CN113528650B - Tmp21基因的表达可以作为自闭症早期筛查、早期识别和症状严重程度预测的客观指标 - Google Patents
Tmp21基因的表达可以作为自闭症早期筛查、早期识别和症状严重程度预测的客观指标 Download PDFInfo
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Abstract
本发明公开了一种与孤独症病程相关的报告基因TMP21，孤独症患者体内TMP21低表达，通过给药萝卜硫素(Sulforaphane,SFN)，能够有效缓解孤独症症状，并且提高TMP21表达量，从而为孤独症严重程度和用药治疗提供了客观指标。
Description
技术领域
本发明涉及疾病诊断和治疗领域，具体的说，涉及孤独症谱系障碍病程相关核酸表达的诊断和药物治疗。
背景技术
孤独症谱系障碍(Autism Spectrum Disorder,ASD)是一种高发病率的广泛性儿童神经发育障碍性疾病。这类障碍主要包括狭义自闭症、亚斯伯格症、儿童崩解症、广泛性发育障碍等一系列症状共通而程度不一的疾病。世界卫生组织最新报告显示全球ASD平均患病率约为62/10000(0.62％)，我国ASD患病率约为1％，男性大于女性，农村大于城市，且每年持续上升。
尽管进行了大量的研究工作，但是目前ASD的病因和发病机制尚未完全明确，普遍认为涉及遗传和环境因素之间复杂的相互作用。ASD病因的复杂性和临床表现的异质性限制了有效的治疗药物和干预措施的发展。美国食品和药物管理局(FDA)批准了两种非典型抗精神病药物用于临床ASD患者治疗。但药物无法改变ASD基本病程，仅限于控制某些行为症状，如刻板或强迫性行为、多动或冲动性行为、攻击或自伤性行为等，对于ASD核心症状作用较小。
虽然没有单一的药物或干预措施能够全面改善ASD的行为症状，但相关研究仍在不断取得进展。目前治疗体系倾向于根据患儿不同年龄和症状特点，采取灵活多样的综合干预措施，以行为干预为主，药物治疗为辅。全球已有多家临床机构已经完成或正在开展萝卜硫素(Sulforaphane,SFN)对自闭症治疗效果的临床试验。
早期识别早期干预是提高自闭症治疗有效性的重要环节，然而，目前尚无可靠的客观指标能早期识别自闭症患者。另一方面，SFN对自闭症治疗的有效性也存在极大的个体差异，目前尚不清楚SFN治疗自闭症有效性的生物学机制。目前亟待寻找与疾病症状严重程度相关的客观指标，一方面有助于早期识别自闭症患者，预测其症状严重程度；另一方面为有效治疗自闭症提供新的靶点。
发明内容
本发明针对自闭症症状严重程度相关的客观指标，提供了一种与自闭症病症状病程相关的基因TMP21，设计了其扩增引物，通过检测TMP21基因的表达水平，监测自闭症症状严重程度和病情改善程度，且进一步阐明了SFN通过 TMP21改善自闭症症状可能的机制，提示TMP21基因的表达可以作为自闭症早期识别和症状严重程度预测的客观指标。
具体的，本发明提供了以下技术方案：
第一方面，本发明对SFN治疗自闭症的效果进行了验证，针对自闭症患者进行药物治疗和对照实验；其中，所述药物是SFN，对照组为服用安慰剂 (Placebo,PLA)，根据自闭症症状改善程度，对施用药物进行分组，判断SFN 药物的有效程度。
使用医生评定量表来评估患者治疗前后的临床症状变化。医生评定量表《OSU孤独症评定量表—DSM-IV》(OSU Autism Rating Scale-DSM-IV,OARS-4) (OSU总分平均分是社交障碍、沟通障碍和重复刻板行为评定的三者平均分)，此量表不仅有总分可以评估被试相应问题的总体严重程度，而且都包含丰富维度，适合应用于临床表型与生物特征的关联研究。我们发现OSU总分平均分在治疗前后有改变的趋势但无显著差异。经过分组后，根据施用药物对比，发现SFN对自闭症的治疗具有个体差异。
