CN116004790A - 生物标志物的检测产品在制备辅助诊断、诊断或预后评判神经管畸形的产品中的用途 - Google Patents
生物标志物的检测产品在制备辅助诊断、诊断或预后评判神经管畸形的产品中的用途 Download PDFInfo
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Abstract
本发明提供的生物标志物的检测产品在制备辅助诊断、诊断或预后评判神经管畸形的产品中的用途，所述生物标志物为ACSS2基因或其转录产物或其表达产物，本发明经过研究发现，叶酸缺乏通过改变ACSS2导致NTDs的发生，这可能是由于叶酸缺乏导致的NTDs的潜在风险因素，因此，ACCS2基因或其转录产物或其表达产物可以作为生物标志物，该生物标志物的产品可以用于制备辅助诊断、诊断或预后评判神经管畸形的产品，同时抑制该生物标志物的产品能够用于制备缓解、辅助治疗或治疗神经管畸形的产品。
Description
技术领域
本发明涉及生物医药领域，具体涉及一种生物标志物的检测产品在制备辅助诊断、诊断或预后评判神经管畸形的产品中的用途。
背景技术
孕妇的叶酸水平与神经管畸形(NTD)高度相关，母亲补充叶酸NTD风险。NTD可能通过直接影响胚胎代谢生物学而受到环境因素的影响。赖氨酸巴豆酰化(Kcr)可以通过一些未知机制激活基因表达。巴豆酰辅酶A产生酶(ACCS2)，是胃肠道脂肪酸代谢的重要组成部分，在脂质稳态中起着至关重要的作用。然而，目前尚未有相关研究巴豆酰化是否参与NTD，以及ACCS2在叶酸缺乏引起的NTD中的作用。
发明内容
因此，本发明要解决的技术问题在于一种生物标志物的检测产品在制备辅助诊断、诊断或预后评判神经管畸形的产品中的用途。
为此，本发明提供了如下的技术方案：
一种生物标志物的检测产品在制备辅助诊断、诊断或预后评判神经管畸形的产品中的用途，所述生物标志物包括ACSS2基因或其转录产物或其表达产物。
可选的，所述ACSS2基因的转录产物包括ACSS2基因的mRNA。
可选的，所述ACSS2基因的表达产物包括ACSS2蛋白。
可选的，所述生物标志物还包括赖氨酸巴豆酰化水平。
可选的，所述制备辅助诊断、诊断或预后评判神经管畸形的产品包括试剂盒、试纸、试剂、引物、生物芯片、抗体或探针。
可选的，所述检测产品包括试剂盒、试纸、试剂、引物、生物芯片或探针。
一种抑制生物标志物的产品在制备缓解、辅助治疗或治疗神经管畸形的产品中的用途，所述生物标志物包括ACSS2基因或其转录产物或其表达产物。
可选的，所述生物标志物包括赖氨酸巴豆酰化水平。
可选的，所述制备缓解、辅助治疗或治疗神经管畸形的产品包括试剂盒、试纸、试剂、引物、生物芯片、抗体、探针；或
所述抑制生物标志物的产品包括试剂盒、试纸、试剂、引物、生物芯片、抗体、探针。
本发明技术方案，具有如下优点：
1.本发明提供的生物标志物的检测产品在制备辅助诊断、诊断或预后评判神经管畸形的产品中的用途，所述生物标志物为ACSS2基因或其转录产物或其表达产物，本发明经过研究发现，叶酸缺乏导致整体蛋白质组学调节，特别是在关键的巴豆酰辅酶A产生酶中，并引起小鼠胚胎干细胞(MESC)的显著超微结构变化。此外，确定叶酸缺乏会诱导MESC中的乙酰辅酶A合成酶2(ACCS2)和赖氨酸巴豆酰化(Kcr)产生。还研究了叶酸缺乏时的总蛋白质翻译后Kcr，揭示了Kcr在糖酵解/糖异生、柠檬酸循环和脂肪酸生物合成中的关键调节。在小鼠NTDs大脑中观察到丁酸的显著增加，Kcr升高。此外，在小鼠NTD模型的相应低叶酸含量母体血清样品中发现高ACCS2水平。综上研究结果表明，叶酸缺乏通过改变ACSS2导致NTDs的发生，这可能是由于叶酸缺乏导致的NTDs的潜在风险因素，因此，ACCS2基因或其转录产物或其表达产物可以作为生物标志物，该生物标志物的产品可以用于制备辅助诊断、诊断或预后评判神经管畸形的产品，同时抑制该生物标志物的产品能够用于制备缓解、辅助治疗或治疗神经管畸形的产品。
