CN106519002A - Grp78截短体及其应用 - Google Patents
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Abstract
本发明公开了GRP78截短体及其应用。GRP78截短体，其氨基酸序列如SEQ ID NO.1所示。本发明利用生物工程技术，基因重组一段GRP78截短体多肽对应的DNA序列到p3*flag‑cmv‑13‑14真核表达载体。经酶切和序列分析证明重组成功后，将此真核表达重组多肽转染到HepG2细胞中，免疫印迹证明多肽的蛋白表达，实现了多肽的重组。接着对多肽改善IR进行了研究，细胞学实验表明此多肽具有改善IR的重要功能，在制备改善IR药物中的将具有广泛的应用。
Description
技术领域
本发明涉及生物工程技术领域，具体涉及GRP78截短体及其应用。
背景技术
II型糖尿病是一种常见病，多发病，在我国以及全世界都具有很高的发病率，在我国，II型糖尿病已经成为发病率增长最快的疾病。最新资料表明，我国糖尿病患者已超过6000万，占全球糖尿病患者的五分之一。预计截止到2025年我国糖尿病患者总数将接近1亿。
II型糖尿病是一种多病因的代谢疾病，除内在的遗传因素外，还与人们生活环境、生活方式及行为有很大的关系，特别是过度肥胖引起的一些代谢紊乱易导致II型糖尿病。II型糖尿病又称为非胰岛素依赖型糖尿病，是指肌肉和脂肪组织对胰岛素产生抗性，作为补偿，胰岛β细胞则分泌更多的胰岛素，但仍不能把血糖维持在正常范围内。另外，过量的胰岛素分泌使胰岛β细胞功能受到损伤，导致胰岛素分泌不足。胰岛素抵抗是指机体靶组织对胰岛素的反应性低于正常的一种病理生理状态，经常与肥胖，II型糖尿病早期阶段等临床疾病相伴随，是这些疾病的一个重要的特征，也是导致这些疾病发生的重要因素。但是造成胰岛素抵抗以及由此导致的肥胖，II型糖尿病等相关疾病的分子机制并不是很清楚。这就导致了其防治的困难。
葡萄糖调节蛋白78(Glucose Regulated Protein，GRP78)，它位于内质网的管腔，是与细胞防御系统有关的内质网分子伴侣。GRP78是内质网应激的标志性蛋白。在正常情况下，内质网膜上的三种跨膜蛋白双链RNA依赖的蛋白激酶样内质网激酶，活化转录因子6和肌醇需求激酶与GRP78结合，并处于无活性状态；当未折叠蛋白或错误折叠蛋白在内质网腔内蓄积时，GRP78与之解离得到激活，进入胞质，其表达及稳定性明显增加，并通过不同的途径来介导不同的蛋白处理程序，参与内质网应激过程。
有研究表明，相比于雄性GRP78+/+小鼠，雄性GRP78+/-小鼠可增加其体内能量消耗水平，从而缓解高脂饮食(High-fat Induced Diet，HFD)所诱导的肥胖，并对饮食所诱导的高血糖，高胰岛素血症，肝脂肪变性有抵抗作用，从而缓解胰岛素抵抗以及II型糖尿病。
发明内容
发明目的：针对现有技术中存在的不足，本发明的目的是提供GRP78截短体，具有改善胰岛素抵抗(Insulin Resistance，IR)的重要功能。本发明的另一目的是提供GRP78截短体的应用。
技术方案：为了实现上述发明目的，本发明采用的技术方案为：
GRP78截短体，其氨基酸序列如SEQ ID NO.1所示。
编码所述的GRP78截短体的基因，其DNA序列如SEQ ID NO.2所示。
含有所述的GRP78截短体的编码基因的DNA序列的载体。
所述的载体，将GRP78截短体的DNA序列连接进p3*flag-cmv-13-14真核表达载体，构建出重组表达质粒。
所述的GRP78截短体在制备改善IR药物中的应用。
有益效果：与现有技术相比，本发明利用生物工程技术，基因重组一段GRP78截短体多肽对应的DNA序列到p3*flag-cmv-13-14真核表达载体。经酶切和序列分析证明重组成功后，将此真核表达重组多肽转染到HepG2细胞中，免疫印迹证明多肽的蛋白表达，实现了多肽的重组。接着对多肽改善IR进行了研究，细胞学实验表明此多肽具有改善IR的重要功能，在制备改善IR药物中的将具有广泛的应用。
