CN116930512B - 一种用于脑卒中再发风险分析的生物标志物及其应用 - Google Patents
一种用于脑卒中再发风险分析的生物标志物及其应用 Download PDFInfo
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Abstract
本发明属于生物标志物技术领域,具体地说,涉及一种用于脑卒中再发风险分析的生物标志物及其应用。所述的生物标志物为Notch1配体。所述的Notch1配体包括DLL1和Jagged1中的一种或两种。本发明提供了用于脑卒中再发风险分析的生物标志物及其应用。凭借这些生物标志物,可制备脑卒中再发风险分析试剂或试剂盒,以预测受试者患急性缺血性脑卒中再发的风险,或监测患者或受试者急性缺血性脑卒中再发的发生。本发明提供的生物标志物,有助于更好地了解脑卒中再发的病理生理,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。
Description
技术领域
本发明属于生物标志物技术领域,具体地说,涉及一种用于脑卒中再发风险分析的生物标志物及其应用。
背景技术
脑血管疾病(Cerebral vascular 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。
我国现有卒中患者1494万人,每年新发病例330万人,其中70%以上为缺血性脑卒。研究发现,我国的脑卒中患者中,发生脑卒中后的1年内,每6个人中,就有1人复发;3~5年后,每3个人中,就有1人复发。与国际数据相比,我国的脑卒中复发率要高出1倍。脑卒中的高复发率已经成为导致脑卒中患者致残、致死的重要原因。临床研究表明,既往发生过脑卒中的患者心脑血管事件复发的风险很高,继发事件主要包括心肌梗死和脑卒中再发。动脉粥样硬化是心肌梗死和脑卒中首发与再发的共同病理学基础。然而,目前尚不明确脑卒中首发后为何加速外周动脉粥样硬化。因此,进一步探究脑卒中加速外周动脉粥样硬化的病理机制具有重要的科学意义及临床价值。
生物标志物可提示脑卒中加速外周动脉粥样硬化的病理生理过程,对脑卒中复发风险具有预测价值,为临床诊断及治疗提供依据。但是至今尚无公认的对脑卒中再发风险分析的生物标志物,无法满足临床需求。因此,寻找快速准确的脑卒中再发风险分析的生物学标志物具有重要的临床应用前景,将有助于更好地了解脑卒中再发病理机制、并发现新的生物标志物,从而改善脑卒中患者的管理。
有鉴于此,特提出本发明。
发明内容
为了解决现有技术中存在的问题,本发明的目的在于提供一种用于脑卒中再发风险分析的生物标志物及其应用。
为了实现本发明的目的,本发明采用如下技术方案:
一种用于脑卒中再发风险分析的生物标志物,其中,所述的生物标志物为Notch1配体。
进一步地,所述的Notch1配体包括DLL1和Jagged1中的一种或两种。
进一步地,所述的生物标志物来自血浆外泌体。
本发明还提供所述的Notch1配体作为脑卒中再发生物标志物在制备脑卒中再发风险分析试剂或试剂盒中的应用。
进一步地,所述的Notch1配体包括DLL1和Jagged1中的一种或两种。
进一步地,所述的生物标志物来自血浆外泌体。
本发明还涉及所述的Notch1配体在制备预防脑卒中再发药物中的应用。
进一步地,所述的药物通过抑制Notch1信号通路来预防脑卒中再发。
进一步地,所述的药物通过抑制Notch1信号通路降低Notch1配体中DLL1和Jagged1的表达来预防脑卒中再发。
与现有技术相比,本发明具有如下优点:
本发明提供了用于脑卒中再发风险分析的生物标志物及其应用。凭借这些生物标志物,可制备脑卒中再发风险分析试剂或试剂盒,以预测受试者患急性缺血性脑卒中再发的风险,或监测患者或受试者急性缺血性脑卒中再发的发生。
本发明提供的生物标志物,有助于更好地了解脑卒中再发的病理生理,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
图1为脑卒中病人血浆外泌体及外泌体中蛋白表达情况;其中,A图示出了血浆外泌体的TEM图像和NTA鉴定纯化外泌体表征,比例尺,50nm;B图分别显示健康人和脑卒中病人血浆外泌体中蛋白的含量;
