CN114150057A - 一种诊断阿尔茨海默病的外泌体蛋白及其用途 - Google Patents
一种诊断阿尔茨海默病的外泌体蛋白及其用途 Download PDFInfo
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Abstract
本申请公开了一种诊断受试者是否患阿尔茨海默病的外泌体蛋白组合,以及用于确定生物样品中生物标志物水平的试剂在制备试剂盒中的用途。本申请的试剂盒能够替代传统的脑脊液检测,通过6种外泌体蛋白的组合实现对AD的诊断,并且,不仅能够区分AD患者与正常人员,还具有预测认知功能障碍的潜力。
Description
技术领域
本申请涉及医药领域、病毒学领域和免疫学领域,特别是免疫学诊断领域。本申请具体涉及一种诊断受试者是否患阿尔茨海默病的试剂盒,以及用于确定生物样品中生物标志物水平的试剂在制备试剂盒中的用途。
背景技术
阿尔茨海默病(Alzheimer’s disease, AD)是最常见的引起痴呆的神经系统退行性疾病。随着人口老龄化加重,AD带来了严重的社会和经济负担。目前脑脊液和神经影像学中的生物标记物是常规临床诊疗中最有效的AD生物标记物。然而,多为侵入性的且成本昂贵,难以在临床实践中普遍应用。因此,发现外周生物标志物来区分AD患者与健康人群是非常必要的。
外泌体是指各种细胞释放的纳米级细胞外囊泡,广泛存在于几乎所有的体液中。外泌体含有蛋白质、核酸和其他细胞成分,参与神经系统的各种生理和病理过程,包括神经炎症、突触可塑性和病理分子的传播。
蛋白组学是对蛋白质集体量化的一种分析方法,是发现新的生物标志物的有力工具,并且有助于我们理解AD的机制途径。
基于上述问题,急需一种能够有效诊断AD的方法。
发明内容
本申请发明人通过分析两个独立的数据集中AD患者与正常人员的外泌体蛋白的差异并使用差异外泌体蛋白组来建立AD诊断模型,因此,本申请的外泌体蛋白有助于AD的诊断。
因此,在第一方面,本申请提供了一种用于诊断受试者是否患阿尔茨海默病的风险的方法,其包括。
(1)从受试者获得包含生物标志物的生物样品。
(2)测定生物样品中生物标志物的水平。
(3)基于所述生物标志物的水平,诊断受试者是否患阿尔茨海默病。
其中,所述生物标志物为Ig样结构域包含蛋白(Ig-like domain-containingprotein,A0A0G2JRQ6)、补体C1q亚单位C(complement C1q subcomponent subunit C,C1QC)、补体成分C9(complement component C9,CO9)、血小板糖蛋白Ibβ链(plateletglycoprotein Ib beta chain,GP1BB)、RAS抑制蛋白1(ras suppressor protein 1,RSU1)、去整合素和金属蛋白酶结构域10(disintegrin and metalloproteinase domain10,ADA10)。
在某些实施方案中,所述生物样品选自全血,血清,血浆或脑脊液。在某些实施方案中,所述生物样品选自全血,血清和血浆。
在某些实施方案中,所述生物样品选自全血,血清和血浆。在此类实施方案中,优选地,在进行步骤(2)之前,对所述生物样品进行预处理,以获得外泌体;然后进行步骤(2),即,测定外泌体中生物标志物的水平。对生物样品(例如全血,血清和血浆)进行处理以获得外泌体的方法是本领域技术人员已知的。例如,可使用商业化的试剂盒(例如ExoQuick、Exoeasy)从生物样品(例如全血,血清和血浆)中分离获得外泌体。
在某些实施方案中,在步骤(2),通过光谱、液相或气相色谱、质谱、与质谱联用的液相或气相色谱来测定所述生物样品中生物标志物的水平。
在某些实施方案中,提取的肽段通过色谱柱(例如,Acclaim-PepMap μ-precolumn)进行分析。在某些优选的实施方案中,二元流动相为0.1%甲酸-水和0.1%甲酸-乙腈。
在某些实施方案中,在步骤(3)中,通过将所述生物标志物的水平与参考值进行比较,从而诊断受试者是否患阿尔茨海默病。在此类实施方案中,所述生物标志物的水平可以是所述生物标志物的蛋白质水平或mRNA水平。
在某些实施方案中,所述生物标志物的水平是所述生物标志物的蛋白质水平。在此类实施方案中,优选地,所述参考值是所述生物标志物在获自正常人群的生物样品中的水平或范围。在某些实施方案中,通过色谱和/或质谱法的测定、荧光测定、电泳、免疫亲和、杂交、免疫化学、紫外光谱(ultra violet,UV)、荧光分析、放射化学分析、近红外光谱(nearinfrared reflectance,NIR)、核磁共振光谱(nuclear magnetic resonance,NMR)、光散射分析(light scattering,LS)和比浊法来测定所述生物样品中生物标志物的水平。
