CN106093441A - 一种孤独症血清糖蛋白标记物的用途 - Google Patents
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Abstract
本发明公开了一种孤独症血清糖蛋白标记物的用途，通过凝集素芯片联合蛋白质谱正向和凝集素/糖‑抗体芯片反向同时验证了在ASD血清中高表达的糖蛋白Apolipoprotein D(APOD)，此蛋白可以作为孤独症诊断的血清糖蛋白标记物。本发明填补了孤独症生化诊断的空白。
Description
技术领域
本发明属于孤独症血清标记物检测领域，涉及一种孤独症血清糖蛋白标记物的应用，具体涉及糖蛋白Apolipoprotein D(APOD)作为孤独症检测标记物的应用。
背景技术
孤独症(自闭症)谱系障碍(Autism Spectrum Disorders,ASD)是一种先天脑部功能受损而引起的广泛性发展障碍，以社会交往障碍、言语和非言语交流缺陷、兴趣狭窄和行为刻板等为主要临床特征。该障碍最早在1943年被报道，但将其归为“精神分裂症、儿童型”之中，直到1980年才将此障碍与儿童精神病分离开来，并提出了广泛发育障碍的概念和分类，孤独症是其亚型之一，确定了儿童孤独症的分类地位，由此儿童孤独症作为独立疾病也越来越受到关注与研究。
目前，儿童孤独症发病率为1/100，远远高于癌症(1/1500)、21三体综合征(1/800)、糖尿病(1/500)。全世界至少有6700万孤独症患者，我国孤独症患儿约有60至180万，而且每年以10％到17％的比例增长，并有上升趋势。因此，早期诊断儿童孤独症对于及早干预治疗，缓解儿童发育障碍，给患儿和家庭带来希望有非常现实的意义。
目前，孤独症诊断的主要依据是《孤独症诊断访谈(修订版)》和《孤独症诊断观察程序表》，以及必要的心理评估、躯体和神经系统检测，还有一些必要的辅助检测。但这种诊断方式有一定的缺陷性：首先，需要临床医师能够准确掌握客观的病史，充分了解患儿的精神心理发展情况，否则容易和其他精神疾病相混淆；其次，测验耗时长，从初诊到最终确诊需要一年时间；最后，问卷调研对于小于3岁的儿童，存在困难。因此，急需一种在上述病史基础上能够辅助诊断孤独症的客观指标。
血清蛋白标记物的检测目前在肿瘤疾病中已得到广泛应用，如肺癌、胃癌及肝癌等。而孤独症诊断的辅助检测目前只有脑电图及CT、MR，还未见血清蛋白标记物的报道。寻找具有诊断或联合诊断价值的血清标志物是当务之急，也是ASD早发现早治疗的关键。因此，提供在血清中能够特异高表达的基因或蛋白质具有重要的诊断和治疗意义，本领域迫切需要开发可用于检测或判断ASD的血清特异标志物。
发明内容
本发明的目的在于提供一种孤独症血清糖蛋白标记物的应用。
该孤独症血清糖蛋白为凝集素MAL-II识别糖链Siaα2-3Gal/GalNAc酸化的Apolipoprotein D(APOD)。APOD在孤独症(ASD)患儿血清中表达较正常儿童(TD)血清中的表达上调1.9倍，高表达α2-3唾液酸化APOD可以灵敏和特异地区分ASD(AUC是0.88)和正常人群。
本发明是通过以下技术方案来实现：
本发明公开了糖蛋白Apolipoprotein D可以作为血清检测孤独症的诊断标记物的用途。
本发明公开了糖蛋白Apolipoprotein D在制备血清检测孤独症诊断试剂或诊断试剂盒中的用途。
所述糖蛋白Apolipoprotein D为载脂蛋白，在孤独症血清中高表达。
在糖蛋白Apolipoprotein D上具有能够被凝集素MAL-II识别的糖链Siaα 2-3Gal/GalNAc。
能够通过凝集素/糖-抗体芯片对血清中的糖蛋白Apolipoprotein D表达进行检测。
糖蛋白Apolipoprotein D在孤独症患儿血清中表达较正常儿童血清中的表达上调1.9倍。
