CN113791219B - 用于急性缺血性脑卒中复发风险分析的生物标志物及其应用 - Google Patents
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Abstract
本发明公开了用于急性缺血性脑卒中复发风险分析的生物标志物及其应用。通过开发可检测目标蛋白质表达水平的试剂或产品,可对急性缺血性脑卒中的早期复发进行有效分析,所述目标蛋白质为BID,CAH3,CO1A2,HORN,ITAM,KAD1,MYL9,PARK7,PRDX1,RSU1,TAGLN2,TRML1中的一种或多种。本发明进一步地针对CCS1、CCS3、CCS5亚型的急性缺血性脑卒中开发了特定的生物标志物及其组合,可更加有针对性地对不同亚型的急性缺血性脑卒中复发进行有效分析。
Description
技术领域
本发明涉及生物标志物技术领域,尤其涉及用于急性缺血性脑卒中复发风险分析的生物标志物。
背景技术
脑血管疾病(Cerebralvascular disease,CVD)包括短暂性缺血发作(Transientischemic attack,TIA)和脑卒中(Stroke)。其中脑卒中已经超越心血管疾病和恶性肿瘤成为我国居民致死、致残的首要病因,造成巨大的经济和社会负担,包括急性缺血性脑卒中(Acute ischemic stroke,AIS)和出血性卒中(Intracerebral hemorrhage,ICH)。AIS又称急性脑梗死,是各种原因导致的脑组织血液供应障碍,并由此产生的缺血缺氧性坏死,进而出现神经功能障碍的一组临床综合征。急性缺血性脑卒中是最常见的卒中类型,约占全部卒中的60%-80%。然而,急性缺血性脑卒中的治疗却十分有限,目前临床上证明有效的急性期治疗方案为静脉阿替普酶(tPA)溶栓或血管内取栓实现缺血区域的血管再通。但是由于治疗时间窗窄,以及脑水肿、出血转化等并发症风险增加,血管内取栓需要复杂的技术的专业团队保障,临床上仅15%患者可以获益。
急性缺血性脑卒中病人血脑屏障的完整性破坏,但是外周血脑损伤释放的蛋白质和其他物质的出现时间点,含量以及是否能反映脑损伤的情况以及病人的预后,是脑卒中领域悬而未决的问题,具有重要的临床应用前景。目前国际、国内市场上没有用于急性缺血性脑卒中的预后和复发预警生物标志物,无法满足临床需求。因此,寻找预测急性缺血性脑卒中预后和复发的生物标志物已成为脑卒中管理的一个主要挑战。
发明内容
为了解决现有技术中存在的问题,本发明的目的是提供用于卒中复发风险预测的生物标志物及其应用。
为了实现本发明目的,本发明的技术方案如下:
第一方面,本发明提供了以下蛋白中的任意一种或多种作为急性缺血性脑卒中生物标志物在制备急性缺血性脑卒中复发风险分析(预测或辅助预测)试剂或试剂盒中的应用,所述蛋白包括:BID,CAH3(CA3),CO1A2,HORN(HRNR),ITAM(ITGAM),KAD1(AK1),MYL9,PARK7,PRDX1,RSU1,TAGLN2,TRML1。
第二方面,本发明提供用于检测目标蛋白质的试剂在制备用于预测或辅助预测急性缺血性脑卒中复发风险的产品中的应用,所述目标蛋白质为如下(a1)、(a2)或(a3):
(a1)KAD1(AK1)和TAGLN2蛋白;
(a2)CO1A2和MYL9蛋白,或MYL9和BID蛋白,或BID和TRML1蛋白;
(a3)ITAM(ITGAM)和TAGLN2蛋白,或CAH3(CA3)和TAGLN2蛋白,或TAGLN2和RSU1蛋白,或TAGLN2和PARK7蛋白,或CAH3(CA3)蛋白,或ITAM(ITGAM)蛋白,或TAGLN2和HORN(HRNR)蛋白,或TAGLN2蛋白,或ITAM(ITGAM)和PRDX1蛋白,或ITAM(ITGAM)和MYL9蛋白,或PRDX1和PARK7蛋白。
上述(a1)中的目标蛋白质,可对CCS1型卒中
第三方面,本发明提供用于预测或辅助预测急性缺血性脑卒中复发风险的试剂和试剂盒。
所述试剂包括检测受试者生物测试样本中以下至少一种生物标志物表达水平的试剂:BID,CAH3(CA3),CO1A2,HORN(HRNR),ITAM(ITGAM),KAD1(AK1),MYL9,PARK7,PRDX1,RSU1,TAGLN2,TRML1。