进一步的，叶酸缺乏通过改变ACSS2导致与NTD相关的Kcr上调，因此所述生物标志物还可以包括赖氨酸巴豆酰化水平，该生物标志物的产品可以用于制备辅助诊断、诊断或预后评判神经管畸形的产品，同时抑制该生物标志物的产品能够用于制备缓解、辅助治疗或治疗神经管畸形的产品。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案，下面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图是本发明的一些实施方式，对于本领域普通技术人员来讲，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附图。
图1是本发明实施例中导神经管畸形模型组和正常组的观察表型图；
图2是本发明实施例中叶酸缺乏组的蛋白质热图分析结果；
图3是本发明实施例中细胞组分(Cell Component，CC)分析；
图4是本发明实施例中分子功能(Molecular Function，MF)分析；
图5是本发明实施例中生物过程(Biological Process，BP)分析；
图6是本发明实施例中KEGG途径富集分析结果；
图7是本发明实施例中不同表达蛋白质的热图；图中Con1、Con2、Con3表示叶酸正常组平行试验第1次、2次、3次；Case1、Case2、Case3表示叶酸缺乏组平行试验第1次、2次、3次；
图8是本发明实施中叶酸缺乏组和叶酸正常组的小鼠胚胎干细胞中western blot分析结果；
图9是图8的定量结果；图中横坐标“4”表示叶酸正常组，“0”表示叶酸缺乏组，“0+FA”表示4mg/L+Folic；
图10是本发明实施中叶酸缺乏组和叶酸正常组的小鼠胚胎干细胞的免疫荧光染色分析结果；图中“FA4”表示叶酸正常组，“FA0”表示叶酸缺乏组，“FA0+Folic”表示4mg/L+Folic组；
图11是图10的定量结果；图中横坐标“4”表示叶酸正常组，“0”表示叶酸缺乏组，“0+FA”表示4mg/L+Folic；
图12是本发明实施例中叶酸缺乏组用抗巴豆酰赖氨酸抗体进行westernblotting分析结果；图中Case表示叶酸缺乏组，Con_F表示叶酸正常组；
图13是本发明实施例中3组的mESCs中的巴豆酰赖氨酸进行免疫荧光染色分析结果；图中“4”表示叶酸正常组，“0”表示叶酸缺乏组，“0+FA”表示4mg/L+Folic；
图14是图11的定量结果；图中横坐标“4”表示叶酸正常组，“0”表示叶酸缺乏组，“0+FA”表示4mg/L+Folic；
图15是实施例中正常叶酸(4mg/L)和无叶酸(0mg/L)条件下Kcr位点总数双阈值的火山图；每个点代表一个量化的Kcr位点。上象限和外象限中带颜色的点表示Kcr位点，绿色表示丰度相对减少，橘色表示丰度相对增加(FC≥1.40或≤0.71，P<0.05)；
图16是实施例中叶酸缺乏组和叶酸正常组的分层聚类热图；正常叶酸(4mg/L)和无叶酸(0mg/L)mESCs(每组3个)之间的单个样本和Kcr位点差异；图中Con1、Con2、Con3表示叶酸正常组平行试验第1次、2次、3次；Case1、Case2、Case3表示叶酸缺乏组平行试验第1次、2次、3次；
图17是实施例中差异修饰位点的统计图结果；
图18是实施例中正常叶酸(4mg/L)与无叶酸(0mg/L)mESCs之间确定的赖氨酸-巴豆酰化点的统计数据；
图19是显示已识别巴豆酰化蛋白的亚细胞定位的饼图结果；
图20是实施例中正常组和模型组E13.5胚胎脑神经组织中ACSS2蛋白的Westernblot分析结果；图中CON表示正常组，NTDs表示模型组；
图21是实施例中正常组和模型组的SDS-PAGE检测结果；图中左图为SDS-PAGE结果，右图是western blot结果；
图22是实施例中正常组和模型组(E13.5)的短链脂肪酸检测结果；