进一步的，所述治疗药物可以是其他控制某些行为症状，如刻板或强迫性行为、多动或冲动性行为、攻击或自伤性行为的药物，例如利培酮和阿立哌唑等。
第二方面，本发明提供了一种基因TMP21作为自闭症患者症状严重程度和改善程度的客观指标TMP21，所述TMP21基因的GenBank登录号为： NM_006827。
通过抽取自闭症患者和正常人外周血，提取mRNA，进行转录组测序。同时患者在治疗前后，根据OSU平均分改变程度，将患者改善程度不同分为四组：萝卜硫素组OSU改变程度大、萝卜硫素组OSU改变程度小、安慰剂组 OSU改变程度大、安慰剂组OSU改变程度小，并进行转录组数据分析。在三百多差异表达的基因中，我们筛选出一个重要的差异基因，即TMP21的表达在患者中较正常对照组显著下降，经过SFN治疗之后TMP21的表达有明显上升，尤其是在治疗有效组中的TMP21表达显著上升(p＝0.0513)。
转录组测序分析统计方法如下所示：使用非配对的t检验进行两组间的比较，定义置信区间为95％，双尾检验。P<0.05认为具有显著性差异(*)，P<0.01 认为差异很显著(**)，P<0.001认为差异极其显著(***)。
进一步公开了检测TMP21基因表达水平的引物以及抗体；利用所述引物进行转录组检测，以及利用所述抗体进行特异性结合。分析发现OSU的改变程度和TMP21表达的变化程度成负相关，这些结果提示SFN显著改善自闭症症状的机制可能是由于改变TMP21的表达所引起的，TMP21的表达与自闭症症状的改善程度显著相关。
第三方面，本发明公开了SFN改变TMP21表达水平的作用机制。
通过基因工程手段构建Nrf2基因沉默和过表达细胞模型，采用相同培养条件培养，添加SFN后，定时检测TMP21以及Nrf2的表达情况，并设置内参。同时构建荧光蛋白标记，共聚焦显微镜下观察TMP21以及Nrf2表达变化。
结果显示，SFN能够激活细胞中Nrf2表达进而调控TMP21的表达。
优选地，在添加SFN后，沉默Nrf2或者高表达Nrf2开始计时，分别在不同时间段取样，提取细胞总蛋白和总mRNA，对总蛋白使用前述抗体进行蛋白电泳，对Nrf2 mRNA和TMP21mRNA反转录并使用前述引物进行扩增。并且将表达量明显区别于对照组的基因作为待选基因。
优选地，所述取样时间为0h、24h、48h。
优选地，所述检测蛋白和基因表达使用的方法为：Western blot，qPCR以及其蛋白荧光标记等手段。
优选地，根据上述细胞模型，使用的是神经细胞系SH-SY5Y。
优选地，上述基因工程手段构建的Nrf2基因沉默细胞模型可以是瞬时沉默，沉默组为将靶向Nrf2的siRNA转染至上述细胞(Nrf2-siRNA)，对照组为转染空白质粒(Ctr-siRNA)。
优选地，上述基因工程操作中，过表达Nrf2细胞模型中，过表达组转染使用高表达质粒pCDNA4-Nrf2，对照组转染使用pcDNA4空白质粒。
优选地，检测TMP21以及Nrf2两种蛋白表达水平可以使用分别针对Nrf2 和TMP21的单克隆或多克隆抗体。
优选地，所述蛋白荧光标记可以是红色荧光标签和绿色荧光标签，也可以是其他不同颜色的蛋白荧光标记。
优选地，所述SFN改变TMP21表达水平的作用机制是通过调节Nrf2的表达，进而调控TMP21基因的表达。
第四方面，Nrf2调控TMP21基因表达的动物模型验证。
所述验证是通过下述方法实现的：
构建Nrf2基因敲除小鼠模型(Nrf2 KO)，并以野生型(WT)作为对照，从小鼠出生开始计时，分别在不同时间分离小鼠脑海马组织，提取海马组织总蛋白和总mRNA，对总蛋白进行蛋白电泳后使用前述抗体结合，对TMP21 mRNA 反转录并使用前述引物进行扩增，检测不同日龄的小鼠体内TMP21和Nrf2含量变化。
