CN110042157A - miR-380-3p在制备诊断、预防和/或治疗非酒精性脂肪肝的产品中的应用 - Google Patents
miR-380-3p在制备诊断、预防和/或治疗非酒精性脂肪肝的产品中的应用 Download PDFInfo
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- CN110042157A CN110042157A CN201910334338.3A CN201910334338A CN110042157A CN 110042157 A CN110042157 A CN 110042157A CN 201910334338 A CN201910334338 A CN 201910334338A CN 110042157 A CN110042157 A CN 110042157A
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Abstract
本发明公开了miR‑380‑3p在制备诊断、预防和/或治疗非酒精性脂肪肝的产品中的应用。本发明还提供了用于检测非酒精性脂肪肝的诊断试剂盒。本发明还提供了用于预防和/或治疗非酒精性脂肪肝的药物组合物，所述药物组合物包含miR‑380‑3p抑制剂作为活性成分。本发明发现miR‑380‑3p不仅为非酒精性脂肪肝的诊断提供了新的检测方式，而且为基因治疗、药物治疗等临床应用提供了治疗靶点和重要依据。
Description
技术领域
本发明涉及生物医药技术领域，具体涉及miR-380-3p在制备诊断、预防和/或治疗非酒精性脂肪肝的产品中的应用。
背景技术
非酒精性脂肪肝病(nonalcoholic fatty liver disease,NAFLD)是一种与胰岛素抵抗(insulin resistance,IR)和遗传易感密切相关的代谢应激性肝脏损伤，其病理学改变与酒精性肝病(alcoholic liver disease,ALD)相似，但患者无过量饮酒史。NAFLD包括单纯性脂肪肝(simple fatty liver,SFL)、非酒精性脂肪肝炎(Nonalcoholicsteatohepatitis,NASH)及其相关肝硬化和肝细胞癌。随着肥胖及其相关代谢综合征全球化的流行趋势，非酒精性脂肪肝病现已成为欧美等发达国家和我国富裕地区慢性肝病的重要病因，普通成人NAFLD患病率20％～30％，其中NASH和肝硬化分别占10％～20％和2％～3％。
肥胖症患者NAFLD患病率为60％～90％、NASH为20％～25％、肝硬化为2％～8％，2型糖尿病和高脂血症患者NAFLD患病率分别为28％～55％和27％～92％。近20年亚洲国家NAFLD增长迅速且呈低龄化发病趋势，中国的上海、广州和香港等发达地区成人NAFLD患病率在15％左右。导致NAFLD的危险因素包括高脂肪高热量膳食结构、多坐少动的生活方式、IR、代谢综合征及其组分(肥胖症、高血压、血脂紊乱和2型糖尿病)。过去20余年间，非酒精性脂肪肝病从一种鲜为人知的疾病发展为全球最常见的慢性肝脏疾病。目前，全球大约四分之一的成人有非酒精性脂肪肝病，其中25％的患者为其严重类型——非酒精性脂肪肝炎，后者可以进展为肝硬化、肝细胞癌及其相关死亡。与成人相似，非酒精性脂肪肝病和非酒精性脂肪肝炎亦是儿童青少年的常见病。
非酒精性脂肪肝病，除可直接导致失代偿期肝硬化、肝细胞癌和移植肝复发外，还可影响其他慢性肝病的进展，并参与2型糖尿病和动脉粥样硬化的发病。代谢综合征相关的恶性肿瘤、动脉硬化性心脑血管疾病以及肝硬化，是影响非酒精性脂肪肝病患者生活质量和预期寿命的重要因素。因此，非酒精性脂肪肝病成为当代医学领域的新挑战，是全球公认的第一大慢性肝病，近期内非酒精性脂肪肝病对人类健康的危害仍将不断增加。
