yīng)用；而Marincola認(rèn)為轉(zhuǎn)化醫(yī)學(xué)是高效地將醫(yī)學(xué)基礎(chǔ)研究的成果轉(zhuǎn)化為臨床技術(shù)和產(chǎn)品，并把臨床治療凝練得到的科學(xué)問題反饋給實(shí)驗(yàn)室，作為進(jìn)一步研究的基礎(chǔ)7。這種雙向通道的模式不僅打破了基礎(chǔ)研究和應(yīng)用之間的壁壘，而且可以推動(dòng)醫(yī)療水平持續(xù)的進(jìn)步與完善。疾病的發(fā)生和發(fā)展與基因組、轉(zhuǎn)錄組、蛋白組及代謝組等多個(gè)不同層次的病理過程息息相關(guān)1～15。組學(xué)概念出現(xiàn)于21世紀(jì)初期，隨著生物技術(shù)的不斷更新與蓬勃發(fā)展，已拓展到不同的研究領(lǐng)域。多組學(xué)技術(shù)平臺(tái)的快速更新為轉(zhuǎn)化醫(yī)學(xué)體系的發(fā)展、完善提供了多層次的高通量組學(xué)數(shù)據(jù)研究和獲取的策略，如疾病基因的查找，生物標(biāo)志物、給藥靶點(diǎn)的篩選，信號(hào)通路的分析等，為疾病預(yù)防、診斷、治療等提供了更多必要的8～途徑和重要的手段1617。

1 各組學(xué)與轉(zhuǎn)化醫(yī)學(xué)

1.1 基因組學(xué)與轉(zhuǎn)化醫(yī)學(xué)

全基因組關(guān)聯(lián)分析（genomewide association study，GWAS）可在人類全基因組范圍內(nèi)找出存在的序列變異，通過對(duì)比分析病例與對(duì)照樣本的基因組學(xué)數(shù)據(jù)信息，獲得與疾病相關(guān)的靶點(diǎn)1819。自2005年首個(gè)GWAS研究與年齡相關(guān)性黃斑變性相關(guān)的報(bào)道發(fā)表在《科學(xué)》雜志以來，該技術(shù)使許多復(fù)雜疾病的研究獲得了突破性進(jìn)展，在醫(yī)學(xué)領(lǐng)域中受到了極大的重視18～20。人們已通過GWAS技術(shù)發(fā)現(xiàn)并鑒定了大量與復(fù)雜性狀相關(guān)聯(lián)的遺傳變異。截至2016年9月18日，GWAS Catalog數(shù)據(jù)庫共收載了GWAS相關(guān)研究文章2546篇，發(fā)現(xiàn)了22 037個(gè)單核苷酸多態(tài)性（SNP）與24 916個(gè)疾病/性狀關(guān)聯(lián)。包括消化系統(tǒng)疾病、心血管疾病、代謝性疾病、神經(jīng)系統(tǒng)疾病、免疫系統(tǒng)疾病和腫瘤等多種疾病/性狀被 美國NIH權(quán)威數(shù)據(jù)庫收錄。2009年，張學(xué)軍教授團(tuán)隊(duì)驗(yàn)證了銀屑病中已報(bào)道的MHC和IL12B基因，并發(fā)現(xiàn)了一個(gè)新的易感基因LCE，該成果作為中國第一篇GWAS論文以“Psoriasis genomewide association study identifies susceptibility variants within LCE gene cluster at 1q21”為題發(fā)表在《Nature Genetics》雜志上21。張學(xué)軍教授認(rèn)為，未來GWAS研究將應(yīng)用在疾病預(yù)警、遺傳咨詢、早期診斷、風(fēng)險(xiǎn)評(píng)估以及藥物選擇中。隨著基因組學(xué)技術(shù)的不斷發(fā)展，人們將會(huì)對(duì)變異與疾病之間的關(guān)系有更深入、更系統(tǒng)的理解，并將其高效地轉(zhuǎn)化到臨床應(yīng)用中。

1.2 轉(zhuǎn)錄組學(xué)與轉(zhuǎn)化醫(yī)學(xué)

從廣義上講，轉(zhuǎn)錄組的研究對(duì)象為特定細(xì)胞在某一生理狀態(tài)下所轉(zhuǎn)錄加工的RNA分子，包括信使RNA、核糖體RNA、轉(zhuǎn)運(yùn)RNA及非編碼RNA等功能單元22。其主要研究內(nèi)容是RNA與蛋白質(zhì)分子和它們所組成的基因功能網(wǎng)絡(luò)分析，及它們與細(xì)胞功能的關(guān)系等變化規(guī)律。轉(zhuǎn)錄組譜不但可以根據(jù)某些基因表達(dá)的信息推斷相應(yīng)未知基因的功能，探究特定調(diào)節(jié)基因的作用機(jī)制，而且還可以依照基因表達(dá)譜的分子標(biāo)簽用于疾病的診斷分析23～25。