在某些实施方案中,所述生物标志物的水平是编码所述生物标志物的mRNA的水平。在此类实施方案中,优选地,所述参考值是所述mRNA在获自正常人群的生物样品中的水平或范围。在某些实施方案中,通过定量PCR来测定所述生物样品中生物标志物的水平。
在某些实施方案中,相对于参考值,Ig样结构域包含蛋白、补体C1q亚单位C、补体成分C9、血小板糖蛋白Ibβ链和RAS抑制蛋白1的水平的升高表明,受试者患有AD。在某些实施方案中,相对于参考值,去整合素和金属蛋白酶结构域10的水平的降低表明,受试者患有AD。
在某些实施方案中,在步骤(3)中,使用弹性网络回归对所述6种生物标志物的水平进行岭回归,从而获得预测模型;然后,使用所述预测模型诊断受试者是否患有AD。在此类实施方案中,所述生物标志物的水平可以是所述生物标志物的蛋白质水平或mRNA水平。在某些优选实施方案中,所述生物标志物的水平是所述生物标志物的蛋白 质水平。
在某些实施方案中,所述受试者为哺乳动物,例如人。
在某些实施方案中,所述Ig样结构域包含蛋白的氨基酸序列如SEQ ID NO:1所示。在某些实施方案中,所述补体C1q亚单位C的氨基酸序列如SEQ ID NO: 2所示。在某些实施方案中,所述补体成分C9的氨基酸序列如SEQ ID NO:3所示。在某些实施方案中,所述血小板糖蛋白Ibβ链的氨基酸序列如SEQ ID NO:4所示。在某些实施方案中,所述RAS抑制蛋白1的氨基酸序列如SEQ ID NO:5所示。在某些实施方案中,所述去整合素和金属蛋白酶结构域10的氨基酸序列如SEQ ID NO:6所示。
在某些实施方案中,所述方法能够诊断受试者是否患阿尔茨海默病。
在第二方面,提供了一种用于确定生物样品中生物标志物水平的试剂在制备试剂盒中的用途,所述试剂盒用于诊断受试者是否患阿尔茨海默病的风险;其中,所述生物标志物为Ig样结构域包含蛋白、补体C1q亚单位C、补体成分C9、血小板糖蛋白Ibβ链、RAS抑制蛋白1和去整合素和金属蛋白酶结构域10。
在某些实施方案中,所述生物标志物的水平是所述生物标志物的蛋白质或mRNA水平。
在某些实施方案中,所述生物标志物的水平是所述生物标志物的蛋白质水平。在某些实施方案中,所述试剂(例如第一、第二、第三、第四、第五和/或第六试剂或试剂组合)通过以下方法测定所述生物样品中生物标志物的水平:色谱和/或质谱法的测定、荧光测定、电泳、免疫亲和、杂交、免疫化学、紫外光谱(UV)、荧光分析、放射化学分析、近红外光谱(NIR)、核磁共振光谱(NMR)、光散射分析(LS)和比浊法。
在某些实施方案中,所述试剂通过光谱、液相或气相色谱、质谱、与质谱联用的液相或气相色谱来测定所述生物样品中生物标志物的水平。
在某些实施方案中,所述试剂盒还包括用于光谱的试剂和/或耗材,用于色谱的试剂和/或耗材,用于质谱的试剂和/或耗材,或其任何组合。
在某些实施方案中,所述用于色谱的试剂和/或耗材选自色谱柱,乙腈水溶液(例如,2%乙腈水溶液,100%乙腈水溶液),三氟乙酸,甲酸,或其任何组合。
在某些实施方案中,所述用于质谱的试剂和/或耗材选自质谱柱,甲酸,乙腈,或其任何组合。
在某些实施方案中,所述生物标志物的水平是编码所述生物标志物的mRNA的水平。在某些实施方案中,所述试剂(例如第一、第二、第三、第四、第五和/或第六试剂或试剂组合)通过定量PCR来测定所述生物样品中生物标志物的水平。
在某些实施方案中,所述第一试剂或试剂组合包含能够定量编码Ig样结构域包含蛋白的mRNA水平的引物和/或探针。在某些实施方案中,所述第二试剂或试剂组合包含能够定量编码补体C1q亚单位C的mRNA水平的引物和/或探针。在某些实施方案中,所述第三试剂或试剂组合包含能够定量编码补体成分C9的mRNA水平的引物和/或探针。在某些实施方案中,所述第四试剂或试剂组合包含能够定量编码血小板糖蛋白Ibβ链的mRNA水平的引物和/或探针。在某些实施方案中,所述第五试剂或试剂组合包含能够定量编码RAS抑制蛋白1的mRNA水平的引物和/或探针。在某些实施方案中,所述第六试剂或试剂组合包含能够定量编码去整合素和金属蛋白酶结构域10的mRNA水平的引物和/或探针。
在某些实施方案中,所述生物样品为获自受试者的全血,血清,血浆或脑脊液。在某些实施方案中,所述生物样品选自全血,血清,和血浆。
在某些实施方案中,所述生物样品包含外泌体。
