CN113373214B - Cd30在诊断脑神经相关疾病中的用途 - Google Patents
Cd30在诊断脑神经相关疾病中的用途 Download PDFInfo
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Abstract
本发明人通过对长期面对较大精神心里压力的青年男性在执行任务前、后的外周静脉血血清中差异表达的蛋白进行筛选，筛选到了可能与认知功能下降相关的蛋白，并收集病患病例进行了进一步的验证，证明受试者血清中CD30的浓度可以用于诊断认知功能相关的疾病。
Description
技术领域
本发明涉及生物技术、生物医药领域，具体涉及CD30在诊断脑神经相关疾病中的用途。
背景技术
痴呆症属于脑部疾病，是由于脑部不正常的退化引起的疾病。有统计显示，患者多为老年人，临床表现为：患者由于大脑功能衰退，无论在记忆、运算、学习、理解、甚至语言、判断力、方向感等方面都受到影响。该疾患不仅患者自身痛苦，对于其家庭乃至整个社会都会造成极为消极的影响。随着老龄人的增多，老年性痴呆症患者也在不断增加。阿尔茨海默病(Alzheimer's disease，AD)即老年痴呆症是退行性痴呆症的一种常见形式。目前全世界大约有2500万以上的AD患者。由于其发病年龄段的特点，备受处于老龄化阶段国家的重视，因此，对于AD的研究意义重大。
抑郁障碍是人群中最为常见的精神障碍之一，世界卫生组织WHO调查结果显示，全世界抑郁症发病率约为3.1％。抑郁症是由多种因素引起的心情障碍或情感障碍。主要表现为情绪低落，思维迟缓，意志活动减退，认知功能损害，丧失活动兴趣和能力下降，丧失自尊，不恰当的内疚感，死亡和自杀念头，注意力集中程度降低，睡眠障碍和食欲减退，性欲减退，还可伴有各种躯体症状。在西方发达国家，终身抑郁症的发病率在6％-8％之间，随着人口的逐步老龄化，抑郁症在60岁以上人群中的发病率将高达20％-50％。抑郁症的发病机制甚为复杂，抑郁症的发生可能与脑内单胺类递质的神经功能失衡有关。
发明内容
本发明人通过对长期面对较大精神心里压力的青年男性执行重大任务前后后的外周静脉血血清中差异表达的蛋白进行筛选，筛选到了可能与认知功能相关的蛋白，并收集病患病例进行了进一步的验证，证明受试者血清中CD30的浓度可以用于诊断脑神经相关的疾病。
诊断疾病的应用
一方面本发明提供了检测CD30表达量的试剂在制备诊断受试者是否患有脑神经相关疾病的产品中的应用。
优选地，所述脑神经相关疾病包括精神疾病和/或痴呆症。
优选地，所述精神疾病包括焦虑和/或抑郁。
优选地，所述精神疾病是抑郁焦虑症。
优选地，所述痴呆症包括阿尔茨海默病、血管性痴呆症、额颞叶痴呆、路易体痴呆、帕金森病。
优选地，所述痴呆症是阿尔茨海默病和/或血管性痴呆症。
优选地，所述CD30在患者中高表达。
优选地，所述高表达指CD30表达水平大于健康对照群体中CD30表达水平，相对于对照表达水平高至少1.1倍，例如至少1.1倍、1.2倍、1.3倍、1.4倍、1.5倍、1.6倍、1.7倍、1.8倍、1.9倍、2.0倍、2.1倍、2.2倍、2.3倍、2.4倍、2.5倍、2.6倍、2.7倍、2.8倍、2.9倍、3.0倍、3.1倍、3.2倍、3.3倍、3.4倍、3.5倍或更多。
优选地，所述检测CD30表达量的试剂包括检测CD30蛋白表达量和/或CD30mRNA表达量的试剂。
优选地，所述检测CD30蛋白表达量的试剂包括以下方法中使用的试剂：蛋白质印迹(Western Blot法)、酶联免疫吸附测定(ELISA)、放射性免疫测定(RIA)、夹心测定、免疫组织化学染色、质谱法、免疫沉淀分析法、补体结合分析法、流式细胞荧光分边技术和蛋白质芯片法。
优选地，所述检测CD30蛋白表达量的试剂包括蛋白质芯片法所使用的试剂。
优选地，所述蛋白质芯片法所使用的芯片是Raybiotech公司的AAH-BLG-1芯片。