新一代高通量測序技術(shù)RNA-seq是目前深入研究轉(zhuǎn)錄組的強(qiáng)大工具26～28。Chen等

29對(duì)肝癌進(jìn)行轉(zhuǎn)錄組測序分析，結(jié)果顯示編碼抑制酶AZIN1的RNA編輯發(fā)生了改變，導(dǎo)致其空間構(gòu)象也發(fā)生了變化，進(jìn)而增強(qiáng)了癌癥細(xì)胞的侵襲性。在非小細(xì)胞肺癌的研究30發(fā)現(xiàn)新的融合基因（ALK-PTPN3）會(huì)促使抑癌基因PTPN3的等位失活，該發(fā)現(xiàn)對(duì)肺癌的診斷和靶向治療有重要意義。通過RNA-seq和 ChIRP-seq等技術(shù)對(duì)非編碼RNA進(jìn)行研究，發(fā)現(xiàn) lncRNA在前列腺癌、肺癌和心臟病等疾病中也具有重要作用中，Jung等33通過對(duì) 7256組RNA-seq數(shù)據(jù)進(jìn)行分析比較，發(fā)現(xiàn)機(jī)體中高達(dá)68%的轉(zhuǎn)錄產(chǎn)物為lncRNA，大約有7%的lncRNA和疾病相關(guān)的SNP重合。

目前，轉(zhuǎn)錄組研究已經(jīng)成為揭示疾病的基因突變規(guī)律、探究疾病發(fā)生和發(fā)展的重要機(jī)制、發(fā)現(xiàn)致病基因調(diào)控的關(guān)鍵靶點(diǎn)等問題的重要手段， 對(duì)分子病因?qū)W分析、藥物個(gè)性化治療、預(yù)后評(píng)價(jià)及發(fā)現(xiàn)新的藥物靶點(diǎn)等諸多新領(lǐng)域具有重要意義73132。 Lyer等34～36。

1.3 蛋白組學(xué)與轉(zhuǎn)化醫(yī)學(xué)

蛋白組學(xué)通過對(duì)機(jī)體的細(xì)胞或組織內(nèi)的蛋白質(zhì)組成、表達(dá)水平、修飾情況以及蛋白質(zhì)間相互作用關(guān)系等進(jìn)行系統(tǒng)的分析，揭示蛋白質(zhì)與生命活動(dòng)的內(nèi)在聯(lián)系和規(guī)律。在臨床醫(yī)學(xué)研究中，通過對(duì)比分析正常機(jī)體及病理?xiàng)l件下的機(jī)體蛋白質(zhì)組差異，發(fā)現(xiàn)與疾病密切相關(guān)的特異性的蛋白質(zhì)分子，進(jìn)而推測某些特異性蛋白質(zhì)與疾病的關(guān)系。這些蛋白質(zhì)不但可以作為疾病早期診斷的生物標(biāo)記物，還可能作為新藥設(shè)計(jì)的潛在靶點(diǎn)37。

在癌癥預(yù)測與診斷中，生物標(biāo)記物的應(yīng)用已較為成熟，如HER-2/ neu 可特異地作為 乳腺癌及胃癌診斷的重要參考指標(biāo)，CD20抗原則與淋巴癌聯(lián)系緊密38～40。在阿爾茨海默癥的研究中，Song等41通過蛋白組學(xué)技術(shù)對(duì)411位認(rèn)知正常的對(duì)照受試者、261位輕度認(rèn)知障礙者和19位阿爾茨海默癥患者的血漿蛋白樣本進(jìn)行分析，并通過Western對(duì)質(zhì)譜數(shù)據(jù)進(jìn)一步驗(yàn)證，發(fā)現(xiàn) 30種蛋白在阿爾茨海默癥患者和輕度認(rèn)知障礙者樣本中調(diào)節(jié)異常， Afamin和IGHM兩種蛋白質(zhì)的表達(dá)在阿爾茨海默癥患者樣本中發(fā)生了顯著的改變，可作為該疾病診斷的潛在生物標(biāo)記物。新一代蛋白質(zhì)芯片技術(shù)的發(fā)展將使臨床疾病的篩查和治療變得更便捷、高效42～44。

1.4 代謝組學(xué)與轉(zhuǎn)化醫(yī)學(xué)

代謝組學(xué)通過高分辨的質(zhì)譜、核磁等技術(shù)，對(duì)機(jī)體體液或組織中代謝物進(jìn)行高通量分析，并結(jié)合多元統(tǒng)計(jì)學(xué)，模式識(shí)別模型篩選與疾病相關(guān)且具有顯著差異的代謝標(biāo)志物，為疾病的診治提供科學(xué)依據(jù)。