进一步地,所述试剂用于检测受试者生物测试样本中目标蛋白质的表达水平,所述目标蛋白质为如下(a1)、(a2)或(a3):
(a1)KAD1(AK1)和TAGLN2蛋白;
(a2)CO1A2和MYL9蛋白,或MYL9和BID蛋白,或BID和TRML1蛋白;
(a3)ITAM(ITGAM)和TAGLN2蛋白,或CAH3(CA3)和TAGLN2蛋白,或TAGLN2和RSU1蛋白,或TAGLN2和PARK7蛋白,或CAH3(CA3)蛋白,或ITAM(ITGAM)蛋白,或TAGLN2和HORN(HRNR)蛋白,或TAGLN2蛋白,或ITAM(ITGAM)和PRDX1蛋白,或ITAM(ITGAM)和MYL9蛋白,或PRDX1和PARK7蛋白。
所述试剂盒含有前述试剂。
第四方面,本发明提供用于预测或辅助预测急性缺血性脑卒中复发的系统,所述系统执行如下步骤:
(1)利用权利要求3或4所述的试剂检测受试者生物测试样品中相应生物标志物的表达量和/或活性数值;
(2)将检测到的生物标志物的表达量和/或活性数值与所述生物标志物的正常或参照表达量和/或活性数值进行对比。
作为优选,所述生物测试样品为血浆。
更进一步地,所述用于预测或辅助预测急性缺血性脑卒中复发的系统,包括数据输入模块、数据比较模块和结论输出模块;
所述数据输入模块用于输入检测得到的受试者生物测试样品中目标蛋白质表达量和/或活性数值;
所述数据比较模块用于将受试者生物测试样品中目标蛋白质表达量和/或活性数值与对照数值进行比较,所述对照数值为卒中复发低风险患者样本中目标蛋白质表达量和/或活性;
所述结论输出模块用于按照如下标准输出结论:如果受试者生物测试样品中目标蛋白质的表达量和/或活性数值大于对照数值,则受试者为或候选为急性缺血性脑卒中复发高风险患者;
所述目标蛋白质为如下(a1)、(a2)或(a3):
(a1)KAD1(AK1)和TAGLN2蛋白;
(a2)CO1A2和MYL9蛋白,或MYL9和BID蛋白,或ID和TRML1蛋白;
(a3)ITAM(ITGAM)和TAGLN2蛋白,或CAH3(CA3)和TAGLN2蛋白,或TAGLN2和RSU1蛋白,或TAGLN2和PARK7蛋白,或CAH3(CA3)蛋白,或ITAM(ITGAM)蛋白,或TAGLN2和HORN(HRNR)蛋白,或TAGLN2蛋白,或ITAM(ITGAM)和PRDX1蛋白,或ITAM(ITGAM)和MYL9蛋白,或PRDX1和PARK7蛋白。
所述大于具体可为具有统计学意义的大于。
所述急性缺血性脑卒中复发具体可为急性脑梗死或短暂性脑缺血的复发。
本发明的有益效果在于:
本发明提供了用于急性缺血性脑卒中复发风险预测的生物标志物及其应用。凭借这些生物标志物,可制备用于急性缺血性脑卒中复发风险预测的试剂或试剂盒,以预测受试者急性脑梗死或短暂性脑缺血的复发的风险。
本发明提供的生物标志物组,有助于更好地了解脑卒中的病理生理,将为诊断和预后提供新的机会,从而改善脑卒中患者的临床服务。
附图说明
此处的附图被并入说明书中并构成本说明书的一部分,示出了符合本发明的实施例,并与说明书一起用于解释本发明的原理。
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,对于本领域普通技术人员而言,在不付出创造性劳动性的前提下,还可以根据这些附图获得其他的附图。
图1为在复发和不复发组中筛选得到的存在差异表达的蛋白。
图2为CCS1、CCS3、CCS5型卒中筛选得到的存在差异表达的蛋白。
图3为CCS1型卒中生物标志物表达检测及ROC曲线。
图4为CCS5型卒中生物标志物表达检测及ROC曲线。
图5为CCS3型卒中生物标志物表达检测及ROC曲线。
具体实施方式
在本发明中,词语“包含”、“具有”、“包括”或“含有”是指包括在内的或开放式的,并不排除额外的、未引述的元件或方法步骤。与此同时,“包含”、“具有”、“包括”或“含有”也可以表示封闭式的,排除额外的、未引述的元件或方法步骤。
虽然所公开的内容支持术语“或”的定义仅为替代物以及“和/或”,但除非明确表示仅为替代物或替代物之间相互排斥外,权利要求中的术语“或”是指“和/或”。
