CN107459546B - 一种tRF-Gly反义链抑制剂及其应用 - Google Patents
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Abstract
本发明公开了一种tRF‑Gly反义链抑制剂及其应用。本发明利用小鼠酒精性肝病模型，对酒精性肝病小鼠肝组织和正常对照肝组织进行小分子RNA深度测序，通过分析差异表达的小分子RNA，筛选得到tRF‑Gly。通过甲基化和胆固醇修饰以及在两端添加修饰序列，化学合成tRF‑Gly反义链抑制剂，进行小鼠体内实验，结果表明tRF‑Gly反义链抑制剂有效地降低ALT和AST，同时明显降低肝脏中脂肪累积，说明tRF‑Gly反义链抑制剂可以保护肝功能和减轻酒精性脂肪肝病。人体中tRF‑Gly序列与小鼠是相同的，因此，tRF‑Gly反义链抑制剂有望开发成为一种新的治疗酒精性脂肪肝病的小分子RNA药物。
Description
技术领域：
本发明属于生物医学技术领域，具体涉及一种tRF-Gly反义链抑制剂及其应用。
背景技术：
酒精性肝病(alcoholic liver disease,ALD)是长期大量摄入酒精所诱发的肝脏疾病，早期表现为酒精性脂肪肝，随着病情恶化可进一步发展为酒精性肝炎、肝硬化，甚至肝癌。在所有致病和死亡的危险因素中，滥用酒精排在第五位，已成为全球性的公共卫生问题。ALD在我国的发病率逐年上升，已成为第二大肝病病因，威胁人类健康。目前其发病机制尚不完全清楚，缺乏有效治疗方法。
非编码小分子RNA是一类20-30个核苷酸的内源性非蛋白质编码的小RNA。研究发现：无论是动物模型标本还是人体样本，酒精性肝病组织都存在小分子RNA表达的失调，并且通过不同的机制参与ALD的发病过程。虽然已经有相关的研究报道，但小分子RNA调控肝脏脂质代谢分子机制还有待深入研究。随着小分子RNA深度测序技术的推广，科学家发现细胞中存在一类来源于tRNA的新型小分子RNA(tRNA-derived fragments，tRFs)。我们知道，tRNA除了参与蛋白质合成，还有许多重要功能，比如与细胞信号通路、细胞凋亡、细胞存活以及细胞应激反应等生物学过程紧密相关。tRNA不仅是各种生物学功能的直接执行分子还是许多小分子RNA的前体。研究发现从细菌到哺乳动物，包括人类在内各种细胞中都存在tRFs。哺乳动物中的tRFs是2009年在人的HCT116结肠癌细胞中发现的。起初，人们认为这些小分子RNA是tRNA的降解产物。随着tRNA来源的小分子RNA的功能和机制取得突破进展，现在可以明确这些tRNA来源的小RNA片段是一类具有重要功能的新型小分子RNA。最近，有一项研究结果显示，高脂饮食雄性小鼠的后代会出现糖耐量减低和胰岛素抵抗，而且这种糖耐量减低与tRF有关。在高脂饮食小鼠的后代中，不少代谢基因的表达水平显著减少。另一研究结果揭示了tRF在哺乳动物精子成熟和受精过程中的功能，他们发现睾丸中未成熟精子的小RNA与低蛋白饮食没有对应关系，但附睾中成熟精子的小RNA受到了显著的影响。以上研究结果充分说明tRF在生物体内具有重要的功能。
发明内容：
本发明的目的是提供一种可以保护肝功能和减轻酒精性脂肪肝病的tRF-Gly反义链抑制剂及其应用。
本发明的第一个目的是提供一种tRF-Gly反义链抑制剂，其为SEQ ID NO.2所示的核苷酸序列或者在SEQ ID NO.2所示的核苷酸序列的5’端和/或3’端添加有修饰序列的核苷酸序列。
所述的在SEQ ID NO.2所示的核苷酸序列的5’端和/或3’端添加有修饰序列的核苷酸序列，其核苷酸序列如SEQ ID NO.3所示。