优选地，所述检测CD30蛋白表达量的试剂还可以包括CD30的抗体或其片段，所述CD30的抗体或其片段能特异性的与CD30蛋白结合。
优选地，所述检测CD30蛋白表达量的试剂还包括二抗，所述二抗能与前述CD30的抗体或其片段结合并且显示出可检测信号。
优选地，所述可检测信号可以是可检测标记物发出的。
优选地，所述CD30的抗体或其片段还可以与可检测标记物结合，检测到所述可检测标记物既表示CD30蛋白有表达。
优选地，所述可检测标记物包括但不限于荧光染料、荧光分子、化学发光标记物、生物素、放射性同位素中的一种或多种。
优选地，所述荧光染料包括但不限于罗丹明类、ROX染料、AlexaFluor染料、ATTO染料、DyLight染料、cyanine染料、FluoProbes染料、SulfoCy染料、Seta染料、IRIS染料、SeTau染料、SRfluor染料、Square染料。
优选地，所述荧光分子包括FAM、FITC、VIC、JOE、TET、CY3、CY5、ROX、Texas Red或LCRED460。
优选地，所述化学发光标记物包括过氧化物酶、碱性磷酸酶、荧光素酶、水母发光蛋白、官能化的铁-卟啉衍生物、鲁米那、鲁米诺、异鲁米诺、吖啶酯、磺酰胺。
优选地，所述检测CD30 mRNA表达量的试剂包括以下方法中使用到的试剂：基于PCR的检测方法、Southern杂交方法、Northern杂交方法、点杂交方法、荧光原位杂交方法、DNA微阵列方法、ASO法、高通量测序平台方法。
优选地，所述产品中还包括收集和/或处理样品的试剂。
优选地，所述样品包括：血清、血浆、全血、尿液、唾液、精液、乳汁、脑脊髓液、泪液、鼻上皮细胞、痰、组织、粘液、淋巴、胞液、腹水、胸膜积液、羊水、膀胱冲洗液和支气管肺泡灌洗液。
优选地，所述样品是血清。
优选地，所述血清分离自外周静脉血。
产品
另一方面本发明提供了一种诊断受试者是否患有脑神经相关疾病的试剂盒，所述试剂盒包括前述检测受试者的CD30的表达量所使用的试剂。
优选地，所述试剂盒中还可以包含以下任意一种或多种：mRNA表达量辅助检测试剂、蛋白表达量辅助检测试剂、mRNA表达量辅助检测仪器、蛋白表达量辅助检测仪器。
优选地，所述mRNA表达量辅助检测试剂包括但不限于：使所述引物对应的扩增子可视化的反应试剂，例如通过琼脂糖凝胶电泳法、酶联凝胶法、化学发光法、原位杂交法、荧光检测法等使扩增子可视化的试剂，RNA提取试剂，逆转录试剂，cDNA扩增试剂，制备标准曲线所用的标准品，阳性对照品，阴性对照品。
优选地，所述蛋白表达量辅助检测试剂包括但不限于：封闭液，抗体稀释液，洗涤缓冲液，显色终止液，制备标准曲线的标准品。
另一方面本发明提供了一种治疗脑神经相关疾病的药物组合物，所述药物组合物包括CD30的抑制剂，所述抑制剂可以敲除CD30的表达基因或者降低CD30的含量。
优选地，所述抑制剂可以是特异性中和CD30的抗体。
优选地，所述抑制剂还可以是siRNA干扰、CRISPR/cas9方法、同源重组、基因敲除、基因置换、基因沉默、定点突变、化学药物方法所使用的试剂。
优选地，所述药物组合物可以为片剂，丸剂，粉剂，颗粒剂，胶囊剂，锭剂，糖浆剂，液体，乳剂，混悬剂，控制释放制剂，气雾剂，膜剂，注射剂，静脉滴注剂，透皮吸收制剂，软膏剂，洗剂，粘附制剂，栓剂，小药丸，鼻制剂，肺制剂，眼睛滴剂等等，口服或胃肠外制剂。
优选地，所述脑神经相关疾病包括精神疾病和/或痴呆症。
优选地，所述精神疾病是抑郁焦虑症候群。
优选地，所述痴呆症是阿尔茨海默病和/或血管性痴呆。
方法
另一方面本发明提供诊断受试者是否患有脑神经相关疾病的方法，所述方法包括通过受试者CD30表达量的检测结果判断受试者患病情况。
优选地，所述方法还包括检测受试者的CD30的表达量的步骤。
优选地，所述脑神经相关疾病包括精神疾病和/或痴呆症。
优选地，所述精神疾病是抑郁焦虑症候群。
优选地，所述痴呆症是阿尔茨海默病和/或血管性痴呆。
附图说明
图1为男性青年任务前后血清中CD30密度差异分析结果图。