在本发明中,术语“急性缺血性脑卒中(AIS)”又称急性脑梗死,是各种原因导致的脑组织血液供应障碍,并由此产生的缺血缺氧性坏死,进而出现神经功能障碍的一组临床综合征。急性缺血性脑卒中是最常见的卒中类型,约占全部卒中的60%-80%。
在本发明中,术语“生物标志物(Biomarker)”是指可以标记系统、器官、组织、细胞及亚细胞结构或功能的改变或可能发生的改变的生化指标。其可用于疾病诊断、判断疾病分期或者用来评价新药或新疗法在目标人群中的安全性及有效性等用途。
在本发明中,受试者(例如患者)的“风险评估”、“风险分类”、“风险鉴定”或“风险分级”是指评价包括生物标志物的因子以预测包括疾病发作或疾病进展的未来事件发生的风险,以便可以在更加知情的基础上做出关于受试者的治疗决定。
在本发明中,术语“预测”和相关术语是指特定病症(例如急性缺血性脑卒中疾病)的可能结果的描述。
在本发明中,“样品”、“生物样品”,“测试样品”、“样本”、“来自受试者的样品”和“患者样品”可以互换使用,并且可以是血液、组织、尿液、血清、血浆、羊水、脑脊液、胎盘细胞或组织、内皮细胞、白细胞或单核细胞的样品。以本文所讨论的某种方式或本领域已知的其它方式可以用于直接从患者获得样品,或者可以(例如通过过滤、蒸馏、提取、浓缩、离心,干扰组分的灭活和添加试剂等)预处理样品以改变样品的特性。
在本发明中,“标记”和“可检测标记”通常是指直接或间接连接到分析物结合分子(例如其抗体或分析物反应性片段)或分析物以使分析物结合分子(例如其抗体或分析物反应性片段、核酸探针等)与分析物之间发生反应的可检测部分,并且如此标记的分析物结合分子(例如其抗体或分析物反应性片段)或分析物被称为“可检测标记的”。标记可以(例如通过视觉或仪器手段)产生可检测的信号。在一些方面,标记可以是任何产生信号的部分,并且有时在本文中称为报告基团。如本文所用,标记(或信号产生部分)产生可测量的信号,该信号可通过外部手段检测(例如通过测量电磁辐射),并且依赖于所采用的系统,信号水平可以变化到标记在固体支持物(例如电极、微粒或珠子)环境中的程度。
在本发明中,检测生物标志物的水平的方法包括Western印迹分析,蛋白/肽功能测定,免疫组织化学分析,ELISA分析。示例性的,上述方法可以用于检测蛋白。
在本发明中,通过血浆的蛋白质组关联分析来检测急性缺血性脑卒中患者中潜在的候选生物标志物都是现有技术中已知的蛋白。具体来说:BID(BH3Interacting DomainDeath Agonist)为BH3相互作用域死亡激动剂(NCBI Entrez Gene:637),CAH3(CA3)(Carbonic anhydrase 3)为碳酸酐酶3(NCBI Entrez Gene:761),CO1A2(Collagen Type IAlpha 2 Chain)为I型胶原蛋白α2链(NCBI Entrez Gene:1278),HORN(HRNR)(Hornerin)为角蛋白(NCBI Entrez Gene:388697),ITAM(ITGAM)(Integrin Subunit Alpha M)为整合素亚基M(NCBI Entrez Gene:3684),KAD1(AK1)(Adenylate Kinase 1)为腺苷酸激酶1(NCBIEntrez Gene:203),MYL9(Myosin Light Chain 9)为肌球蛋白轻链9(NCBI Entrez Gene:10398),PARK7(Parkinsonism Associated Deglycase)为帕金森相关脱糖酶(NCBI EntrezGene:11315),PRDX1(Peroxiredoxin 1)为过氧化物酶1(NCBI Entrez Gene:5052),RSU1(Ras Suppressor Protein 1)为Ras抑制蛋白1(NCBI Entrez Gene:6251),TAGLN2(Transgelin 2)为转运蛋白2(NCBI Entrez Gene:8407),TRML1(Triggering ReceptorExpressed On Myeloid Cells Like 1)为髓细胞样诱发表达受体1(NCBI Entrez Gene:340205)。