附图说明
图1是GRP78截短体多肽对应的DNA序列免疫印迹蛋白表达结果图，大小为40KD；
图2是免疫印迹分析检测胰岛素抵抗指标p-AKT、p-GSK3β的蛋白表达水平图；
图3是免疫印迹分析检测内质网应激相关通路分子的蛋白表达水平图。
具体实施方式
下面结合具体实施例对本发明做进一步的说明。实施例中未注明具体条件的实验方法，通常按照常规条件，例如分子克隆实验指南(第四版，M.R.格林，J.萨姆布鲁克著，科学出版社，2013年)中所述的条件，或按照制造厂商所建议的条件进行。
实施例1
1)GRP78截短体多肽重组
提取人的mRNA，逆转录为cDNA，以cDNA为模板，应用PCR技术(引物序列：5'-AAGCTT ATG GAG GTA GAA AAG GCC AAA CG-3'，5'-CTC GAG CAA CTC ATC TTT TTC TGC TGT-3'，反应条件：95℃，5min→95℃，30s→55℃，20s→72℃，1min(共30循环)→72℃，1min/kb)成功扩增出GRP78截短体(SEQ ID NO.1所示)对应的1092bp的mRNA序列(SEQ ID NO.2所示)。扩增得到的片段与p3*flag-cmv-13-14载体连接，将连接产物转入感受态大肠杆菌DH5α中，在含Amp+琼脂平板上挑选克隆，以碱裂解法小提重组质粒后，以ECOR1酶切鉴定并测序，验证结果正确。
2)多肽类似物真核表达载体构建及其表达检测
将含有GRP78截短体多肽核酸片段的p3*flag-cmv-13-14质粒经ECOR1酶切后，利用回收试剂盒获得该片段，同时用相同的酶处理质粒p3*flag-cmv-13-14，然后将回收多肽核酸片段和经酶切的载体p3*flag-cmv-13-14在T4 DNA连接酶作用下于16℃连接过夜。酶切鉴定重组体。将正确连接的364aa多肽真核表达载体转染HepG2细胞，48小时后搜集样品，RIPA细胞裂解液裂解，免疫印迹结果如图1所示，证明了多肽的表达。
实施例2重组肽改善胰岛素抵抗功能的检测
1)分析IR的HepG2细胞中AKT、p-AKT、GSK3β、p-GSK3β的表达变化
①细胞模型：HepG2细胞先置于含0.25mm/L PA不含血清的DMEM培养基中孵育24小时；接着置于含100nmol/L胰岛素的培养液中孵育15分钟后提取蛋白。
②将细胞弃去培养基，冰浴PBS洗涤后在培养皿中加入蛋白裂解液(以一个80-90％融合度的6cm培养皿加入1mL的裂解液为准)刮取细胞，提取蛋白，利用western blot实验手段检测胰岛素信号通路相关分子(AKT、p-AKT、GSK3β、p-GSK3β)的蛋白表达水平，结果如图2所示，在肝癌细胞HepG2中转染364aa多肽后，胰岛素抵抗标记：p-AKT、p-GSK3β的表达量上升。
2)分析IR的HepG2细胞中GRP78、CHOP的表达变化
①细胞模型构建同上。
②将细胞弃去培养基，冰浴PBS洗涤后在培养皿中加入蛋白裂解液(以一个80-90％融合度的6cm培养皿加入1ml的裂解液为准)刮取细胞，提取蛋白，利用western blot实验手段检测内质网应激相关通路(GRP78、CHOP)的蛋白表达水平，结果如图3所示，在肝癌细胞HepG2中转染364aa多肽后，内质网应激下游CHOP的表达量下降。
Claims (5)
1.GRP78截短体，其氨基酸序列如SEQ ID NO.1所示。
2.编码权利要求1所述的GRP78截短体的基因，其DNA序列如SEQ ID NO.2所示。
3.含有权利要求2所述的GRP78截短体的编码基因的DNA序列的载体。
4.根据权利要求3所述的载体，其特征在于：将GRP78截短体的DNA序列连接进p3*flag-cmv-13-14真核表达载体，构建出重组表达质粒。
5.权利要求1所述的GRP78截短体在制备改善IR药物中的应用。
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