优选的，WT和Nrf2基因敲除小鼠(Nrf2 KO)来源于赛业生物Nrf2基因敲除杂合子小鼠(Nrf2+/-)相互繁殖的后代。Nrf2基因敲除杂合子小鼠品系名称为 C57BL/6-Nfe212tm1cyagen，品系编号为KOCMP-21018-Nfe212。
优选地，所述取样时间为4天，15天，35天，75天，120天，180天。
优选地，动物体内研究表明，Nrf2和TMP21的表达具有正相关性，Nrf2 调控TMP21的表达。
第五方面，本申请公开的TMP21基因作为自闭症的客观指标，用来作为筛选药物以及诊断用途，可以极大的丰富治疗自闭症的药物的可选择性以及提高自闭症的确诊率。
进一步的，将所述基因表达的产品制备成改善自闭症的药物。
过表达或敲低TMP21基因的表达在构建小鼠模型以及模型筛选药物中的应用。
本发明的有益效果包括：
1.本发明首次证实了TMP21在ASD患者中表达量显著下降，而经过SFN 治疗后，TMP21的表达增加，尤其是治疗有效的患者，TMP21的表达是显著上升的。
2.本发明首次公开了SFN通过影响TMP21的表达从而改善自闭症症状的机制，即通过促进Nrf2的表达增加TMP21的表达，表达TMP21是自闭症治疗的一个新靶点，为自闭症病程改变提供了参考依据。
附图说明
为了更清楚的说明本申请实施例中的技术方案，下面将对实施例中所需要使用的附图做简单的介绍，显而易见的下面描述中的附图，仅仅是本申请中记载的一些实施例，对于本领域普通技术人员来说，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的技术方案以及相应的附图。
图1 SFN和安慰剂治疗自闭症效果图，其中，(A)SFN治疗组和安慰剂组 OSU评分，(B)SFN和安慰剂组不同改变程度比较。
图2自闭症病程相关基因筛选图，其中，(A)TMP21在自闭症和正常人外周血中表达量差异，(B)SFN和安慰剂治疗自闭症过程中TMP21表达量变化， (C)SFN和安慰剂组不同改变程度中TMP21表达量分析。
图3 SFN组不同改变程度对TMP21 mRNA表达量变化影响。
图4 OSU评分和TMP21表达量关系。
图5 SFN对Nrf2和TMP21表达量变化的影响，其中，(A)为Western blot 检测在SH-SY5Y细胞经过溶媒对照、SFN处理24h和48h后Nrf2和TMP21的蛋白表达；B为qPCR检测对照组、SFN处理24h和SFN处理48h后Nrf2和 TMP21的mRNA表达；(C)为过表达Nrf2、沉默Nrf2以及添加SFN对TMP21 表达量的影响；(D)为SH-SY5Y细胞经过溶媒对照、SFN处理24h和48h后，Nrf2和TMP21蛋白表达量荧光标记，Nrf2：绿色荧光标记、TMP21：红色荧光标记。
图6 Nrf2敲除小鼠模型和野生型小鼠中TMP21和Nrf2表达量变化，其中(A)为Nrf2沉默小鼠和野生型小鼠不同时间段TMP21和Nrf2蛋白表达量变化；(B)Nrf2沉默小鼠和野生型小鼠不同时间段TMP21mRNA含量变化。
具体实施方式
实施例1：SFN治疗自闭症效果检测
收集24例患者以及21例性别年龄匹配的正常对照作为研究对象，其中12 个患者服用SFN，12个患者服用安慰。使用医生评定量表来评估患者治疗前后的临床症状变化。医生评定量表《OSU孤独症评定量表—DSM-IV》(OSU Autism Rating Scale-DSM-IV，OARS-4)(OSU总分平均分是社交障碍、沟通障碍和重复刻板行为评定的三者平均分)，此量表不仅有总分可以评估被试相应问题的总体严重程度，而且都包含丰富维度，适合应用于临床表型与生物特征的关联研究。
