CN106434939A - 一种帕金森病诊断试剂盒及其应用 - Google Patents
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Abstract
本发明涉及一种帕金森病诊断试剂盒及其应用。本发明对263例帕金森病患者和242例年龄性别匹配的健康对照组血浆中的miR‑105‑5p,miR‑21‑5p,miR‑29a‑5p,miR‑30e‑5p表达水平进行单盲检测,发现这4种miRNAs在帕金森病患者和健康人群血浆中有明显差异,提示这四种miRNAs可作为分子标志物用于制备诊断帕金森病的试剂盒,或用于制备治疗帕金森病的药物。本发明同时发现服药情况对miR‑21‑5p有显著影响,提示其可用于筛选治疗帕金森病的药物。
Description
技术领域
本发明涉及生物技术,疾病诊断和生物医药领域,具体地说,涉及一种帕金森病诊断试剂盒及其应用。
背景技术
帕金森病(Parkinson’s disease,PD)又称震颤麻痹,是仅次于阿尔茨海默病的第二常见神经系统变性疾病。除黑质纹状体变性引起的静止性震颤、肌强直及运动迟缓等运动症状外,非运动症状如嗅觉缺失、抑郁、自主神经功能障碍、快动眼睡眠行为异常(rapideye movement sleep behavior disorder,RBD)及认知损害等也是PD的重要组成部分。随着人口老龄化的加剧,PD的患病率呈逐年上升趋势,给患者的家庭和社会造成了严重负担。当PD患者出现临床症状时,其黑质多巴胺神经元死亡已超过60%,此时,药物治疗仅能改善患者的临床症状,并不能减缓其疾病的进展。对PD临床前期或早期的识别和诊断,是PD及其他神经变性疾病发病机制研究和新药研发的基础。
目前临床上常规的药物主要有(1)多巴胺替代药物;(2)单胺氧化酶(MAO)抑制剂;(3)儿茶酚胺氧位甲基转移酶(COMT)抑制剂;(4)抗胆碱能药物;(5)多巴胺受体激动剂等等。以上药物能够暂时缓解和改善相关症状,但不能推迟病程,也不能治愈该病。近年来,随着PD病理机制研究进一步深入,与PD有关的致病基因及调控此类基因的非编码RNA(例如miRNA)备受瞩目。
miRNA(microRNA,miR)是有21-23个核苷酸的非编码单链微小RNA,能够通过序列特异性的方式来调节靶基因表达。miRNA具有高度保守性、组织特异性、阶段特异性和时序性等特点。近期研究表明,有大量的miRNA与PD病理机制密切相关,可能为PD治疗提供新的思路。miRNA可调节与遗传性PD相关的基因,如miR-7和miR-153可以调控PD致病基因PARK1/PARK4,miR-205可以调控PARK8,miR-34b/miR-34c可以调控PARK2,miR-494可以调控PARK7等;miRNA也可以调控多种与PD发病机制相关的基因,如miR-34a、miR-132、miR-133b可以分别调控与多巴胺能神经元发育有关的基因Nurr1、Notch1、Pitx3,miR-320可以调控与突触形成有关的基因ARPP-19,miR-433可以调控与神经营养因子有关的基因FGF20等。直接调控PD致病基因的miRNA可能具有直接的治疗作用,而调节PD相关基因的miRNA可能具有辅助治疗作用。miRNA能够调控PD致病基因与相关基因的表达,是一种非常具有前景的治疗手段。因此,进一步研究miRNA在PD发病机制探索以及临床诊断中具有重要的意义。
发明内容
本发明的目的是针对现有技术中的不足,提供四种miRNAs:miR-105-5p,miR-21-5p,miR-29a-5p和miR-30e-5p的新用途。
第一方面,本发明提供了miRNA在制备诊断帕金森病的试剂中的应用,所述的miRNA选自下列中的任一种:
a)miR-105-5p,
b)miR-21-5p,
c)miR-29a-5p,
d)miR-30e-5p,
e)miR-105-5p,miR-21-5p,miR-29a-5p和miR-30e-5p中任两种或任几种的组合。
第二方面,本发明提供了检测血浆中miRNA表达水平的试剂在制备诊断帕金森病的试剂中的应用,所述的miRNA选自下列中的任一种:
a)miR-105-5p,
b)miR-21-5p,
c)miR-29a-5p,
d)miR-30e-5p,
e)miR-105-5p,miR-21-5p,miR-29a-5p和miR-30e-5p中任两种或任几种的组合。
作为本发明的一种具体实施方式,所述的试剂为检测miRNA的引物。
第三方面,本发明提供了一种帕金森病诊断试剂盒,所述的试剂盒含有检测血浆中miRNA表达水平的试剂,所述的miRNA选自下列中的任一种:
a)miR-105-5p,
b)miR-21-5p,
c)miR-29a-5p,
d)miR-30e-5p,
e)miR-105-5p,miR-21-5p,miR-29a-5p和miR-30e-5p中任两种或任几种的组合。
第四方面,本发明提供了miR-105-5p,miR-21-5p,miR-29a-5p或miR-30e-5p的抑制剂在制备治疗帕金森病的药物中的应用。
第五方面,本发明提供了miR-21-5p在制备筛选治疗帕金森病的药物中的应用。