与现有技术相比，本发明具有以下有益的技术效果：
本发明公开了一种孤独症血清糖蛋白标记物的用途，通过凝集素芯片联合蛋白质谱正向和凝集素/糖-抗体芯片反向同时验证了在ASD血清中高表达的糖蛋白Apolipoprotein D(APOD)，此蛋白可以作为孤独症诊断的血清糖蛋白标记物。本发明填补了孤独症生化诊断的空白。
本发明通过制备凝集素芯片，将ASD血清与TD血清标记cy3后与凝集素芯片杂交，鉴定出在ASD中高表凝集素MAL-II；其次将血清样本点在芯片上，cy3标的MAL-II与其杂交，反向验证ASD组的MAL-II修饰蛋白表达明显高于TD组；最后将MAL-II与磁珠偶联，偶联磁珠的MAL-II与血清样本结合，将与MAL-II连接糖链结合的蛋白洗脱、解离后，用蛋白质谱鉴定洗脱蛋白，鉴定出在ASD血清中高表达的糖蛋白是APOD。该糖蛋白可以作为ASD血清标记物在临床诊断中予以应用。
附图说明
图1a为50例ASD患儿凝集素芯片杂交图；
图1b为50例TD儿童凝集素芯片杂交图；
图2为凝集素芯片反应聚类分析图；
图3为血清样本中MAL-II western blot检测结果图；
图4a为血清样本芯片；
图4b为杂交信号结果统计图；
图5为MAL-II结合糖蛋白的分离与鉴定示意图；
图6为SDS-PAGE银染分析分离出来的MAL-II结合糖蛋白鉴定结果图；
图7a为糖蛋白抗体芯片；
图7b为糖蛋白抗体反向验证结果图。
具体实施方式
下面结合具体的实施例对本发明做进一步的详细说明，所述是对本发明的解释而不是限定。
1、样本的收集
分别自西安市儿童医院、西安交通大学第一附属医院及第二附属医院收集确诊ASD 65例患儿血清及正常65例对照儿童血清。其中的50例用于凝集素芯片的检测，15例用于验证实验。抽取的血液在室温静置25min后，1500g离心10min，收集上清，保存于-80℃冰箱至检测时。
2、凝集素芯片检测及样品分析
将50例ASD和50例TD血清随机按每10例一组，每组分为ASD-1，ASD-2，ASD-3，ASD-4，ASD-5及TD-1，TD-2，TD-3，TD-4，TD-5。每10例血清分别混合为混合样本，用cy3标记后与凝集素芯片进行杂交。杂交信号扫描后，用Genepix 3.0软件分析结果。
3、用血清芯片验证凝集素芯片结果
1)分别取15例ASD和TD血清样本，制备为血清芯片。
2)用cy3标记MAL-II。
3)将标记好的MAL-II与血清芯片杂交。
4)杂交信号扫描后用Genepix 3.0软件分析结果。
4、分离和鉴定差异表达糖蛋白
1)用磁珠偶联MAL-II凝集素；
2)将偶联好磁珠的MAL-II与两组混合血清分别共孵育，之后洗脱MAL-II结合蛋白；
3)洗脱后的MAL-II结合蛋白用胰蛋白酶和糖苷酶消化后，收集糖蛋白混合物；
4)用蛋白质谱鉴定糖蛋白。
5、凝集素/糖-抗体芯片验证ASD患儿血清中APOD的高表达
1)将APOD抗体点到芯片上。
2)将血清样品与芯片杂交。
3)洗脱、甩干后与cy3标记的MAL-II杂交。
4)洗脱、甩干后用Genepix 4000B扫描、Genepix Pro 3.0分析。
结果参见附图，图1a为50例ASD患儿凝集素芯片杂交图，图1b为50例TD儿童凝集素芯片杂交图，可见ASD组与MAL-II凝集素结合的糖链高表达。
参照图2，凝集素芯片反应聚类分析图。将Genepix 3.0分析结果用Expander 6.0(http://acgt.cs.tau.ac.il/expander/)分析，生成聚类图。
参照图3所示，血清样本中MAL-II western blot检测。结果所示，在ASD组，MAL-II凝集素结合糖蛋白明显上调。
血清样本芯片与MAL-II杂交图参照图4a，为ASD组与TD组血清样本各取15例点于芯片上，与MAL-II杂交，结果显示ASD组与MAL-II结合的糖蛋白较正常组上调。图4b为杂交信号结果统计图。