miRNA(microRNA)是一类长度为20～25个核苷酸的非编码小分子RNA，通过影响其靶基因的稳定性或抑制其翻译转录水平来调控细胞的分化、增殖和凋亡。miRNA在细胞中表达失调会导致癌症在内的多种疾病的发生。现有研究发现，一些miRNA在非酒精性脂肪性肝病患者中出现差异性表达，这些差异性表达有多种功能，包括调节脂质和糖代谢，参与折叠蛋白反应、内质网应激、氧化应激、细胞分化、炎性反应及细胞凋亡。因此有必要寻找与非酒精性脂肪肝发生、发展有关的miRNA，从而为临床上诊断、预防和/或治疗非酒精性脂肪肝提供一种有效手段。
发明内容
为了寻找与非酒精性脂肪肝发生、发展有关的miRNA，本发明一个目的在于提供miR-380-3p在制备诊断、预防和/或治疗非酒精性脂肪肝的产品中的应用。
本发明还一个目的是提供诊断、预防和/或治疗非酒精性脂肪肝的产品。
本发明的发明人在对非酒精性脂肪肝的相关研究中发现miR-380-3p在非酒精性脂肪肝患者血清中含量显著升高，也即相对于健康人来说非酒精性脂肪肝患者血清中miR-380-3p的相对表达水平上调。另外在非酒精性脂肪肝大鼠模型血清中、加入油酸培养诱导的HepG2细胞模型细胞中，均得到相应的miR-380-3p的相对表达水平上调结果。本发明的实验表明，miR-380-3p是与非酒精性脂肪肝显著相关的标志物。
在本发明中，术语“miR-380-3p”是指包含SEQ ID No.1(UAUGUAAUAUGGUCCACAUCUU)所示人源序列或其同源序列的miRNA。
本发明的“miR-380-3p”还包含上述天然存在的miR-380-3p序列经取代、缺失或添加一个或几个核苷酸，或经过生物学化学修饰后仍具有miR-380-3p生物活性的miR-380-3p衍生物。
本发明的“miR-380-3p”还包含人工合成的以及可以通过购买市售商品方式获得的具有miR-380-3p生物学活性的miR-380-3p模拟物。
此外，本发明所述的miR-380-3p也可以为前体形式，miR-380-3p前体是指在被施用对象的细胞内或体内可以被加工成为miR-380-3p的前体。获得天然存在的miR-380-3p前体的方法为本领域技术人员所公知。
本领域技术人员公知，miR-380-3p的初始转录产物经过一系列的加工后，形成成熟的miR-380-3p。miR-380-3p前体只有在加工为成熟的miR-380-3p后才具有相应的生物学功能。
本发明的一个方面提供了用于检测非酒精性脂肪肝的诊断试剂盒，所述试剂盒包括对与非酒精性脂肪肝相关的miR-380-3p进行特异性cDNA扩增的引物和说明书；所述引物包括序列为SEQ ID NO:2的反转录引物，以及序列分别为SEQ ID NO:3(正向引物)和SEQ IDNO:4(反向引物)的cDNA扩增引物对；所述试剂盒还包括10×Buffer、dNTP、MgCl2、Taq酶和SYBR Green荧光染料。
本发明的另一个方面提供了miR-380-3p抑制剂在制备预防和/或治疗非酒精性脂肪肝的生物制剂中的应用。在本发明的一些实施方案中，所述应用包括将miR-380-3p抑制剂与载体结合后与其他治疗非酒精性脂肪肝药物和/或药物可接受的辅料复配制成药物组合物。
进一步地，所述miRNA-380-3p抑制剂选自：能降低miRNA-380-3p表达量的siRNA、dsRNA、shRNA、miRNA、反义核苷酸；或者能表达或形成所述siRNA、dsRNA、shRNA、miRNA、反义核苷酸的构建物。
本发明又一个方面还提供了用于预防和/或治疗非酒精性脂肪肝的药物组合物，所述药物组合物含有有效量的miR-380-3p抑制剂和药物可接受的辅料。
本发明的miR-380-3p抑制剂的有效剂量可以随给药的模式和待治疗的疾病的严重程度等进行相应的调整。优选的有效量的可以由本领域普通技术人员综合各因素来确定。所述因素包括但不限于：miR-380-3p抑制剂的药代动力学参数、受治疗的患者的健康状况、体重、给药途径等。