目前，代謝標(biāo)志物被廣泛應(yīng)用在臨床各類癌癥的預(yù)測分析。前列腺癌患者的血漿中，葡萄糖、賴氨酸、苯丙氨酸、乙酰半胱氨酸等代謝標(biāo)志物濃度明顯升高而脂質(zhì)的濃度降低，在臨床預(yù)測中，其準(zhǔn)確率達(dá)93%以上45。在卵巢癌預(yù)測分析中，酮體、丙氨酸、纈氨酸、低密度脂蛋白、神經(jīng)酰胺和溶血磷脂等標(biāo)志物通常作為重要的參考依據(jù)46。此外，對(duì)癌細(xì)胞的代謝通路進(jìn)行研究發(fā)現(xiàn)，其代謝通路中的IDH1和IDH2兩個(gè)異檸檬酸脫氫酶突變體可以促進(jìn)癌細(xì)胞的能量代謝，提高癌細(xì)胞的存活率。因此，代謝組學(xué)不但可以通過代謝標(biāo)志物對(duì)疾病的進(jìn)程做出直觀的預(yù)測，而且能夠通過代謝通路探尋疾病發(fā)生的機(jī)理47。

1.5 多組學(xué)與轉(zhuǎn)化醫(yī)學(xué)

傳統(tǒng)的單組學(xué)研究已為疾病的篩查、診斷、治療和預(yù)防等提供了重要的參考信息，極大地提高了人們對(duì)疾病的深層認(rèn)知水平，豐富了臨床治療的手段。然而，機(jī)體是一個(gè)非常復(fù)雜的生命系統(tǒng)，疾病的發(fā)生將促使機(jī)體產(chǎn)生一系列的連鎖反應(yīng)，單組學(xué)數(shù)據(jù)分析通常只能探尋疾病狀態(tài)多種變化的單一層面信息2548～51。隨著高通量組學(xué)技術(shù)對(duì)疾病研究的不斷深入，單組學(xué)分析愈加難以滿足轉(zhuǎn)化醫(yī)學(xué)的需求。多組學(xué)的關(guān)聯(lián)組合分析，不僅可以更全面、更系統(tǒng)地發(fā)掘疾病的形成機(jī)理，也可以通過相互補(bǔ)充、確證來提升診療的成功率52～56。

多組學(xué)分析與轉(zhuǎn)化醫(yī)學(xué)的具體研究策略為多源數(shù)據(jù)的 標(biāo)準(zhǔn)化處理-數(shù)據(jù)間相互關(guān)聯(lián)的建立-疾病相關(guān)因子的過濾篩選-疾病診療模型的建立-對(duì)疾病進(jìn)行預(yù)測和干預(yù)的實(shí)施-診療后臨床數(shù)據(jù)的分析-對(duì)診療模型的進(jìn)一步完善48。

2 組學(xué)與轉(zhuǎn)化醫(yī)學(xué)的發(fā)展展望

從宏觀角度分析，機(jī)體由健康狀態(tài)向疾病狀態(tài)的轉(zhuǎn)變，是各種因素綜合作用的結(jié)果。在疾病發(fā)展進(jìn)程中，各種生物分子的種類及含量不斷發(fā)生改變，且疾病發(fā)展的趨勢也不盡相同，各種復(fù)雜的因素的疊加給疾病的研究與臨床治療的整合（即轉(zhuǎn)化醫(yī)學(xué)）帶來了巨大的挑戰(zhàn)，而組學(xué)技術(shù)的蓬勃發(fā)展為轉(zhuǎn)化醫(yī)學(xué)的發(fā)展帶來了新的契機(jī)。

基因組學(xué)、轉(zhuǎn)錄組學(xué)、蛋白組學(xué)和代謝組學(xué)等多項(xiàng)組學(xué)綜合技術(shù)平臺(tái)的構(gòu)建，多組學(xué)信息庫的發(fā)展與完善，使人們可以對(duì)機(jī)體病理狀態(tài)下不同層次的調(diào)控因子的改變進(jìn)行深層發(fā)掘和解析。例如，通過基因組學(xué)和轉(zhuǎn)錄組學(xué)查找疾病控制基因及靶點(diǎn)，通過蛋白組學(xué)探究發(fā)病關(guān)聯(lián)信號(hào)通路機(jī)理、生物標(biāo)志物及相關(guān)靶點(diǎn)，通過代謝組學(xué)分析基因表達(dá)蛋白調(diào)控的最終影響和表現(xiàn)55。從不同水平系統(tǒng)分析、相互驗(yàn)證，54全面地解讀疾病發(fā)生、發(fā)展進(jìn)程，從而為臨床疾病診斷、治療提供全新而有效的方案36。以臨床的實(shí)際需求為切入點(diǎn)，通過對(duì)不同來源數(shù)據(jù)信息系統(tǒng)地分析與研究，使之轉(zhuǎn)化為高效的診療技術(shù)，并最終服務(wù)于臨床。

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10.3969/j.issn.1674-0319.2016.06.003