糖蛋白的分离鉴定，参见图5，为MAL-II结合糖蛋白的分离与鉴定示意图；图6是SDS-PAGE银染分析分离出来的MAL-II结合糖蛋白。ASD组洗脱出的蛋白量高于TD组。
糖蛋白抗体芯片反向验证，参见图7a用凝集素/糖-抗体芯片检测ASD和TD血清样品中的APOD表达。即将APOD抗体点样在芯片上，首先用ASD和TD血样与芯片杂交，洗脱未结合蛋白后，与cy3标记的MAL-II杂交，之后用Genepix 4000B扫描杂交信号，Genepix Pro3.0软件分析荧光信号值。结果显示ASD组荧光值明显高于TD组，与前述结果相符。图7b为ROC曲线分析血清中α2-3唾液酸化APOD蛋白的相对量，AUC为0.88，ASD组相对于TD组其特异性和敏感性分别为86.7％和80.6％。
综上所述，本发明通过凝集素芯片联合蛋白质谱正向和凝集素/糖-抗体芯片反向同时验证了在ASD血清中高表达的糖蛋白APOD，此蛋白可以作为孤独症诊断的血清糖蛋白标记物，填补了孤独症生化诊断的空白。
Claims (5)
1.糖蛋白Apolipoprotein D在制备血清检测孤独症诊断试剂或诊断试剂盒中的用途。
2.如权利要求1所述的用途，其特征在于，所述糖蛋白Apolipoprotein D为载脂蛋白，在孤独症血清中高表达。
3.如权利要求1所述的用途，其特征在于，在糖蛋白Apolipoprotein D上具有能够被凝集素MAL-II识别的糖链Siaα2-3Gal/GalNAc。
4.如权利要求3所述的用途，其特征在于，能够通过凝集素/糖-抗体芯片对血清中的糖蛋白Apolipoprotein D表达进行检测。
5.如权利要求1所述的用途，其特征在于，糖蛋白Apolipoprotein D在孤独症患儿血清中表达较正常儿童血清中的表达上调1.9倍。
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| CN109946447A (zh) * | 2019-03-13 | 2019-06-28 | 深圳大学 | 一种用于检测孤独症谱系障碍的诊断标志物、设备及应用 |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107796946A (zh) * | 2017-10-20 | 2018-03-13 | 中国医学科学院基础医学研究所 | 尿液中冠心病的蛋白标志物及其用途 |
| CN107796946B (zh) * | 2017-10-20 | 2019-10-25 | 中国医学科学院基础医学研究所 | 尿液中冠心病的蛋白标志物及其用途 |
| CN109946447A (zh) * | 2019-03-13 | 2019-06-28 | 深圳大学 | 一种用于检测孤独症谱系障碍的诊断标志物、设备及应用 |
| CN110045125A (zh) * | 2019-04-03 | 2019-07-23 | 中国医学科学院北京协和医院 | 一种用于诊断腹膜后纤维化的生物标志物及其用途 |
| CN110045125B (zh) * | 2019-04-03 | 2022-08-09 | 中国医学科学院北京协和医院 | 一种用于诊断腹膜后纤维化的生物标志物及其用途 |
| CN111471759A (zh) * | 2020-05-08 | 2020-07-31 | 西安交通大学 | 一种孤独症血清神经元来源外泌体标志物ostc的应用 |
| CN114457153A (zh) * | 2022-03-15 | 2022-05-10 | 西安交通大学 | 一种孤独症血清神经元来源外泌体标志物chrm1的应用 |
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