进一步地，所述miRNA-380-3p抑制剂选自：能降低miRNA-380-3p表达量的siRNA、dsRNA、shRNA、miRNA、反义核苷酸；或者能表达或形成所述siRNA、dsRNA、shRNA、miRNA、反义核苷酸的构建物。
在本发明的一些实施方案中，所述药物组合物含有与载体结合的miR-380-3p抑制剂和药物可接受的辅料；所述载体可以为本领域常用的适于miRNA在宿主细胞中表达的载体种类如脂质体、壳聚糖、病毒载体如慢病毒表达载体、或真核载体；所述辅料包括在药物使用中但不引起明显副作用的各种赋形剂、稀释剂和佐剂，包括但不限于：生理盐水、缓冲液、葡萄糖、水、甘油、乙醇等。所述药物组合物的形式可适合于直接裸miRNA注射法、脂质体包裹RNA直接注射法、繁殖缺陷细菌携带质粒DNA法或复制缺陷腺病毒携带目的DNA法等。在本发明的一些实施方案中，所述表达载体为慢病毒表达载体。
在本发明的一些实施方案中，所述药物组合物还任选地包含一种或多种其他对治疗非酒精性脂肪肝有效的药物，这些药物是本领域技术人员所熟知的。
本发明中，所述药物组合物的给药途径可为静脉内、动脉内灌注或局部注射等，也可以采用本领域技术人员所熟知的其他给药途径进行给药。本发明的药物组合物可以与其他治疗手段联合施用，用于非酒精性脂肪肝的预防和/或治疗。
有益效果：
本发明提供的用于检测非酒精性脂肪肝的诊断试剂盒，可用于诊断miR-380-3p相关的非酒精性脂肪肝，从而为有针对性地治疗该疾病提供依据。本发明还提供一种预防和/或治疗非酒精性脂肪肝的药物组合物，所述药物组合物含有有效量miR-380-3p抑制剂作为活性成分，从而实现预防和/或治疗非酒精性脂肪肝的作用。本发明发现，miR-380-3p不仅为非酒精性脂肪肝的诊断提供了新的检测方式，而且为基因治疗、药物治疗等临床应用提供了治疗靶点和重要依据。
附图说明
图1为miR-380-3p分别在正常人群血清(对照组)和非酒精性脂肪肝人群血清中的相对含量；
图2为miR-380-3p分别在正常大鼠血清(对照组)和非酒精性脂肪肝大鼠模型血清中的相对含量；
图3为miR-380-3p分别在正常培养的HepG2细胞(对照组)、加入油酸12小时后的HepG2细胞(12小时处理组)、加入油酸48小时后的HepG2细胞(48小时处理组)中的相对含量；
图4为正常培养的人肝癌细胞系HepG2细胞(对照组)的染色图；
图5为加入油酸培养后(12小时处理组)人肝癌细胞系HepG2细胞的染色图；
图6为加入油酸培养后(48小时处理组)人肝癌细胞系HepG2细胞的染色图。
具体实施方式
以下实施例用于说明本发明，但不用来限制本发明的范围。若未特别指明，实施例中所用的技术手段为本领域技术人员所熟知的常规手段。
下面通过具体实施例对本发明进行详细说明。
实施例1
本实施例证明，miR-380-3p在非酒精性脂肪肝人群血清中的含量明显高于其在健康人群血清中的含量。
1.miRNA提取
收集健康人和非酒精性脂肪肝患者的血清样本各10例。使用Tiangen的miRNA提取试剂盒(生产商：天根生化科技(北京)有限公司；产品批号：TP501)，每200μl血清中加入等体积裂解液，振荡器振荡混匀30秒。室温放置5min后，12,000rpm离心10min；取上清，加入200μl氯仿，剧烈振荡15秒；室温放置5min后，12,000rpm离心15min；样品会分成三层：黄色的有机相，中间层和无色的水相，RNA主要在水相中；把水相转移到新管中，缓慢加入转移液体积1/3体积的无水乙醇混匀；一起转入吸附柱，室温放置2min,12,000rpm离心30秒；保留流出液。缓慢加入流出液体积2/3体积的无水乙醇，混匀，一起转入吸附柱；室温放置2min后，12,000rpm离心30秒；离心后保留吸附柱。向吸附柱中加入500μl去蛋白液，室温12,000rpm离心30秒，弃废液；加入500μl漂洗液，室温12,000rpm离心30秒；将吸附柱放入2ml收集管中，室温12,000rpm离心1min，去除残余液体。再将吸附柱转入一个新的1.5ml离心管中，加15-30μl无RNA酶的水，室温12,000rpm离心2min。