在某些实施方案中,所述试剂盒还包含,对生物样品进行预处理的预处理试剂或试剂组合。
在某些实施方案中,所述预处理试剂或试剂组合用于对所述生物样品(例如全血,血清或血浆)进行预处理,以获得外泌体。
在某些实施方案中,所述预处理试剂或试剂包含外泌体沉淀溶液,以及任选的缓冲液。
在某些实施方案中,其中,所述受试者为哺乳动物,例如人。
在某些实施方案中,所述试剂盒用于区分患阿尔茨海默病的受试者和正常受试者。
在某些实施方案中,所述Ig样结构域包含蛋白的氨基酸序列如SEQ ID NO:1所示。在某些实施方案中,所述补体C1q亚单位C的氨基酸序列如SEQ ID NO: 2所示。在某些实施方案中,所述补体成分C9的氨基酸序列如SEQ ID NO:3所示。在某些实施方案中,所述血小板糖蛋白Ibβ链的氨基酸序列如SEQ ID NO:4所示。在某些实施方案中,所述RAS抑制蛋白1的氨基酸序列如SEQ ID NO:5所示。在某些实施方案中,所述去整合素和金属蛋白酶结构域10的氨基酸序列如SEQ ID NO:6所示。
在本申请的第三方面,一种用于诊断受试者是否患阿尔茨海默病的试剂盒,所述试剂盒包含用于确定生物样品中生物标志物水平的试剂,所述生物标志物为Ig样结构域包含蛋白、补体C1q亚单位C、补体成分C9、血小板糖蛋白Ibβ链、RAS抑制蛋白1、去整合素和金属蛋白酶结构域10。
在某些实施方案中,所述生物标志物的水平是所述生物标志物的蛋白质或mRNA水平。
在某些实施方案中,其中,所述试剂(例如第一、第二、第三、第四、第五和/或第六试剂或试剂组合)通过以下方法测定所述生物样品中生物标志物的水平:色谱和/或质谱法的测定、荧光测定、电泳、免疫亲和、杂交、免疫化学、紫外光谱(UV)、荧光分析、放射化学分析、近红外光谱(NIR)、核磁共振光谱(NMR)、光散射分析(LS)和比浊法。
在某些实施方案中,所述试剂通过光谱、液相或气相色谱、质谱、与质谱联用的液相或气相色谱来测定所述生物样品中生物标志物的水平。在某些实施方案中,所述试剂盒还包括用于光谱的试剂和/或耗材,色谱的试剂和/或耗材,用于质谱的试剂和/或耗材,或其任何组合。
在某些实施方案中,所述用于色谱的试剂和/或耗材选自色谱柱,乙腈水溶液(例如,2%乙腈水溶液,100%乙腈水溶液),三氟乙酸,甲酸,或其任何组合。
在某些实施方案中,所述用于质谱的试剂和/或耗材选自质谱柱,甲酸,乙腈,或其任何组合。
在某些实施方案中,所述生物标志物的水平是编码所述生物标志物的mRNA的水平。在某些实施方案中,所述试剂(例如第一、第二、第三、第四、第五和/或第六试剂或试剂组合)通过定量PCR来测定所述生物样品中生物标志物的水平。
在某些实施方案中,所述第一试剂或试剂组合包含能够定量编码Ig样结构域包含蛋白的mRNA水平的引物和/或探针。在某些实施方案中,所述第二试剂或试剂组合包含能够定量编码补体C1q亚单位C的mRNA水平的引物和/或探针。在某些实施方案中,所述第三试剂或试剂组合包含能够定量编码补体成分C9的mRNA水平的引物和/或探针。在某些实施方案中,所述第四试剂或试剂组合包含能够定量编码血小板糖蛋白Ibβ链的mRNA水平的引物和/或探针。在某些实施方案中,所述第五试剂或试剂组合包含能够定量编码RAS抑制蛋白1的mRNA水平的引物和/或探针。在某些实施方案中,所述第六试剂或试剂组合包含能够定量编码去整合素和金属蛋白酶结构域10的mRNA水平的引物和/或探针。
在某些实施方案中,所述生物样品为获自受试者的全血,血清,血浆或脑脊液。在某些实施方案中,所述生物样品选自全血,血清和血浆。
在某些实施方案中,所述生物样品包含外泌体。在某些实施方案中,所述试剂盒还包含,对生物样品进行预处理的预处理试剂或试剂组合。在某些实施方案中,所述预处理试剂或试剂组合用于对所述生物样品(例如全血,血清或血浆)进行预处理,以获得外泌体。在某些实施方案中,所述预处理试剂或试剂包含外泌体沉淀溶液,以及任选的缓冲液。
在某些实施方案中,其中,所述受试者为哺乳动物,例如人。
在某些实施方案中,所述试剂盒用于区分患阿尔茨海默病的受试者和正常受试者。
在某些实施方案中,所述试剂盒通过上文所述的方法诊断受试者是否患阿尔茨海默病。
在某些实施方案中,所述Ig样结构域包含蛋白的氨基酸序列如SEQ ID NO:1所示。在某些实施方案中,所述补体C1q亚单位C的氨基酸序列如SEQ ID NO: 2所示。在某些实施方案中,所述补体成分C9的氨基酸序列如SEQ ID NO:3所示。在某些实施方案中,所述血小板糖蛋白Ibβ链的氨基酸序列如SEQ ID NO:4所示。在某些实施方案中,所述RAS抑制蛋白1的氨基酸序列如SEQ ID NO:5所示。在某些实施方案中,所述去整合素和金属蛋白酶结构域10的氨基酸序列如SEQ ID NO:6所示。