图23是实施例中正常组和模型组(E13.5)的颅神经组织中的Kcr的免疫组化分析结果；图中CON表示正常组，NTD表示模型组；
图24是图23的定量结果；图中CON表示正常组，NTDs表示模型组；
图25是实施例中正常组和模型组(E13.5)的颅神经组织中ACOX1的免疫组化分析结果；图中CON表示正常组，NTD表示模型组；
图26是图25的定量结果；图中CON表示正常组，NTDs表示模型组；
图27是实施例中正常组和模型组(E13.5)的颅神经组织中的ACSS2的免疫组化分析结果；
图28是图27的定量结果；图中CON表示正常组，NTDs表示模型组；
上述附图中，p<0.05,p<0.01,和p<0.001表示具有显著的差异。
具体实施方式
提供下述实施例是为了更好地进一步理解本发明，并不局限于所述最佳实施方式，不对本发明的内容和保护范围构成限制，任何人在本发明的启示下或是将本发明与其他现有技术的特征进行组合而得出的任何与本发明相同或相近似的产品，均落在本发明的保护范围之内。
实施例中未注明具体实验步骤或条件者，按照本领域内的文献所描述的常规实验步骤的操作或条件即可进行。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试剂产品。
下述实施例中的Kcr修饰抗体来自景杰公司；抗体ACCS2、ACADS、ACOX1来自Abcam公司。
Dulbecco改良Eagle’s培养基(Gibco,美国)配方：0.1mM的β-巯基乙醇(Gibco,美国)，0.1mM非必需氨基酸(Invitrogen,Carlsbad,美国)、0.1mM谷氨酸盐(Invitrogen,Carlsbad,美国))、15％胎牛血清(Gibco,美国)、4mg/l叶酸盐(Sigma-Aldrich)和1000U/mL小鼠白血病抑制因子(Millipore,Billerica,美国))。
实施例
一、模型的构建
1、动物模型的构建
将雄性和雌性C57BL/6小鼠性成熟小鼠(SPF级)进行一夜交配，第二天早上8点检测到阴道堵塞，记录为受精后胚胎发育天数(E0.5)，同时孕鼠改为低叶酸饮食(低叶酸饲料的配方：低叶酸饮食配方包括酪蛋白23重量份，胱氨酸0.3重量份，玉米淀粉38重量份，麦芽糖糊精13重量份，蔗糖10重量份，纤维素5重量份，豆油8重量份，酒石酸氢胆碱0.3重量份，AIN93多矿3份，AIN93多维1份，该部分已公开在[1]裴培,崔小岱,张霆,王珊.低叶酸联合甲氨蝶呤诱导神经管畸形小鼠模型的建立[J].中华神经外科杂志,2019(02):193-196.))，设置正常组，正常组孕鼠喂养正常叶酸含量饲料，正常叶酸含量饲料购自北京维通利华实验动物技术有限公司。在E7.5，通过腹腔注射1.5mg/kg(小鼠体重)甲氨蝶呤诱导神经管畸形(NTD)模型，正常组腹腔注射等量的生理盐水。待孕13.5天时，颈椎脱臼处死孕鼠，进行解剖，从子宫内剖出胎鼠，观察表型，神经管畸形组(模型组)得到神经管畸形表型明显的胎鼠，见图1所示。
2、细胞模型的构建
取小鼠胚胎干细胞(mESCs，细胞系Sv129)进行培养，设置叶酸缺乏组和叶酸正常组，叶酸缺乏组中培养基中叶酸含量为0mg/L(即Dulbecco改良Eagle’s培养基中叶酸盐含量为0mg/L)，叶酸正常组为叶酸含量为4mg/L(Dulbecco改良Eagle’s培养基)，培养方法和制备方法参见文献(Chang S,Wang L,Guan Y,Shangguan S,Du Q,Wang Y,Zhang T,ZhangY.Long interspersed nucleotide element-1hypomethylation in folate-deficientmouse embryonic stem cells.J Cell Biochem.2013Jul；114(7):1549-58.doi:10.1002/jcb.24496.PMID:23297156.)。
二、实验方法和结果