图2为脑卒中病人血浆外泌体中Jagged1、Jagged2和DLL1、DLL3、DLL4的表达结果;其中,A图示出了ELISA检测脑卒中患者和健康对照个体循环外泌体DLL1、及血浆DLL1的含量,脑卒中早期(发病小于2天)和脑卒中晚期(发病后第14天),(Means±SEM,*p<0.05,**p<0.01;基于Dunn多重比较检验的单因素方差分析,健康对照组、脑卒中早期状态的患者和脑卒中晚期状态的患者中n=17、25、25);B图示出了ELISA检测脑卒中患者和健康对照个体循环外泌体Jagged1及血浆Jagged1的含量,脑卒中早期(发病小于2天)和脑卒中晚期(发病后第14天),(Means±SEM,*p<0.05,**p<0.01;基于Dunn多重比较检验的单因素方差分析,健康对照组、脑卒中早期状态的患者和脑卒中晚期状态的患者中n=17、25、25);C图示出了ELISA检测脑卒中患者和健康对照个体循环外泌体DLL3及血浆DLL3的含量,脑卒中早期(发病小于2天)和脑卒中晚期(发病后第14天),(Means±SEM,*p<0.05,**p<0.01;基于Dunn多重比较检验的单因素方差分析,健康对照组、脑卒中早期状态的患者和脑卒中晚期状态的患者中n=17、25、25);D图示出了ELISA检测脑卒中患者和健康对照个体循环外泌体DLL4及血浆DLL4的含量,脑卒中早期(发病小于2天)和脑卒中晚期(发病后第14天),(Means±SEM,*p<0.05,**p<0.01;基于Dunn多重比较检验的单因素方差分析,健康对照组、脑卒中早期状态的患者和脑卒中晚期状态的患者中n=17、25、25);E图示出了ELISA检测脑卒中患者和健康对照个体循环外泌体Jagged2及血浆Jagged2的含量,脑卒中早期(发病小于2天)和脑卒中晚期(发病后第14天),(Means±SEM,*p<0.05,**p<0.01;基于Dunn多重比较检验的单因素方差分析,健康对照组、脑卒中早期状态的患者和脑卒中晚期状态的患者中n=17、25、25);
图3为MCAO小鼠远端血管内皮细胞Notch1的表达结果;其中,A图示出了Notch1分别在对照和MCAO组的表达情况(Means±SEM,*p<0.05;未配对双尾t检验,n=6);B图示出了流式细胞术分析MCAO后小鼠血管内皮细胞Notch1的表达情况;C图示出了Notch1表达水平的统计图(Means±SEM,***p<0.01;基于Dunn多重比较检验的单因素方差分析,n=6);
图4为小鼠MCAO组和假手术组流出道处斑块面积图;其中,A图示出了实验设计示意图,西方饮食喂养的APOE-小鼠接受MCAO手术,4周后取材;B图示出了小鼠主动脉油红O染色,分析血管大脂质沉积,比例尺:4mm;C图示出了小鼠心脏流出道进行HE染色,对动脉粥样硬化斑块面积统计分析(比例尺:500um,Means±SEM,**p<0.0l;基于Dunn多重比较检验的单因素方差分析,n=6)。
具体实施方式
以下为本发明的具体实施方式,所述的实施例是为了进一步描述本发明,而不是限制本发明。
试验例1、脑卒中病人血浆外泌体及外泌体中蛋白表达情况
1、脑卒中病人的收集
本研究纳入自2022年3月至2023年1月天津医科大学总医院住院患者。急性缺血性脑卒中患者入组标准:(1)发病年龄位于18-80岁之间;(2)根据患者临床及影像学资料明确诊断为急性脑梗死患者:纳入临床信息包括:患者一般基本信息及临床特点,大动脉粥样硬化性高危因素(高血压、糖尿病、冠心病、高血脂等),急性期治疗方案。脑卒中早期(发病小于2天)和脑卒中晚期(发病后第14天)。
2、提取血浆外泌体
利用Invitrogen(4484450)血浆外泌体提取试剂盒提取血浆外泌体。
提取方法为:血浆样本,室温1000g离心20min,再次取上清于新的EP管,清除碎片;取得100μl血浆样本,加50μlPBS,混匀加入,30μl外泌体分离液,再次混匀,室温静置10min;室温10000g离心5min,EP管底部沉淀即为外泌体。
3、实验方法
利用蛋白质芯片技术分析,筛选出差异表达蛋白,得到复发、预后评估生物标志物的检测组合。
芯片检测操作如下:
1)芯片封闭;
2)芯片杂交:
1、完全移除每个孔中的样品稀释液;每孔加入经样品稀释液稀释的相应标准品和样品100μL,贴上胶条,置于水平摇床,55rpm,4℃,过夜。
2、完全移除每个孔中的的样品,加入150μL 1×洗涤缓冲液I,室温轻摇洗涤5次,每次5min。