术语解释。
如本文中所使用的,术语“神经退行性疾病”是一类进行性发展的疾病,以特异性神经元的大量丢失为主要特征。主要包括帕金森病(Parkinson’s disease,PD),阿尔茨海默病(AD),轻度认知功能障碍(mild cognitive impairment,MCI)和肌萎缩侧索硬化症(amyotrophic lateralizing sclerosis,ALS)等。
如本文中所使用的,术语“阿尔茨海默病(AD)”是老年人常见的神经退行性疾病,以认知功能障碍为主要临床特征。对于AD的诊断可采用磁共振成像(magnetic resonanceimaging,MRI)、正电子发射断层显像(positron emission computed tomography,PET)和生物标志物诊断等方法。
如本文中所使用的,术语“外泌体(exosome)”是指直径大约为30-150nm的微小膜泡,由多种细胞分泌,含有特定的蛋白质(例如,外泌体膜上富含参与外泌体运输的跨膜蛋白家族CD63, CD81和CD9)、脂质、细胞因子或遗传物质。多种细胞在正常及病理状态下均可分泌外泌体,它们广泛存在于血液、唾液、尿液、脑脊液和乳汁等体液中,被视为特异性分泌的膜泡,参与细胞间通讯。
如本文中所使用的,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患的改变的生化指标,具有非常广泛的用途。生物标志物可用于疾病诊断、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。
如本文中所使用的,术语“参考值”是指生物标志物的预定值,其是根据对照样品(例如获自正常人群的生物样品)的生物标志物的水平得出的。参考值可以用作阈值,以区分可能存在疾病风险的受试者和不存在该疾病风险的受试者。参考值可以是相对值,有上限和下限的数值范围,平均值,中间值等。本领域技术人员根据现有技术中公开的方法可以选择合适的对照样品、测定并获得参考值。上述方法可以参见,例如,Burtis C. A. etal., 2008, Chapter 14, section “statistical treatment of reference values,其以全部引用方式并入本文。
如本文中所使用的,术语“受试者”包括但不限于各种动物,特别是哺乳动物,例如人。
如本文中所使用的,术语“ApoEε4基因型”是指ApoE基因的一种变异形式,APOE基因有多种可能的变异形式,例如,ε2ε2、ε3ε3、ε4ε4、ε2ε3、ε2ε4和ε3ε4。一些研究表明,携带APOE基因ε4变异体的人群在晚年更容易发展为阿尔茨海默病。
发明的有益效果。
本申请的方法能够替代传统的脑脊液检测,通过6种外泌体蛋白的组合实现对AD的诊断,以区分AD患者与正常人员。并且,本申请的方法仅取静脉血即可完成检测,相较传统的腰椎穿刺脑脊液检测,本申请方法具有以下有益技术效果:(1)具有几乎无创伤,低风险等优势;(2)具有成本低的优势,无需在医院或专业医疗机构完成,可在社区或简易的医疗机构完成,受检测人员无需住院;(3)可在大范围人群中筛查AD,使得大范围的老年人口筛查成为可能。
附图说明
图1显示了对外泌体样品的确认结果。其中,图1A为一例AD患者的外泌体的典型透射电镜图像;图1B为蛋白质印迹分析结果,外泌体标记蛋白Alix在样本中高度表达,而上清液中该标记为阴性。图1C为所有样本中CD9的水平;图1D为所有样本中CD63的水平;图1E为所有样本中CD681的水平。
图2显示了数据集1中,与对照组相比,AD组检测到的31种差异表达蛋白质的水平。
图3显示了数据集2中,12种差异表达的蛋白质得到了进一步的验证。其中,AD为阿尔茨海默氏病患者;FC为倍数变化。
图4显示了差异表达蛋白的GO(GO,基因本体论)富集分析。
图5显示了差异表达蛋白的KEGG(KEGG,系统分析基因功能、基因组信息数据库)通路富集分析。其中,图5A为前20个KEGG富集途径;图5B为KEGG富集通路的分类;图5C为KEGG富集通路的相关网络;图5D为前20位KEGG富集基因通路相关疾病。
图6显示了数据集2中阿尔茨海默病诊断模型建立。图6A为结合6种外泌体蛋白进行受试者工作特征(ROC)曲线分析,图6B为每个外泌体蛋白的ROC分析结果。AUC为曲线下面积。
本申请涉及的部分序列的信息提供于下面的表1中。