1、鉴定无叶酸mESCs中差异表达的多种蛋白质
分别从叶酸缺乏组和叶酸正常组的小鼠胚胎干细胞获得的可溶性蛋白(采用0.1％ Triton X-100的PBS溶液提取可溶性蛋白)，进行三次重复的LC-MS/MS鉴定，总共鉴定出6546个蛋白质，其中6011个蛋白质是可量化的。热图分析表明叶酸缺乏诱导mESCs广泛的蛋白质组调控(图2)。为了研究叶酸缺乏对宿主功能的影响，进行了GO富集分析(基因本体论，Gene Ontology，GO)，以确定富含显著调节蛋白的生物过程，如图3、图4、图5所示。根据Fisher精确试验P值，差异表达蛋白(DEPs)的前三个生物过程组如下：羧酸代谢过程、羧酸分解代谢过程、离子跨膜转运。前三个细胞成分是溶酶体、溶液泡和液泡腔。与这些蛋白质相关的前三个分子功能如下：氧化还原酶活性、钙离子结合和质子跨膜转运蛋白活性。然后利用同源蛋白质组聚类(COG)分析对识别的蛋白质进行功能分类。
2、在无叶酸mESCs中诱导并富集关键巴豆酰辅酶A生成酶
使用KEGG途径富集分析鉴定蛋白质数量(叶酸缺乏组和叶酸正常组的小鼠胚胎干细胞获得的可溶性蛋白)，发现大多数参与氨基糖和核苷酸糖代谢、戊糖磷酸途径、精氨酸和脯氨酸代谢以及半胱氨酸蛋氨酸代谢，如图6所示。此外，叶酸缺乏组的小鼠胚胎干细胞(无叶酸mESCs)中几种代谢富集蛋白的高表达，包括巴豆酰辅酶A生成酶，似乎与更好的预后结果相关(对数秩检验，P<0.05)(图7)。巴豆酰辅酶A是脂肪酸氧化和赖氨酸/色氨酸降解过程中产生的内源性中间代谢产物。
为了验证上述的假设，即在叶酸缺乏的情况下，巴豆酰辅酶A的生成和组蛋白巴豆酰化增加，首先分析了无叶酸mESCs中关键巴豆酰CoA生成酶的表达。评估了叶酸的细胞水平是否影响ACSS2的表达。Western blot分析显示，在没有叶酸(0mg/L)的情况下，ACSS2水平升高(图8-9)。mESCs的进一步免疫荧光染色分析证实，无叶酸mESCs中诱导了ACSS2的表达(图10-11，绿色)。这些生成巴豆酰辅酶a的酶的重要部分定位于细胞核，表明这些酶在无叶酸mESCs中具有核作用。
接下来，将一部分叶酸缺乏组的mESCs细胞培养至6代时，用亚叶酸(50mg/L)补充无叶酸培养基，并将其添加到该部分的叶酸缺乏组的mESCs中，得到细胞混合物(亚叶酸的终浓度为4mg/L)，培养24小时后收集细胞，得到4mg/L+Folic组。将该4mg/L+Folic组进行ACSS2蛋白的Western blot分析，结果表明，在叶酸缺乏的情况下，ACSS2上调，而叶酸补充可逆转这种效应(如图8-9)。这表明叶酸补充减弱了叶酸缺乏引起的ACSS2水平升高。此外，本发明发现用亚叶酸处理的细胞中ACSS2病灶显著减少(图10-11)。这些结果进一步表明，mESCs叶酸缺乏诱导ACSS2与叶酸水平密切相关。以上研究结果表明，叶酸缺乏与培养细胞内的巴豆酰辅酶A生成酶的表达增加特别相关。
3、无叶酸mESCs中的全局巴豆酰化(Kcr)
将叶酸缺乏组用抗巴豆酰赖氨酸抗体进行western blotting分析，证实了无叶酸mESCs中的蛋白质修饰(图12)。本发明还对3组的mESCs中的巴豆酰赖氨酸进行免疫荧光染色分析，研究发现，暴露于叶酸缺乏症后，细胞核聚集点中Kcr含量丰富。此外，还发现用亚叶酸处理的细胞中Kcr病灶显著减少(图13-14)。
为了全面了解叶酸缺乏的调节作用，对叶酸缺乏组mESCs(n＝3)和叶酸正常组mEsc(n＝3)进行了总体Kcr底物分析。使用高效液相色谱分离、免疫亲和富集和高分辨率LC-MS/MS来研究无叶酸mESCs中的Kcr底物，检测mESCs细胞。共鉴定出3734个蛋白质中的14311个Kcr位点。与叶酸正常组(图15-17)相比，在叶酸缺乏组的无叶酸mESCs中，共发现292个蛋白上有354个蛋白下调Kcr位点，127个蛋白上有149个上调Kcr位点(倍数变化>0.5；P<0.05)。在这些Kcr蛋白中，1307个蛋白有一个Kcr位点，1267个蛋白有六个以上的Kcr位点(图18)。使用COMPART-230MENTS数据库进行亚细胞定位分析(Lin，Yu，Wu，2019)表明，这些巴豆酰化蛋白在多个腔室中发挥不同的功能，包括细胞核、细胞质、线粒体和质膜(图19)。综上所述，这些结果表明，这可能导致蛋白质巴豆酰化的全局变化。