本发明的第二个目的是提供上述的tRF-Gly反义链抑制剂在制备预防或治疗酒精性脂肪肝病药物或保健品中的应用。
本发明的第三个目的是提供上述的tRF-Gly反义链抑制剂在制备保肝降脂药物或保健品中的应用。
本发明利用小鼠酒精性肝病模型，对酒精性肝病小鼠肝组织和正常对照肝组织进行小分子RNA深度测序，通过分析差异表达的小分子RNA，筛选得到tRF-Gly。通过甲基化和胆固醇修饰以及在两端添加修饰序列，化学合成tRF-Gly反义链抑制剂，进行小鼠体内实验，结果表明tRF-Gly反义链抑制剂有效地降低肝功能指标谷丙转氨酶(ALT)和谷草转氨酶(AST)，同时明显降低肝脏中脂肪累积，说明tRF-Gly反义链抑制剂可以保护肝功能和减轻酒精性脂肪肝病。人体中tRF-Gly序列与小鼠是相同的，因此，tRF-Gly反义链抑制剂有望开发成为一种新的治疗酒精性脂肪肝病的小分子RNA药物。
附图说明：
图1是小鼠短期酒精性肝病模型的肝功能检测；其中，Pair-fed-S为对照组，EtOH-fed-S为短期酒精饲料实验组(16天)。
图2是小鼠短期酒精性肝病模型的肝脏组织脂肪变性检测；其中A为对照组油红O染色，B为短期酒精饲料实验组油红O染色，C为对照组H&E染色，D为短期酒精饲料实验组H&E染色。
图3是定量RT-PCR检测tRF-Gly在酒精性肝病和对照组的肝组织中表达水平；其中，A为短期酒精饲料试验；B为长期酒精饲料试验(5周)；Pair-fed-S和Pair-fed-L为对照组，EtOH-fed-S为短期酒精饲料实验组，EtOH-fed-L为长期酒精饲料实验组。
图4是tRF-Gly反义链抑制剂对酒精性肝病小鼠肝功能的影响；其中，Pair-fed-L为对照组，EtOH-fed-L为长期酒精饲料实验组(5周)，EtOH-fed-L+control为长期酒精饲料实验组(5周)，并注射随机对照序列RNA；EtOH-fed-L+tRF-Gly inhibitor为长期酒精饲料实验组(5周)，并注射tRF-Gly反义链抑制剂。
图5是tRF-Gly反义链抑制剂对酒精性肝病小鼠肝脏脂肪累积的影响；其中，A、B、C和D为油红O染色，E、F、G和H为H&E染色；Pair-fed-L为对照组，EtOH-fed-L为长期酒精饲料实验组(5周)，EtOH-fed-L+control为长期酒精饲料实验组(5周)，并注射随机对照序列RNA；EtOH-fed-L+tRF-Gly inhibitor为长期酒精饲料实验组(5周)，并注射tRF-Gly反义链抑制剂。
具体实施方式：
以下实施例是对本发明的进一步说明，而不是对本发明的限制。
实施例1：
1.小鼠酒精性肝病模型及肝功能指标检测
用C57BL/6小鼠，每组6只。短期酒精饲养模型的造模过程包括：对照组喂食不含酒精的Lieber-DeCarli对照饲料；短期酒精饲料实验组，先用不含酒精的Lieber-DeCarli液体饲料喂养小鼠5天(适应期)，再用含有5％酒精的Lieber-DeCarli液体饲料喂养小鼠11天(造模期)，最后一天加酒精灌胃(5g/kg体重)1次，收集标本。
长期酒精饲养模型的造模过程包括：对照组喂食不含酒精的Lieber-DeCarli对照饲料；长期酒精饲料实验组，先用不含酒精的Lieber-DeCarli液体饲料喂养小鼠3天(适应期)，用含1％酒精的Lieber-DeCarli液体饲料喂养小鼠2天，用含2％酒精的Lieber-DeCarli液体饲料喂养小鼠2天，用含4％酒精的Lieber-DeCarli液体饲料喂养小鼠1周，最后用含5％酒精的Lieber-DeCarli液体饲料喂养小鼠3周，收集标本。