表1:序列的描述。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
实施例1:数据集与统计方法。
1.1研究的数据集。
本研究共纳入2个数据集。
数据集1从北京中心地区招募受试者(n = 40例,其中包括AD患者20例、健康对照组20例),用来分析外泌体蛋白的差异。
数据集2从山东、河南和广西各省的研究中心招募受试者(n = 114例,其中包括AD患者56例、健康对照组58例),来验证差异性以及建立诊断模型。
AD的诊断标准依据2011年美国国家衰老研究院-阿尔茨海默协会(NationalInstitute on Aging-Alzheimer’s Association, NIA-AA)诊断标准。此外,根据脑脊液P-tau /Aβ42(临界值取0.14)的比值确定AD和正常对照,该值是根据我们之前发表的数据计算得出的,与其他研究报道一致(参见Jia L, Qiu Q, Zhang H, Chu L, Du Y, Zhang J,et al. Concordance between the assessment of Abeta42, T-tau, and P-T181-tauin peripheral blood neuronal-derived exosomes and cerebrospinal fluid.Alzheimers Dement. 2019;15:1071-80)。根据ATN框架,低水平的脑脊液Aβ42是AD关键的病理改变。因此我们使用了已经报道的脑脊液Aβ42临界值500pg/ml作为另一个确定AD和正常对照的标准(参见Jia L, Qiu Q, Zhang H, Chu L, Du Y, Zhang J, et al.Concordance between the assessment of Abeta42, T-tau, and P-T181-tau inperipheral blood neuronal-derived exosomes and cerebrospinal fluid.Alzheimers Dement. 2019;15:1071-80)。所有受试者或其法定监护人均已取得充分知情并签署书面同意书。本研究获得首都医科大学宣武医院机构审查委员会的批准。
1.2参与者特征
如下所示,表2-3列出了研究对象的特征。
表2. 数据集1参与者的特征。
表3. 数据集2参与者的特征。
注:年龄、受教育年限、发病前估计年份和MMSE的值以平均值(标准差)表示。缩写:ApoE ε4,apolipoprotein ε4;MMSE,简易精神状态检查;SD,标准差;*P < 0.05与对照组相比。
如上表所示,在两个数据集中,AD组和对照组在年龄和性别方面没有观察到显著差异,而携带ApoE ε4人数比例、MMSE评分、脑脊液Aβ42和P-tau均有显著差异(P <0.05)。
实施例2:外泌体蛋白的提取与分析。
2.1脑脊液收集和检测。
依照国际指南收集脑脊液标本,简单地说,受试者在清晨空腹(禁食12小时)状态下取左侧卧位,选择L3-L5椎间隙作为穿刺部位。用防止损伤的20号穿刺针收集15ml脑脊液,于室温下2,000 × g离心10min,依据已经推出的标准来检验Aβ42, T-tau和P-tau。
2.2外周血外泌体的收集。
采集所有受试者的清晨空腹(禁食12小时)静脉血20ml,采集管使用含乙二胺四乙酸(EDTA)的聚丙烯管。外泌体的分离首先使用ExoQuick外泌体沉淀溶液(EXOQ;SystemBiosciences,CA)从血清中收集总的外泌体。
2.3外周血外泌体的验证。
根据已发表的方案,采用透射电镜(TEM)和蛋白质印迹法明确外泌体分离结果,外泌体的透射电镜如图1A所示。蛋白质印迹法分析表明,Alix(其作为外泌体或者细胞外囊泡的标志物)仅在外泌体中表达,在上清液中不表达(图1B),以上结果证实了本研究成功收集了外泌体。
2.4 蛋白水平检测。
采用酶联免疫吸附试验(ELISA)检测脑脊液中Aβ42、T-tau和P-T181tau的水平,以及外周血外泌体标志物CD9、CD63和CD81的水平。所有结果均在ELISA试剂盒的检测范围内,采用盲法进行测量。
2.5肽段提取。
在变性条件下,用Tris-甘氨酸凝胶从沉淀中分离出外泌体蛋白样品。经过染色、脱色、还原、烷化、脱水、水化后用乙腈水浴超声提取肽链并在真空离心机中干燥,最后悬浮于乙腈和三氟乙酸的溶液中,以进行蛋白组学分析。
2.6蛋白组学分析。