图2为对照组与患者的血清中CD30密度差异分析结果图。
图3为焦虑抑郁症候群诊断的ROC曲线图。
图4为痴呆症诊断的ROC曲线图。
具体实施方式
下面结合实施例对本发明做进一步的说明，以下所述，仅是对本发明的较佳实施例而已，并非对本发明做其他形式的限制，任何熟悉本专业的技术人员可能利用上述揭示的技术内容加以变更为同等变化的等效实施例。凡是未脱离本发明方案内容，依据本发明的技术实质对以下实施例所做的任何简单修改或等同变化，均落在本发明的保护范围内。
实施例1、蛋白芯片筛选
针对执行某长期任务中面对较大精神心里压力的青年男性，分别于执行任务前、后取外周静脉血，其中执行任务前样品8例，任务后样品12例。利用的是Raybiotech公司AAH-BLG-1芯片，从507个因子中筛选目标蛋白。读出结果为荧光强度，经过标准化后，数值越高表明蛋白浓度越高。结果发现血清中CD30上升(p＝0.0331038)，具体结果如图1所示。
实施例2、焦虑抑郁患者临床验证与鉴别诊断
取获取所有对象的肘正中静脉血5ml，室温静置30min，1000×g离心15min，分装冻存于-70度冰箱。使用定制型Raybiotech公司AAH-BLG-1芯片，专门分析血清中CD30的水平。患者来源及检测数据如下表1所示。
抑郁焦虑症候群患者：
2019年6月到2019年8月期间在解放军总医院第一医学中心就诊的抑郁焦虑症候群患者，共24例(表1中抑郁焦虑一列的前24个检测数据)。2020年10月23日四川省成都市第四人民医院住院的抑郁焦虑症候群患者19例(表1中抑郁焦虑一列的第25-43个检测数据)。
精神分裂症患者：
2020年10月23日四川省成都市第四人民医院住院精神分裂症患者20例(表1中精神分裂一列的第1-20个检测数据)。
痴呆症：
2020年10月23日四川省成都市第四人民医院住院的阿尔茨海默病患者13例，血管性痴呆患者6例(阿尔兹海默症患者和血管性痴呆患者数据合并为痴呆症，是表1中痴呆一列的19个数据)。
对照：
对照来源于同时期解放军总医院第一医学中心体检但各项指标均正常的健康志愿者，共收集20例。
表1.患者血清中CD30水平
结果分析：
焦虑抑郁症候群：无论是北京的焦虑抑郁症候群患者，还是四川的患者，均呈现血清CD30水平升高，北京患者与健康对照的差异显著(p＝0.003259)，四川患者与健康对照的差异也显著(p＝0.00274)。北京患者与四川患者之间无统计学差异。焦虑抑郁症候群的差异分析结果图如图2左图所示，诊断的ROC曲线如图3所示。
痴呆：痴呆患者与健康对照的差异显著(p＝0.000529)。焦虑抑郁症候群、精神分裂症、痴呆症的差异分析结果图如图2右图所示。痴呆症诊断的ROC曲线如图4所示。
精神分裂症患者：精神分裂症患者血清CD30水平与健康对照无统计学差异。
所以以上数据显示，CD30有一定诊断的意义，其可以应用在诊断焦虑抑郁症和痴呆症中，而且提示其血清水平的升高与认知功能下降有一定关系。
Claims (6)
1.检测可溶性CD30在血清中表达量的试剂在制备诊断受试者是否患有阿尔茨海默病的产品中的应用，所述可溶性CD30在患者血清中高表达。
2.如权利要求1所述的应用，其特征在于，所述可溶性CD30在血清中表达量的试剂包括以下方法中使用的试剂：蛋白质印迹、酶联免疫吸附测定、放射性免疫测定、夹心测定、免疫组织化学染色、质谱法、免疫沉淀分析法、补体结合分析法、流式细胞仪荧光分析技术和蛋白质芯片法。
3.如权利要求2所述的应用，其特征在于，所述检测可溶性CD30蛋白表达量的试剂包括蛋白质芯片法所使用的试剂。
4.如权利要求1所述的应用，其特征在于，所述试剂中还包括收集和/或处理样品的试剂。
5.如权利要求4所述的应用，其特征在于，所述样品是血清。
6.如权利要求5所述的应用，其特征在于，所述血清分离自外周静脉血。
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