本文中,各miRNA具有如下序列:
miR-105-5p:UCAAAUGCUCAGACUCCUGUGGU(SEQ ID NO.1),
miR-21-5p:UAGCUUAUCAGACUGAUGUUGA(SEQ ID NO.2),
miR-29a-5p:ACUGAUUUCUUUUGGUGUUCAG(SEQ ID NO.3),
miR-30e-5p:UGUAAACAUCCUUGACUGGAAG(SEQ ID NO.4)。
本发明优点在于:
本发明对263例帕金森病患者和242例年龄性别匹配的健康对照组血浆中的miR-105-5p,miR-21-5p,miR-29a-5p,miR-30e-5p表达水平进行单盲检测,发现这4种miRNAs在帕金森病患者和健康人群血浆中有明显差异,提示四种miRNAs包括miR-105-5p,miR-21-5p,miR-29a-5p,miR-30e-5p可作为诊断分子标志物用于制备诊断帕金森病的试剂盒,或用于制备治疗帕金森病的药物。同时,我们发现服药情况对miR-21-5p有显著影响,提示其可用于筛选治疗帕金森病的药物。本发明对进一步研究miRNAs在帕金森病发病以及临床诊断和治疗中的功能具有重要的意义。
附图说明
图1.miRNAs在帕金森病患者血浆中的表达。荧光定量RT-PCR方法检测健康对照(n=242)和帕金森病患者(n=263)血浆中miR-105-5p,miR-21-5p,miR-29a-5p,miR-30e-5p的表达。HC:健康对照;PD:帕金森病患者。
图2.服药情况对帕金森病患者血浆中miRNAs的影响。分析与健康对照相比,帕金森病患者未服药(n=66),服用左旋多巴(n=65),服用左旋多巴与多巴胺受体激动剂联合用药(n=71)对血浆中miR-105-5p,miR-21-5p,miR-29a-5p,miR-30e-5p表达的影响。ctrl:健康对照;naive:帕金森病患者未服药组;L-dopa:帕金森病患者服用左旋多巴组;L-dopa+DR:帕金森病患者服用左旋多巴与多巴胺受体激动剂联合用药组。与健康对照组相比,*P<0.05,**P<0.01,***P<0.001。与帕金森病患者未服药组相比,###p<0.001。
图3.年龄对帕金森病患者血浆中miRNAs的影响。将入组帕金森病患者分为四个年龄段40~59岁(HC组n=34;PD组n=58)、60~69岁(HC组n=101;PD组n=85)、70~79岁(HC组n=76;PD组n=87)和80~89岁(HC组n=30;PD组n=27),分析比较健康对照组和帕金森病患者在不同年龄段血浆中miR-105-5p,miR-21-5p,miR-29a-5p,miR-30e-5p表达水平变化。HC:健康对照;PD:帕金森病患者。与健康对照组相比,*P<0.05,**P<0.01,***P<0.001。
图4.性别对帕金森病患者血浆中miRNAs的影响。分析比较不同性别健康对照组和帕金森病患者血浆中miR-105-5p,miR-21-5p,miR-29a-5p,miR-30e-5p表达水平变化。与健康对照组相比,*P<0.05,**P<0.01,***P<0.001。
图5.病程对帕金森病患者血浆中miRNAs的影响。将入组帕金森病患者病程分为四个阶段1~3年(n=86)、4~6年(n=65)、7~9年(n=57)和10~20年(n=39),分析与健康对照组相比,帕金森病患者在病程不同阶段血浆中miR-105-5p,miR-21-5p,miR-29a-5p,miR-30e-5p表达水平变化。与健康对照组相比,*P<0.05,**P<0.01,***P<0.001。
具体实施方式
下面结合附图对本发明提供的具体实施方式作详细说明。
实施例1
一、材料与方法
1.样本收集和miRNA提取
实验共收集了748例血浆样本,其中包括242个健康对照者,263个帕金森病患者和243个神经系统其他疾病患者。经卡方检验,三组人群在性别年龄方面没有显著差异。每个个体采2mL抗凝血,采集完成后送入实验室,3000rpm常温离心15min后分离血浆分装到灭菌的离心管中,-80℃保存。采用miRcute miRNA提取分离试剂盒(天根生化科技(北京)有限公司)提取miRNA,方法按照试剂盒说明实施。
表1入组人群性别年龄情况表
Ref:reference;NS:not significant,无统计学意义。
2.miRNA反转录和检测
取上述miNRA,参照天根生化科技(北京)有限公司的miRcute miRNA cDNA第一链合成试剂盒及miRcute miRNA荧光定量检测试剂盒进行逆转录和荧光定量RT-PCR检测了miR-105-5p,miR-21-5p,miR-29a-5p,miR-30e-5p的表达,方法按照试剂盒说明实施。所用引物购自天根生化科技(北京)有限公司,商品号分别为CD201-0048,CD201-0092,CD201-0328和CD201-0340。内参选用miRNA-16,所用引物序列为5’-GCTAGCAGCACGTAAATATTGGCG-3’(SEQ ID NO.5)。