使用EASY-nLC 1000系统和Orbitrap-Fusion质谱仪(Thermo FisherScientific, Waltham, MA, USA)对样本进行分析,具体方法是基于既往发表的流程修改。把肽段装在Acclaim-PepMap μ-precolumn色谱柱(Thermo Scientific,San Jose, CA,USA)中并通过分析柱进行分析,0.1%甲酸-水和0.1%甲酸-乙腈为二元流动相,然后在电喷雾正模式下进行检测。
2.7蛋白组学数据分析。
使用MaxQuant软件v1.5.28(MaxQuant,Martinsry, Germany)对照UniProtKBHuman数据库分析原始文件。使用以下参数将肽段序列归属于MS/MS谱:半胱氨酸氨基甲基化为固定修饰,蛋氨酸氧化为可变修饰。将最小长度为7个氨基酸的蛋白质和肽段的假发现率(FDR)设置为q<0.01,并通过反向数据库搜索来确定。
从LC-MS/MS分析中获得的差异表达蛋白质进一步通过使用平行反应监测(PRM)的靶向蛋白质组学分析来验证。简单地说,蛋白质样品的制备方法与LC-MS/MS分析方法相同。PRM分析在Q-Exactive质谱仪(Thermo Fisher Science)上进行。通过使用Skyline软件(MacCoss Lab, University of Washington, Seattle, WA, USA)对平行反应监测数据进行分析。
2.8统计分析。
统计分析使用IBM SPSS Statistics for Windows, version 22.0 (IBM Corp,Armonk,NY,USA)和Stata 13.0(StataCorp LLC,College Station,TX,USA)对数据集1和数据集2的数据进行独立分析。对组间基线特征和生物标志物的浓度进行比较,统计方法视情况采用分类资料的χ2检验、连续资料的Welch’s t检验或方差分析(ANOVAS)。为识别出差异表达的蛋白质,利用伪发现率对P值进行校正。在数据集2中,通过以年龄、性别、教育年限和APOE ε4状态为协变量的二元Logistic回归模型生成预测值,然后用受试者工作特征曲线分析来检验。使用容忍度、方差膨胀因子(variance inflation factor,VIF)、特征值和条件指数来计算每个蛋白质之间的多重共线性。所有检验均为双侧检验,显著性差异水平设置为P <0.05。
2.9外泌体蛋白的差异分析。
在数据集1中进行外泌体蛋白的差异分析,量化得到AD患者和对照组血液中的328种外泌体蛋白。根据≥1.2或≤0.80的差异倍数标准,与对照组相比,AD组有15个蛋白质显著上调,16个蛋白质显著下调。与对照组相比,AD组中检测到的31种蛋白质的表达水平如图2所示。
在数据集2中进行进一步分析以验证AD患者和对照组之间差异表达的蛋白质。结果表明(图3),7个上调蛋白——补体C1q亚基C亚单位、补体成分C9、补体因子H(complementfactor H,CFAH)、免疫球蛋白kappa链可变区2D-30(immunoglobulin kappa variable 2D-30,KVD30)、血小板糖蛋白Ibβ链、RAS抑制蛋白1、Ig样结构域蛋白和5个下调蛋白——α2-巨球蛋白( alpha-2-macroglobulin,A2MG)、去整合素和金属蛋白酶结构域10、α1-酸性糖蛋白2(alpha-1-acid glycoprotein 2,A1AG2)、免疫球蛋白重链515恒定区α1(immunoglobulin heavy 515 constant alpha 1,IGHA1)、免疫球蛋白重链可变区4-28(immunoglobulin heavy variable 4-28,HV428)。
生物信息学分析表明,大多数蛋白质参与免疫系统的调节和蛋白活化级联反应(图4A、B),并在不同的细胞过程中作为结合分子发挥作用(图4A、C)。他们大多位于细胞外间隙和细胞外囊泡(图4A、D)。
KEGG通路分析表明,这些蛋白在免疫系统和与感染相关的通路,如补体和凝血级联通路中富集(图5A、B)。此外,B细胞受体信号通路以及补体和凝血级联通路与富集的通路联系最为紧密(图5C)。富集的通路与晚发性AD和脑淀粉样血管病有关(图5D)。
实施例3:外泌体蛋白的诊断模型。
一个相对较大的样本(数据集2)被收集用于进一步确认差异外泌体蛋白。数据集1中预实验的结果在数据集2中得到了证实,这支持了差异外泌体蛋白的意义。通过Logistic分析来评估他们区分AD患者和对照组的能力。