实验结果如图1所示，我们发现OSU总分平均分在治疗前后有改变的趋势但无显著差异(图1A)。
为了更好的确定SFN治疗自闭症的有效性，根据OSU平均分改变程度，我们将24例病患分成四组，所述分组如下：
萝卜硫素组OSU改变程度大(SFN OSU L)；
萝卜硫素组OSU改变程度小(SFN OSU S)；
安慰剂组OSU改变程度大(PLA OSU L)；
安慰剂组OSU改变程度小(PLA OSU S)。
每组各6人，然后进行数据分析，结果如图1B所示：其中SFN OSU L分析显示OSU组前后比较有显著差异，说明SFN OSU L组对SFN治疗最有效。而根据SFN OSU S和SFN OSU L组以及安慰剂组中OSU评分比较，揭示了 SFN对自闭症的治疗具有个体差异。
实施例2：自闭症病程相关基因的筛选
21例正常对照及24例患者在治疗前后分别进行外周血采集，采用标准抽提方法从外周全血中提取mRNA，利用真核生物大部分mRNA都带有polyA 尾的结构特征，通过Oligo(dT)磁珠富集带有polyA尾的mRNA，通过RNA纯度及完整性质控检测之后，进行转录组测序。转录组测序的基本原理是边合成边测序(Sequencing by Synthesis)。在测序的flow cell中加入四种荧光标记的 dNTP、DNA聚合酶以及接头引物进行扩增，在每一个测序簇延伸互补链时，每加入一个被荧光标记的dNTP就能释放出相对应的荧光，测序仪通过捕获荧光信号，并通过计算机软件将光信号转化为测序峰，从而获得待测片段的序列信息。进一步通过与基因组数据库比对，对数据进行基因注释，同时考虑测序深度和基因长度对读数计数的影响，计算映射到每个基因的读数，即基因的表达水平。我们先比较21例正常对照及24例患者在治疗前后的全基因组表达水平，然后进一步根据OSU平均分改变程度，我们将其分成四组，具体分组如实施例1所示，并对所述四组分组进行转录组数据分析。
上述测序使用的引物序列如下所示：
人TMP检测引物：
hTMP E4 F：CCATTAGAGGTAGAGCTGCG
hTMP E5 R：ACTCAATCAATTTCTTGGCC。
转录组测序分析统计方法如下所示：使用非配对的t检验进行两组间的比较，定义置信区间为95％，双尾检验。P<0.05认为具有显著性差异(*)，P<0.01 认为差异很显著(**)，P<0.001认为差异极其显著(***)。
在三百多差异表达的基因中，我们筛选出一个重要的差异基因，即TMP21 的表达在患者中较正常对照组显著下降(图2A)，经过SFN治疗之后TMP21的表达有明显上升(图2B)，尤其是在治疗有效组中的TMP21表达显著上升 (p＝0.0513)(图2C、图3)。由此，可以认为OSU的改变程度和TMP21表达的变化程度成负相关(图4)，这些结果提示SFN显著改善自闭症症状的机制可能是由于改变TMP21的表达所引起的，TMP21的表达与自闭症症状的改善程度显著相关。
实施例3：SFN通过激活Nrf2提高TMP21表达量。
为确定添加SFN是如何引起TMP21表达量变化，筛选了备选基因进行细胞模型验证，具体步骤如下：
1)、使用神经细胞系SH-SY5Y作为实验对象，分别制备Nrf2沉默和高表达细胞模型，并使用空白质粒作为对照；
其中，Nrf2基因沉默细胞模型是通过siRNA技术实现，将携带有靶向 Nrf2的siRNA的质粒转染至上述细胞(Nrf2-siRNA)，对照组为转染空白质粒 (Ctr-siRNA)。同样的，过表达细胞模型使用高表达质粒pCDNA4-Nrf2转染至细胞，对照组转染使用pcDNA4空白质粒，并设置不加SFN的阴性对照组。