4、NTD小鼠叶酸缺乏诱导的ACCS2水平
在上述的研究中，在低叶酸饮食条件下，通过腹腔注射MTX(1.5mg/kg)于E7.5，构建了NTD小鼠模型(Pei，Cheng，Yu，2019)。在这一阶段，后脑/颈部边界水平的闭合失败会导致颅脊柱痉挛。在叶酸缺乏小鼠模型中，母鼠的血清叶酸水平显著降低，表明叶酸缺乏影响妊娠早期胎儿的神经发生。通过Western blot分析，比较正常组和模型组脑组织样本中的ACSS2水平。模型组的NTD表型样本中检测到较高水平的组蛋白ACSS2，MTX诱导的E13.5胚胎脑神经组织中ACSS2显著增加，表明ACSS2异常表达可能导致小鼠NTD的发生(图20)。上述的数据表明，由于叶酸介导的1-碳代谢功能紊乱，ACSS2升高可能是神经管闭合早期失败的基础。经抗巴豆酰化抗体免疫印迹证实NTD患者脑组织中的蛋白质发生了改变。还发现，通过SDS-PAGE检测正常组和模型组的脑组织样本，在MTX诱导的E13.5胚胎脑神经组织中，巴豆基赖氨酸显著升高(图21)。
短链脂肪酸可能是细胞内酰基辅酶a的生理相关来源。ACSS2被认为是从巴豆酸酯中生成巴豆酰辅酶A的酶。接下来，使用LC-MS/MS平台定量短链脂肪酸，包括乙酸、丙酸、丁酸、异戊酸、戊酸和己酸。结果表明，丁酸显著增加100倍，异戊酸增加3倍。然而，未检测到乙酸、丙酸、戊酸或己酸的显著变化。结果见图22。
接下来，检测大脑神经组织中Kcr、ACSS2和其他酶ACOX1(催化丁酰辅酶A转化为巴豆基辅酶A)的水平是否异常改变。为此，通过免疫组化分析检测了三个颅神经组织样本和匹配正常组织中的Kcr、ACSS2和ACOX1水平。与正常组织相比，小鼠NTD样本中总Kcr和ACSS2的染色增加(图23-图28)。ACOX1在统计学上没有显著差异。总之，这些结果表明ACSS2表达的上调与叶酸缺乏诱导的小鼠NTD的发生有关，可能是通过调节Kcr水平。
显然，上述实施例仅仅是为清楚地说明所作的举例，而并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (9)
1.一种生物标志物的检测产品在制备辅助诊断、诊断或预后评判神经管畸形的产品中的用途，其特征在于，所述生物标志物包括ACSS2基因或其转录产物或其表达产物。
2.根据权利要求1所述的用途，其特征在于，所述ACSS2基因的转录产物包括ACSS2基因的mRNA。
3.根据权利要求1或2所述的用途，其特征在于，所述ACSS2基因的表达产物包括ACSS2蛋白。
4.根据权利要求1-3任一项所述的用途，其特征在于，所述生物标志物还包括赖氨酸巴豆酰化水平。
5.根据权利要求1-4任一项所述的用途，其特征在于，所述制备辅助诊断、诊断或预后评判神经管畸形的产品包括试剂盒、试纸、试剂、引物、生物芯片、抗体或探针。
6.根据权利要求1-5任一项所述的用途，其特征在于，所述检测产品包括试剂盒、试纸、试剂、引物、抗体、生物芯片或探针。
7.一种抑制生物标志物的产品在制备缓解、辅助治疗或治疗神经管畸形的产品中的用途，其特征在于，所述生物标志物包括ACSS2基因或其转录产物或其表达产物。
8.根据权利要求7所述的用途，其特征在于，所述生物标志物包括赖氨酸巴豆酰化水平。
9.根据权利要求7或8所述的用途，其特征在于，
所述制备缓解、辅助治疗或治疗神经管畸形的产品包括试剂盒、试纸、试剂、引物、生物芯片、抗体、探针；或
所述抑制生物标志物的产品包括试剂盒、试纸、试剂、引物、生物芯片、抗体、探针。
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