以诊断结果(AD与对照组)为因变量,12种蛋白质为协变量。校正年龄、性别、受教育年限和APOEε4的状态后,发现6种蛋白(上调——A0A0G2JRQ6、C1QC、CO9、GP1BB和RSU1;下调——ADA10)与AD相关。
在Logistic模型中,由于年龄、性别和受教育年限的P值>0.05而被排除在进一步分析之外。AD患者和对照组6种蛋白质的多重共线性诊断结果显示,所有的容忍度均>0.1,方差膨胀因子<10,特征值>0,状态指数<30,表明这6个蛋白质之间没有显著的多重共线性。为了确定六种蛋白的诊断能力,通过ROC曲线分析进一步评估了Logistic模型中的组合的预测值。结果表明,6种蛋白质组合对AD有很好的诊断能力,其曲线下面积(AUC=0.978,P<0.001,图6A)明显高于单个蛋白质的曲线下面积(AUC=0.627-0.774,图6B),结果表明有必要联合使用6种蛋白质以获得有效诊断。
实施例4:外泌体蛋白与MMSE评分的相关性。
为了进一步探讨外泌体蛋白水平与AD认知损害的关系,对AD患者MMSE评分与6种外泌体蛋白水平进行线性相关分析。AD患者外泌体蛋白组合的水平与MMSE评分显著正相关(校正R2=0.563,P<0.001),而单个外泌体蛋白与MMSE评分的相关性较弱(R2=A0A0G2JRQ6,0.193;C1QC,0.207;CO9,0.231;GP1BB,0.176;RUS1,0.148;ADA10,0.125,均P<0.001),提示6种蛋白的组合具有预测认知功能损害的潜力。
尽管本发明的具体实施方式已经得到详细的描述,但本领域技术人员将理解:根据已经公开的所有教导,可以对细节进行各种修改和变动,并且这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。
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<110> 首都医科大学宣武医院
<120> 一种诊断阿尔茨海默病的外泌体蛋白及其用途
<130> 2021.12.12
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Claims (10)
1.用于确定生物样品中生物标志物水平的试剂在制备试剂盒中的用途,所述试剂盒用于诊断受试者是否患阿尔茨海默病的风险;其中,所述生物标志物为Ig样结构域包含蛋白、补体C1q亚单位C、补体成分C9、血小板糖蛋白Ibβ链、RAS抑制蛋白1、去整合素和金属蛋白酶结构域10;
优选地,所述试剂盒包含用于确定受试者的Ig样结构域包含蛋白水平的第一试剂或试剂组合,用于确定受试者的补体C1q亚单位C水平的第二试剂或试剂组合,用于确定受试者的补体成分C9水平的第三试剂或试剂组合,用于确定受试者的血小板糖蛋白Ibβ链水平的第四试剂或试剂组合;用于确定受试者的RAS抑制蛋白1水平的第五试剂或试剂组合和用于确定受试者的去整合素和金属蛋白酶结构域10水平的第六试剂或试剂组合;
优选地,所述生物标志物的水平是所述生物标志物的蛋白质或mRNA水平。
2.权利要求1所述的用途,其中,所述生物标志物的水平是所述生物标志物的蛋白质水平;
优选地,所述试剂(例如第一、第二、第三、第四、第五和/或第六试剂或试剂组合)通过以下方法测定所述生物样品中生物标志物的水平:色谱和/或质谱法的测定、荧光测定、电泳、免疫亲和、杂交、免疫化学、紫外光谱(UV)、荧光分析、放射化学分析、近红外光谱(NIR)、核磁共振光谱(NMR)、光散射分析(LS)和比浊法;
优选地,所述试剂通过光谱、液相或气相色谱、质谱、与质谱联用的液相或气相色谱来测定所述生物样品中生物标志物的水平;
优选地,所述试剂盒还包括用于光谱的试剂和/或耗材,用于色谱的试剂和/或耗材,用于质谱的试剂和/或耗材,或其任何组合;
优选地,所述用于色谱的试剂和/或耗材选自色谱柱,乙腈水溶液(例如,2%乙腈水溶液,100%乙腈水溶液),三氟乙酸,甲酸,或其任何组合;
优选地,所述用于质谱的试剂和/或耗材选自质谱柱,甲酸,乙腈,或其任何组合。
3.权利要求1所述的试剂盒,其中,所述生物标志物的水平是编码所述生物标志物的mRNA的水平;
优选地,所述试剂(例如第一、第二、第三、第四、第五和/或第六试剂或试剂组合)通过定量PCR来测定所述生物样品中生物标志物的水平;
优选地,所述第一试剂或试剂组合包含能够定量编码Ig样结构域包含蛋白的mRNA水平的引物和/或探针;
优选地,所述第二试剂或试剂组合包含能够定量编码补体C1q亚单位C的mRNA水平的引物和/或探针;
优选地,所述第三试剂或试剂组合包含能够定量编码补体成分C9的mRNA水平的引物和/或探针;