3.分析服药情况、年龄、性别和病程对帕金森病患者miRNAs影响
收集入组人群临床病例,对帕金森病患者服药情况、年龄、性别和病程信息进行汇总,并分析其对miR-105-5p,miR-21-5p,miR-29a-5p,miR-30e-5p表达的影响。
4.统计分析和数据处理
所有数据以平均数±标准误差(Means±SEM)表示。用GraphPad Prism softwareversion 4(GraphPad Inc.,San Diego,CA,USA)对两组数据进行独立样本t-检验,多组数据比较采用Oneway-ANOVA,P<0.05视为有统计学差异。二、实验结果
1.miRNAs在帕金森病患者血浆中的表达
我们发现与健康对照者相比,帕金森病患者血浆中miR-105-5p,miR-21-5p,miR-29a-5p,miR-30e-5p的表达均显著增加,分别增加了267.72%、832.62%、187.76%和163.10%(图1)。
2.服药情况对帕金森病患者血浆中miRNAs的影响
根据入组帕金森病患者的服药情况(包括未服药,服用左旋多巴,服用左旋多巴和多巴胺受体激动剂联合用药),发现帕金森病患者服用多巴胺受体激动剂能明显上调miR-21-5p的表达,而对检测的其他miRNA无明显影响(图2)。
3.年龄对帕金森病患者血浆中miRNAs的影响
将入组健康对照和帕金森病患者按其年龄分为40~59、60~69、70~79和80~89四个年龄段,发现除了40~59年龄段健康对照和帕金森病患者miR-105-5p表达水平相比无统计学意义,帕金森病患者在不同年龄段miR-105-5p,miR-21-5p,miR-29a-5p,miR-30e-5p表达水平均显著上调(图3)。
4.性别对帕金森病患者血浆中miRNAs的影响
我们发现与健康对照者相比,帕金森病患者男性和女性血浆中miR-105-5p,miR-21-5p的表达均显著上调。男性帕金森病患者血浆中miR-30e-5p的表达水平比男性健康对照组显著增多,而女性帕金森患者不明显。miR-29a-5p在帕金森病患者男性和女性血浆中有增高趋势但尚无统计学意义(图4)。
5.病程对帕金森病患者血浆中miRNAs的影响
我们将入组帕金森病患者病程分为四个阶段1~3年、4~6年、7~9年和10~20年,发现与健康对照者相比,帕金森病患者血浆中miR-30e-5p,miR-21-5p在病程不同阶段的表达均显著上调。帕金森病患者血浆中miR-105-5p的表达水平在病程的前三个阶段显著增高,其在患病10~20年的帕金森病患者血浆中的表达有上升趋势。miR-29a-5p在帕金森病患者不同病程阶段血浆中变化不显著(图5)。
三、讨论
本发明在帕金森病患者血浆中验证了4种miRNAs:miR-105-5p,miR-21-5p,miR-29a-5p,miR-30e-5p可作为帕金森病生物标志物或治疗靶点,血浆中miR-105-5p,miR-21-5p,miR-29a-5p,miR-30e-5p或它们的组合,及其引物可用于制备诊断试剂盒,用于帕金森病的辅助早期诊断,miR-105-5p,miR-21-5p,miR-29a-5p,miR-30e-5p的抑制剂可用于制备治疗帕金森病的药物。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员,在不脱离本发明方法的前提下,还可以做出若干改进和补充,这些改进和补充也应视为本发明的保护范围。
Claims (6)
1.miRNA在制备诊断帕金森病的试剂或试剂盒中的应用,其特征在于,所述的miRNA选自下列中的任一种:
a)miR-105-5p,
b)miR-21-5p,
c)miR-29a-5p,
d)miR-30e-5p,
e)miR-105-5p,miR-21-5p,miR-29a-5p和miR-30e-5p中任两种或任几种的组合。
2.检测血浆中miRNA表达水平的试剂在制备诊断帕金森病的试剂或试剂盒中的应用,其特征在于,所述的miRNA选自下列中的任一种:
a)miR-105-5p,
b)miR-21-5p,
c)miR-29a-5p,
d)miR-30e-5p,
e)miR-105-5p,miR-21-5p,miR-29a-5p和miR-30e-5p中任两种或任几种的组合。
3.根据权利要求2所述的应用,其特征在于,所述的试剂为检测miRNA的引物。
4.一种帕金森病诊断试剂盒,其特征在于,所述的试剂盒含有检测血浆中miRNA表达水平的试剂,所述的miRNA选自下列中的任一种:
a)miR-105-5p,
b)miR-21-5p,
c)miR-29a-5p,
d)miR-30e-5p,
e)miR-105-5p,miR-21-5p,miR-29a-5p和miR-30e-5p中任两种或任几种的组合。
5.miR-105-5p,miR-21-5p,miR-29a-5p或miR-30e-5p的抑制剂在制备治疗帕金森病的药物中的应用。
6.miR-21-5p在制备筛选治疗帕金森病的药物中的应用。
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