3、将芯片放入洗涤盒中,加入足够量的1×洗涤缓冲液I;置于水平摇床,70rpm,室温,洗涤2次,每次10min;完全移除1×洗涤缓冲液I,加入150μL 1×洗涤缓冲液II;置于水平摇床,70rpm,室温,洗涤2次,每次5min。
4、取出Biotin-Antibody Cocktail,将其离心后加入1400μL样品稀释液稀释,涡旋混匀;每孔加入80μL稀释后的Biotin-Antibody Cocktail,室温,孵育2hr。
5、从每个孔中完全移除Biotin-Antibody Cocktail,按步骤2、3洗涤。
6、取出Cy3-Streptavidin,离心后加入1400μL样品稀释液,轻摇混匀。
7、每孔加入80μL稀释后的Cy3-Streptavidin,贴上胶条,铝箔避光,室温,孵育1hr。
8、从每孔中完全移除Cy3-Streptavidin,按步骤2洗涤。
3)芯片扫描:
1、完全移除1×洗涤缓冲液I,将芯片框架卸下。
2、在洗涤盒中加入足够量的1×洗涤缓冲液I;室温,轻摇洗涤15min。
3、移除1×洗涤缓冲液I,在洗涤盒中加入足够量的1×洗涤缓冲液II,室温,轻摇洗涤5min。
4、1000rpm离心3min,甩干芯片。
5、Agilent SureScan Dx Microarray Scanner芯片扫描仪,于532nm,Power 100%下扫描芯片。
4)数据结果:
原始数据、归一化数据、标准曲线及方程、样本检测浓度/原液浓度、组间比较。
4、实验结果
实验结果见图1和图2所示。
从图1可以看出,脑卒中病人血浆外泌体中DLL1和Jagged1配体含量明显增加。
从图2可以看出,脑卒中病人血浆外泌体中DLL1和Jagged1配体含量明显增加持续升高,Jagged2、DLL3和DLL4的含量则无明显改变。
试验例2、MCAO后小鼠血管内皮细胞Notch1的表达情况
1、实验动物与试剂
动物:雌雄8周龄C657B6L小鼠30只。
试剂:1%异氟烷。
2、大脑中动脉栓塞(MCAO)模型构建
小鼠用1%异氟烷诱导麻醉后,参照Zea Longa方法诱导60min构建MCAO模型。将5-0的线栓,栓入颈内动脉颅内段,MCAO模型成功标准为小鼠的栓塞对侧的肢体偏瘫,行走时向梗塞对侧转圈。假手术组的小鼠仅接受手术,但是栓线不进入颅内段,在颈内和颈外动脉分叉处前行0.5cm即固定结扎,作为对照组。
3、实验方法
MCAO后0、3、28天,通过流式细胞术分析,小鼠主动脉内皮细胞中Notch1的表达情况。
4、实验结果
实验结果如图3所示。
从图3可以看出,脑卒中持续性上调外周血管内皮细胞Notch1的表达。
试验例3、MCAO和假手术后小鼠动脉粥样硬化进展情况
1、实验动物与试剂
动物:雄性8周龄Apoe-/-小鼠,共12只。
试剂:高胆固醇(HCD),1%异氟烷。
2、大脑中动脉栓塞(MCAO)模型构建
同试验例2。
3、实验方法
雄性8周龄Apoe-/-小鼠给予高胆固醇(HCD)饮食喂养4周之后,分别进行MCAO手术和假手术(同试验例2)。分别利用油红O染色和HE染色分析小鼠血管内膜层脂质沉积及心脏流出道处动脉粥样硬化斑块面积。(病理染色,每组小鼠6只)。
4、实验结果
实验结果如图4所示。
从图4可以看出,与假手术组小鼠相比,MCAO小鼠血管内膜层脂质沉积明显增加,小鼠心脏流出道处斑块面积明显增大。
Claims (7)
1.一种用于脑卒中再发风险分析的生物标志物,其特征在于,所述的生物标志物为Notch1配体,所述的Notch1配体为DLL1和Jagged1中的一种或两种。
2.根据权利要求1所述的生物标志物,其特征在于,所述的生物标志物来自血浆外泌体。
3.Notch1配体作为脑卒中再发生物标志物在制备脑卒中再发风险分析试剂或试剂盒中的应用,其特征在于,所述的Notch1配体为DLL1和Jagged1中的一种或两种。
4.根据权利要求3所述的应用,其特征在于,所述的生物标志物来自血浆外泌体。
5.Notch1配体在制备预防脑卒中再发药物中的应用,其特征在于,所述的Notch1配体为DLL1和Jagged1中的一种或两种。
6.根据权利要求5所述的应用,其特征在于,所述的药物通过抑制Notch1信号通路来预防脑卒中再发。
7.根据权利要求6所述的应用,其特征在于,所述的药物通过抑制Notch1信号通路降低Notch1配体中DLL1和Jagged1的表达来预防脑卒中再发。
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