2.逆转录
将10pg～1μg的RNA模板与2μl 10倍缓冲液、2μl dATP(10mM)、0.5μl引物、0.5μl核糖核酸酶抑制剂和无核糖核酸酶水混合，体积最后为20μl，37℃孵育1h。然后反应管中加入1μl 0.5μg/μl特异性RT引物(5’-GTCGTATCCAGTGCAGGGTCCGAGGTATTCGCACTGGATACGACAAGATG-3’；即SEQ ID NO:2)，70℃孵育5min后立刻冰上孵育至少2min，打断RNA和引物的二级结构。最后，将上述20μl反应混合物与4μl 5倍缓冲液、1μl dNTP(10mM)，0.5μl M-MLV逆转录酶，0.5μl核糖核酸酶抑制剂，10μl polyA反应混合液和4μl无核糖核酸酶水混合，42℃孵育1h。
3.Q-PCR检测
采用25μl反应体系，每个样本设置3个平行管，所有扩增反应均重复三次以上以保证结果的可靠性。配制以下反应体系：SYBR Green聚合酶链式反应体系12.5μl，正向引物(5’-TATGTAATATGGTCCA-3’；即SEQ ID NO:3)(5μM/l)1μl，反向引物(5’-CAGTGCAGGGTCCGAGGTAT-3’；即SEQ ID NO:4)(5μM/l)1μl，模板cDNA 2μl，无酶水8.5μl。各项操作均于冰上进行。扩增程序为：95℃10min,(95℃20s，60℃55s)40个循环。以SYBRGreen作为荧光标记物，在荧光实时定量PCR仪上进行PCR反应。通过融解曲线分析和电泳确定目的条带，ΔΔCT法进行相对定量。
4.结果
如图1所示，miR-380-3p在非酒精性脂肪肝人群血清中的相对含量显著高于在正常人群(对照组)血清中的相对含量，并且该差异具有统计学意义(*p<0.05)；因此，miR-380-3p能够作为检测非酒精性脂肪肝的标记物。
实施例2
本实施例证明，miR-380-3p在非酒精性脂肪肝大鼠模型血清中的含量明显高于其在正常大鼠(对照组)血清中的含量。
1.非酒精性脂肪肝动物模型
幼年大鼠(3周龄)，每日喂养含2％胆固醇、10％猪油、0.3％胆酸钠等成分的高脂饲料，连续8周。立即抽取全血，测定血中总胆固醇(TC)、三酰甘油(TG)、游离脂肪酸(FFA)、丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、三酰甘油(TG)、游离脂肪酸(FFA)的含量，模型大鼠血清中TC、TG、FFA、AST、ALT升高。
2.参考实施例1中实验过程进行miRNA提取、反转录以及通过Q-PCR检测miR-380-3p的相对含量。
3.结果
如图2所示，miR-380-3p在非酒精性脂肪肝大鼠模型中的相对含量显著高于在普通饲料喂养的正常大鼠(对照组)血清中的相对含量，并且该差异具有统计学意义(*p<0.05)；因此，miR-380-3p能够作为检测非酒精性脂肪肝的标记物。
实施例3
本实施例证明，miR-380-3p在加入油酸培养的HepG2细胞中的含量明显高于其在正常培养的HepG2细胞(对照组)中的含量。
1.加入油酸培养HepG2细胞，建立油脂含量较高的细胞模型。将HepG2细胞以2×105/孔接种于六孔培养板中，取生长期细胞进行实验。加入无血清的DMEM培养基，培养24h后，加入含1mM油酸和10％BSA的DMEM再培养48h，建立油脂含量较高的细胞模型。对照模型采用无血清的DMEM培养基培养，不含油酸和BSA。
2.参考实施例1中实验过程进行miRNA提取、反转录以及Q-PCR检测miR-380-3p的相对含量。另外，还利用油红染色，比较正常培养的HepG2细胞(对照组)、加入油酸培养不同时间(12小时、48小时)后HepG2细胞模型组的细胞中油脂含量差异。