本发明中采用的分子生物学方法,均可以参见“最新分子生物学实验方法汇编(Current Protocols in Molecular Biology,Wiley出版)”,“分子克隆实验指南(Molecular Cloning:A Laboratory Manual,冷泉港实验室出版)”等公开出版物中记载的相应方法。
实施例中采用的所有试剂,除非另有强调,否则均可以通过商业途径购买获得,或针对检测对象通过已知方法制备得到。
为了能够更清楚地理解本发明的上述目的、特征和优点,下面将对本发明的方案进行进一步描述。需要说明的是,在不冲突的情况下,本发明的实施例及实施例中的特征可以相互组合。
在下面的描述中阐述了很多具体细节以便于充分理解本发明,但本发明还可以采用其他不同于在此描述的方式来实施;显然,说明书中的实施例只是本发明的一部分实施例,而不是全部的实施例。
下面将结合实施例对本发明的优选实施方式进行详细说明。需要理解的是以下实施例的给出仅是为了起到说明的目的,并不是用于对本发明的范围进行限制。本领域的技术人员在不背离本发明的宗旨和精神的情况下,可以对本发明进行各种修改和替换。
实施例1
1、急性缺血性脑卒中病人及健康对照组的临床资料收集:卒中分型CCS分型、NIHSS评分、生化指标、影像等。
2、急性缺血性脑卒中病人及健康对照组的样本收集和储存。
外周血收集于含抗凝剂EDTA或肝素的紫色管中,样本采集后30min内离心,3000rpm 10min,2-8℃。收集上层血浆,分批储存于-80℃。样本避免反复冻融。注意:样本应充分离心,避免溶血或颗粒存在。
3、基因、蛋白组学技术分析,筛选出差异表达蛋白,形成复发、预后评估Biomarkerpanel。
3.1本项目采用下一代非标记定量蛋白质组学技术完成分析,在数据非依赖型采集(Data independent acquisition,DIA)模式下,它能够提供无与伦比的蛋白质组覆盖,同时实现每个样本大量蛋白质的精确、高度可重复的定量。DIA流程提供一个理想的差异表达蛋白质组定性分析或海量样品的蛋白质组定量平台。DIA流程基于三个必要步骤:
1)构建谱图库:谱图库收集了样本所有可检测的非冗余的高质量肽段信息(MS/MS谱图),作为后续数据分析的肽段鉴定模板。其中包含描述肽段谱峰特性的碎片离子强度和保留时间。谱图库利用对感兴趣的样品进行data dependent acquisition(DDA)检测采集的数据构建。
2)DIA模式下获取大量样本数据:Data independent acquisition(DIA,又称SWATH)模式利用最新的高分辨质谱实现在质量数和保留时间上同时采集肽段离子特性。与传统的提取单一离子进行碎裂分析的方法相比,DIA模式下质谱被设定为宽母离子窗口循环采集并同时碎裂多种肽段离子的分析方式。实现了将样品中所有可检测的蛋白质谱峰信息完整采集,从而能够高重复性的分析大量样本。
3)数据分析,在基于DIA的发现式的蛋白质组研究中,如何更好地进行蛋白质检测和定量目前依然是个巨大的挑战。采集肽段的信息虽然十分完整,但发现高度卷积。在这一步,我们用Spectronaut进行有效地去卷积,从而对数据进行精确地鉴定和定量分析。
3.2筛选出的差异表达蛋白方法:在97个复发、94个不复发样本中共检测到1788个蛋白质,通过Normalization方法,使所有蛋白质表达量的总和一致。在复发和不复发组中,call rate均大于30%的蛋白质进行筛选,得到1092个蛋白质,对于191个样本做差异表达,同时也对CCS1、CCS3、CCS5分别做差异表达。结果如图1、图2所示。总体差异表达分析,显著差异表达阈:下调0个,上调5个(T-test p-value<0.05&Fold Change>1.5),表达有差异趋势:下调5个,上调37个(T-test p-value<0.1&Fold Change>1.3)。进而确定研究蛋白优先级如下:
1级(共5个):总体中显著上调的,即同时满足Pvalue<0.05&Fold Change>1.5,按照在总体中的Fold Change降序排列,依次为SPTB、CA3、MYL9、ATP2A2、ARL6IP5、COL1A2,总体的call rate在37%-80%。