优选地,所述第四试剂或试剂组合包含能够定量编码血小板糖蛋白Ibβ链的mRNA水平的引物和/或探针;
优选地,所述第五试剂或试剂组合包含能够定量编码RAS抑制蛋白1的mRNA水平的引物和/或探针;
优选地,所述第六试剂或试剂组合包含能够定量编码去整合素和金属蛋白酶结构域10的mRNA水平的引物和/或探针。
4.权利要求1或2所述的用途,其中,所述生物样品为获自受试者的全血,血清,血浆或脑脊液;
优选地,所述生物样品选自全血,血清和血浆;
优选地,所述生物样品包含外泌体;
优选地,所述试剂盒还包含,对生物样品进行预处理的预处理试剂或试剂组合;
优选地,所述预处理试剂或试剂组合用于对所述生物样品(例如全血,血清或血浆)进行预处理,以获得外泌体;
优选地,所述预处理试剂或试剂包含外泌体沉淀溶液,以及任选的缓冲液。
5.权利要求1-4任一项所述的用途,其中,所述受试者为哺乳动物,例如人;
优选地,所述试剂盒用于区分患阿尔茨海默病的受试者和正常受试者。
6.一种用于诊断受试者是否患阿尔茨海默病的试剂盒,所述试剂盒包含用于确定生物样品中生物标志物水平的试剂,所述生物标志物为Ig样结构域包含蛋白、补体C1q亚单位C、补体成分C9、血小板糖蛋白Ibβ链、RAS抑制蛋白1、去整合素和金属蛋白酶结构域10;
优选地,所述试剂盒包含用于确定受试者的Ig样结构域包含蛋白水平的第一试剂或试剂组合,用于确定受试者的补体C1q亚单位C水平的第二试剂或试剂组合,用于确定受试者的补体成分C9水平的第三试剂或试剂组合,用于确定受试者的血小板糖蛋白Ibβ链水平的第四试剂或试剂组合;用于确定受试者的RAS抑制蛋白1水平的第五试剂或试剂组合和用于确定受试者的去整合素和金属蛋白酶结构域10水平的第六试剂或试剂组合;
优选地,所述生物标志物的水平是所述生物标志物的蛋白质或mRNA水平。
7.权利要求6所述的试剂盒,其中,所述生物标志物的水平是所述生物标志物的蛋白质水平;
优选地,所述试剂(例如第一、第二、第三、第四、第五和/或第六试剂或试剂组合)通过以下方法测定所述生物样品中生物标志物的水平:色谱和/或质谱法的测定、荧光测定、电泳、免疫亲和、杂交、免疫化学、紫外光谱(UV)、荧光分析、放射化学分析、近红外光谱(NIR)、核磁共振光谱(NMR)、光散射分析(LS)和比浊法;
优选地,所述试剂通过光谱、液相或气相色谱、质谱、与质谱联用的液相或气相色谱来测定所述生物样品中生物标志物的水平;
优选地,所述试剂盒还包括用于光谱的试剂和/或耗材,用于色谱的试剂和/或耗材,用于质谱的试剂和/或耗材,或其任何组合;
优选地,所述用于色谱的试剂和/或耗材选自色谱柱,乙腈水溶液(例如,2%乙腈水溶液,100%乙腈水溶液),三氟乙酸,甲酸,或其任何组合;
优选地,所述用于质谱的试剂和/或耗材选自质谱柱,甲酸,乙腈,或其任何组合。
8.权利要求6所述的试剂盒,其中,所述生物标志物的水平是编码所述生物标志物的mRNA的水平;
优选地,所述试剂(例如第一、第二、第三、第四、第五和/或第六试剂或试剂组合)通过定量PCR来测定所述生物样品中生物标志物的水平;
优选地,所述第一试剂或试剂组合包含能够定量编码Ig样结构域包含蛋白的mRNA水平的引物和/或探针;
优选地,所述第二试剂或试剂组合包含能够定量编码补体C1q亚单位C的mRNA水平的引物和/或探针;
优选地,所述第三试剂或试剂组合包含能够定量编码补体成分C9的mRNA水平的引物和/或探针;
优选地,所述第四试剂或试剂组合包含能够定量编码血小板糖蛋白Ibβ链的mRNA水平的引物和/或探针;
优选地,所述第五试剂或试剂组合包含能够定量编码RAS抑制蛋白1的mRNA水平的引物和/或探针;
优选地,所述第六试剂或试剂组合包含能够定量编码去整合素和金属蛋白酶结构域10的mRNA水平的引物和/或探针。
9.权利要求6-8任一项所述的试剂盒,其中,所述生物样品为获自受试者的全血,血清,血浆或脑脊液;
优选地,所述生物样品选自全血,血清和血浆;
优选地,所述生物样品包含外泌体;
优选地,所述试剂盒还包含,对生物样品进行预处理的预处理试剂或试剂组合;
优选地,所述预处理试剂或试剂组合用于对所述生物样品(例如全血,血清或血浆)进行预处理,以获得外泌体;
优选地,所述预处理试剂或试剂包含外泌体沉淀溶液,以及任选的缓冲液。
10.权利要求6-9任一项所述的试剂盒,其中,所述受试者为哺乳动物,例如人;
优选地,所述试剂盒用于区分患阿尔茨海默病的受试者和正常受试者;
优选地,所述试剂盒通过上文所述的方法诊断受试者是否患阿尔茨海默病。
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