取小鼠静脉血，分离获得血清，通过全自动生化仪检测肝功能AST和ALT等；麻醉小鼠，取肝脏组织并进行冰冻切片，用油红O染色，检测脂肪变性；麻醉小鼠，取肝脏组织，10％福尔马林固定，制备腊块，切片并H&E染色，观察检测肝组织形态学等。结果显示经酒精喂养，小鼠的ALT和AST都显著升高(图1)。油红O染色和H&E染色(图2)结果显示，酒精喂养小鼠的肝脏脂肪累积明显。
2.小鼠酒精性肝病肝组织中的小分子RNA
取短期酒精性肝病小鼠肝组织和对照肝组织进行小分子RNA深度测序(序列长度为18-40nt)并分析，通过生物息学分析，筛选差异表达的小分子RNA。其中甘氨酸转运RNA(tRNA)来源的小分子RNA(tRF-Gly)与对照组相比有显著差异，tRF-Gly的核苷酸序列如SEQID NO.1所示。
3.tRF-Gly在酒精性肝病和对照肝组织中的表达水平
取小鼠酒精性肝病肝组织(长期模型和短期模型)和对照肝组织，提取总RNA，反转录后定量RT-PCR检测，验证tRF-Gly的表达水平。同时检测tRF-Gly在长期模型(5周)与短期模型(16天)肝组织中的表达情况。经定量RT-PCR检测验证，酒精性肝病的肝组织中tRF-Gly的表达都比各自对照组高，并且在长期模型中的表达(约18倍)比短期模型(约2.2倍)更显著地提高(图3)。
4.tRF-Gly反义链抑制剂对长期酒精性肝病小鼠的肝功能及脂代谢的影响
化学合成随机对照序列RNA和tRF-Gly反义链抑制剂(序列为：CGUAAGCGAGAAUUCUACCACUGAACCACCAAUGCACAAU，下划线为修饰序列)，并经过甲基化和胆固醇修饰。把合成的tRF-Gly反义链抑制剂及对照RNA腹腔注射到长期酒精饲养小鼠体内，从喂养含5％酒精饲料时开始注射，每周注射2次，共注射6次，然后收集样本。取小鼠静脉血，分离获得血清，通过全自动生化仪检测肝功能AST和ALT等；麻醉小鼠，取肝脏组织并进行冰冻切片，用油红O染色，检测脂肪变性；麻醉小鼠，取肝脏组织，10％福尔马林固定，制备腊块，切片并HE染色，观察检测肝组织形态学等。从图4可以看到经tRF-Gly反义链抑制剂处理，抑制小鼠体内tRF-Gly，我们发现ALT和AST都明显下降。这些结果说明抑制tRF-Gly对小鼠酒精性肝病的肝损伤有保护作用。油红O染色或H&E染色的结果显示：肝脏脂肪滴显著变小而且数量也明显减少(图5)，表明tRF-Gly反义链抑制剂可以降低肝脏中的脂肪积累。
序列表
<110> 广西医科大学第一附属医院
<120> 一种tRF-Gly反义链抑制剂及其应用
<160> 3
<210> 1
<211> 30
<212> RNA
<213> 小鼠
<400> 1
gcattggtgg ttcagtggta gaattctcgc 30
<210> 2
<211> 30
<212> RNA
<213> 人工序列
<400> 2
gcgagaauuc uaccacugaa ccaccaaugc 30
<210> 3
<211> 40
<212> RNA
<213> 人工序列
<400> 3
cguaagcgag aauucuacca cugaaccacc aaugcacaau 40
Claims (1)
1.tRF-Gly反义链抑制剂在制备预防或治疗酒精性脂肪肝病药物或保健品中的应用，所述的tRF-Gly反义链抑制剂为SEQ ID NO.2或SEQ ID NO.3所示的核苷酸序列。
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