2级(共10个):总体中P value<0.05&CCS3中P value<0.05,且均为上调趋势的,按照在CCS3中的Fold Change降序排列,依次为TAGLN2、ARPC4、ZYX、TPI1、CAPN1、PNP、GSTO1、AK1、F11R、UBE2L3,CCS3的call rate在79%-100%。
3级(共5个):总体中P value<0.05&CCS5中P value<0.05,且均为上调趋势的,按照在CCS5中的Fold Change降序排列,依次为TUBA8、ESD、PARK7、SELP、PRDX1、HRNR、ITGAM,CCS5的call rate在69%-100%。
4级(共26个):CCS1中显著下调的,即P value<0.05,且Fold Change<0.667(没有上调的蛋白质),其中CCS1中的call rate高于70%的有20个,低于70%的有6个,分别按照Fold Change升序排列,依次为DBNL、FERMT3、SH3BGRL3、GDI1、EIF5A、GSTP1、GPI、PPBP、NME2,NME1-NME2、YWHAH、ARHGDIA、FKBP1A、HPSE、TPM3、BID、CAPNS1、AK2、TREML1、KRT83、CTSH、ADGRG2、RAB27B、VNN1、PSMA3、RHOC、POMGNT1、RSU1。在CCS1中下调的26个蛋白质,有8个和中性粒细胞活化相关、5个和凋亡相关。
4、使用质谱多反应监测(multiple reaction monitoring,MRM)对目标蛋白进行表达验证,MRM技术作为一种质谱检测的分析方法,具有特异性强、灵敏度高、准确度高、重现性好、线性动态范围宽、自动化高通量的突出优点,可应用于定量蛋白质组学研究。验证样本包括对照107个,复发107个,一例标本严重溶血剔除。共鉴定了213个样本的蛋白表达。
5、对筛选出的生物标志物组合进行多元线性回归分析并对回归模型进行ROC筛选,筛选靶点原则:1)验证后的蛋白差异表达,2)生物标志物预测性能评价。结果如表1、图3-图5所示。
表1
验证结果为KAD1(AK1)/TAGL2可作为CCS1型复发标记物,CO1A2/MYL9、MYL9/BID、BID/TRML1可作为CCS5型复发标记物,ITAM/TAGLN2、CAH3/TAGLN2、TAGLN2/RSU1、TAGLN2/PARK7、CAH3(CA3)、ITAM、TAGLN2/HORN、TAGLN2、ITAM/PRDX1、ITAM/MYL9、PRDX1/PARK7可作为CCS3型复发标记物。
以上所述仅是本发明的具体实施方式,使本领域技术人员能够理解或实现本发明。对这些实施例的多种修改对本领域的技术人员来说将是显而易见的,本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下,在其它实施例中实现。因此,本发明将不会被限制于本文所述的这些实施例,而是要符合与本文所公开的原理和新颖特点相一致的最宽的范围。
Claims (3)
1.检测以下蛋白组合的试剂在制备用于分析CCS1型急性缺血性脑卒中复发风险的产品中的应用,
其特征在于,所述蛋白组合为腺苷酸激酶1(AK1)和转运蛋白2(TAGLN2)。
2.检测以下蛋白组合的试剂在制备用于分析CCS5型急性缺血性脑卒中复发风险的产品中的应用,
其特征在于,所述蛋白组合为:
I型胶原蛋白α2链(CO1A2)和肌球蛋白轻链9(MYL9);
肌球蛋白轻链9(MYL9)和BH3相互作用域死亡激动剂(BID);
BH3相互作用域死亡激动剂(BID)和髓细胞样诱发表达受体1(TRML1)。
3.检测以下蛋白或蛋白组合的试剂在制备用于分析CCS3型急性缺血性脑卒中复发风险的产品中的应用,
其特征在于,所述蛋白或蛋白组合为:
转运蛋白2(TAGLN2);
转运蛋白2(TAGLN2)和Ras抑制蛋白1(RSU1);
转运蛋白2(TAGLN2)和帕金森相关脱糖酶(PARK7);
转运蛋白2(TAGLN2)和角蛋白(HORN);
过氧化物酶1(PRDX1)和帕金森相关脱糖酶(PARK7)。
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