3.结果
如图3所示，miR-380-3p在油脂含量高的HepG2细胞模型(加入油酸12小时、48小时培养处理)中的相对含量显著高于正常培养的HepG2细胞(对照组)；而且在油脂含量高的HepG2细胞模型中，miR-380-3p在加入油酸培养48小时的细胞中的相对含量高于在加入油酸培养48小时的细胞中的相对含量。
上述培养的HepG2细胞进行油红染色，图4为正常培养的人肝癌细胞系HepG2细胞(对照组)的染色图；图5为加入油酸培养后(12小时处理组)人肝癌细胞系HepG2细胞的染色图；图6为加入油酸培养后(48小时处理组)人肝癌细胞系HepG2细胞的染色图；结果显示加入油酸培养后的模型组HepG2细胞中的油脂含量明显高于对照组，其中在48小时处理组HepG2细胞中的油脂块更大。
以上实验表明，miR-380-3p是与非酒精性脂肪肝显著相关的标志物，且其在患者体内的表达明显上调。因此可以通过检测其在患者的相关生物样品如血液、血清、或血浆、或尿液等中的含量来辅助诊断患者的非酒精性脂肪肝风险程度，以及通过将miR-380-3p抑制剂用于制备治疗非酒精性脂肪肝的药物来应用与相关疾病的治疗。
虽然，上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。
序列表
<110> 河北仁博科技有限公司
<120> miR-380-3p在制备诊断、预防和/或治疗非酒精性脂肪肝的产品中的应用
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<213> 人工序列(Artificial sequence)
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<213> 人工序列(Artificial sequence)
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Claims (10)
1.miR-380-3p在制备诊断、预防和/或治疗非酒精性脂肪肝的产品中的应用。
2.如权利要求1所述的应用，其特征在于，通过高通量测序获知患者生物样本中所述miR-380-3p的表达水平，从而获知所述miR-380-3p与非酒精性脂肪肝的相关性。
3.如权利要求1所述的应用，其特征在于，相对于健康人，非酒精性脂肪肝患者血清中miR-380-3p的相对表达水平上调。
4.用于检测非酒精性脂肪肝的诊断试剂盒，其特征在于，所述试剂盒包括对与非酒精性脂肪肝相关的miR-380-3p进行特异性cDNA扩增的引物和说明书。
5.如权利要求4所述的试剂盒，其特征在于，所述引物包括序列为SEQ ID NO:2的反转录引物，以及序列分别为SEQ ID NO:3和SEQ ID NO:4的cDNA扩增引物对。
6.如权利要求4或5所述的试剂盒，其特征在于，所述试剂盒还包括10×Buffer、dNTP、MgCl2、Taq酶和SYBR Green荧光染料。
7.miR-380-3p抑制剂在制备预防和/或治疗非酒精性脂肪肝的生物制剂中的应用。
8.如权利要求7所述的应用，其特征在于，所述miRNA-380-3p抑制剂选自：能降低miRNA-380-3p表达量的siRNA、dsRNA、shRNA、miRNA、反义核苷酸；或者能表达或形成所述siRNA、dsRNA、shRNA、miRNA、反义核苷酸的构建物。
9.一种药物组合物，其特征在于，所述药物组合物包含miR-380-3p抑制剂和药物可接受的辅料。
10.如权利要求9所述的药物组合物，其特征在于，所述药物组合物还任选地包含一种或多种其他对治疗非酒精性脂肪肝有效的药物。
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