2)、构建模型后24h添加SFN，并在第48h取样，细胞破碎后，提取总蛋白和总mRNA进行蛋白电泳和qPCR分析，并设置内参。检测方法如下：蛋白检测为方法为Western blot，分别使用特异性结合Nrf2和TMP21的单克隆抗体或多克隆抗体进行蛋白印染验证，qPCR检测方法为使用前述引物组扩增测序。
3)、分别使用红色荧光标签和绿色荧光标签对TMP21何Nrf2进行标记，并且添加SFN，后续定期通过共聚焦显微镜观察两种蛋白荧光强度。
结果如下：空白对照组中，SFN作用于神经细胞系SH-SY5Y能显著增加 Nrf2的表达的同时显著增加TMP21的表达(图5A-B)，并且随着SFN加药时间推移，Nrf2和TMP21表达量呈现出先升高后降低的趋势。
进一步确定SFN通过激活Nrf2提高TMP21的表达，可以看出，SFN或高表达Nrf2均可上调TMP21的蛋白表达，而沉默Nrf2基因后SFN促进TMP21 表达的作用效果降低(图5C)。在共聚焦显微镜下拍摄的Nrf2和TMP21的荧光信号(图5D)，与图5A-C结果一致。
实施例4.Nrf2对TMP21表达量影响动物模型实验。
为更加准确的确定Nrf2与TMP21之间的相互作用关系，构建WT小鼠和 Nrf2 KO小鼠模型，进行动物水平实验验证，具体步骤如下：
构建Nrf2基因敲除小鼠模型(Nrf2 KO)，并以野生型(WT)作为对照，WT和 Nrf2基因敲除小鼠(Nrf2 KO)来源于赛业生物Nrf2基因敲除杂合子小鼠(Nrf2+/-) 相互繁殖的后代。Nrf2基因敲除杂合子小鼠品系名称为C57BL/6- Nfe212tm1cyagen，品系编号为KOCMP-21018-Nfe212。从小鼠出生开始计时，分别在小鼠出生的第4天，15天，35天，75天，120天，180天分离小鼠脑海马组织，提取海马组织总蛋白和总mRNA，对总蛋白使用前述抗体进行蛋白电泳，对TMP21 mRNA反转录并使用前述引物进行扩增，检测不同日龄的小鼠体内TMP21和Nrf2含量变化，具体操作步骤如前所述。
其中，小鼠TMP21 qPCR引物序列如下所示：
qP mTMP F:TTGAGAGCAAGGGAACAGGG
qP mTMP R:CGTCGTAACTCCACCTCCAG。
结果显示：Nrf2和TMP21蛋白的表达均随年龄增加呈现出先增后减的趋势，在Nrf2KO小鼠中，TMP21蛋白的表达显著下降(图6)。结合之前临床试验结果，提示SFN是通过Nrf2增加TMP21蛋白的表达，从而达到改善自闭症症状的作用。
Claims (9)
1.检测TMP21基因表达的试剂在制备检测药物治疗孤独症进程的试剂盒中的应用。
2.检测TMP21基因表达的试剂在制备指导药物治疗孤独症进程的试剂盒中的应用。
3.根据权利要求1或2所述应用，其特征在于，所述TMP21基因的GenBank登录号为：NM_006827。
4.根据权利要求1或2所述的应用，其特征在于，所述检测TMP21基因表达的试剂包括针对TMP21的引物、抗体。
5.根据权利要求1或2所述应用，其特征在于，所述药物为萝卜硫素(Sulforaphane，SFN)。
6.敲低TMP21基因表达的载体在制备孤独症小鼠模型中的应用。
7.权利要求1中所述的检测TMP21基因表达的试剂在筛选治疗孤独症药物中的应用，所述试剂包括针对TMP21的抗体、引物。
8.过表达权利要求1所述TMP21基因的核酸构建体在制备治疗或辅助治疗孤独症药物中的应用。
9.权利要求1所述TMP21基因表达的蛋白在制备治疗孤独症药物中的应用。
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