CN113584145A - 检测pgrmc1含量的试剂在制备诊断和预测多囊卵巢综合征的试剂盒中的应用 - Google Patents
检测pgrmc1含量的试剂在制备诊断和预测多囊卵巢综合征的试剂盒中的应用 Download PDFInfo
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Abstract
本发明公开了检测PGRMC1含量的试剂在制备诊断和预测多囊卵巢综合征的试剂盒中的应用。本发明发现PCOS患者卵巢组织中平均PGRMC1蛋白的水平明显高于对照组人群。与对照组相比，PCOS组颗粒细胞中PGRMC1mRNA平均表达水平升高。因此可以将孕激素膜受体1作为PCOS患者的生物标记物在临床应用于诊断和预测多囊卵巢综合征，具有广阔的应用前景。
Description
技术领域：
本发明属于医药领域，具体涉及检测人细胞膜孕激素受体(PGRMC1)含量的试剂在制备诊断和预测多囊卵巢综合征的试剂盒中的应用。
背景技术：
多囊卵巢综合征是常见的生殖内分泌代谢性疾病，是一种临床表现多样，以月经异常及不孕为主要表现，伴有以胰岛素抵抗为基础的多种糖脂代谢异常，可增加2型糖尿病、心脑血管疾病、子宫内膜癌、焦虑症及抑郁症等远期并发症，严重影响患者的生命质量、生育及远期健康。2013年中国大型流行病学调查显示：年龄在19-45岁中国汉族妇女中，PCOS的发病率为5.6％。PCOS的发病机制目前尚不明确，与遗传及环境因素密切相关。因此，积极探索PCOS的病因及发病机制已成为妇科内分泌研究最为热门的领域之一。
PGRMC1(孕激素膜受体1)最初被发现是孕酮结合蛋白复合体的一个组分，也被称为人细胞膜孕激素受体(human membrane progesterone receptor，Hpr6.6)。PGRMC1是高度保守的多功能蛋白质，存在于许多系统中，包括生殖系统。PGRMC1蛋白的结构包括一个单次跨膜区域和一个羧基末端细胞色素b5亚铁血红素结合域，PGRMC1可位于胞内、内质网和细胞膜中。近年来，接连有研究报道PGRMC1可与血红素、孕激素、类固醇以及部分蛋白结合的一种多蛋白复合物。PGRMC1目前已知的生物学功能是与血红素结合，PGRMC1与细胞色素b5具有同源性，细胞色素b5是激活细胞色素P450的一种血红素结合蛋白，PGRMC1可能在调节体内代谢、胆固醇合成、细胞的增殖及凋亡等途径起着重要作用。PGRMC1是具有激素受体特征，并且是糖脂质代谢重要调节因子。有大量研究报道，PGRMC1参与调节胆固醇及脂质合成，PGRMC1结合并激活P450蛋白甾醇14a-去甲基化酶Cyp51，该酶催化胆固醇合成途径中的重要反应。PGRMC1促进低密度脂蛋白受体、极低密度脂蛋白受体及葡萄糖转运蛋白-4(Glucose transporter-4，GLUT4)转移至细胞膜，从而调节脂质及葡萄糖的代谢。PGRMC1也能增加细胞膜上的胰岛素受体，参与调节胰岛素及PI3K-AKT信号通路，影响体内碳水化合物的代谢。PGRMC1在肝脏的脂质代谢也发挥重要作用，Lee等PGRMC1基因敲除小鼠的肝中甘油三酯蓄积水平显着增加，更易患非酒精性脂肪肝。
卵巢颗粒细胞与卵母细胞的关系十分密切，卵母细胞缺乏产生糖酵解和胆固醇代谢产物的能力，卵母细胞85％营养有卵巢颗粒细胞提供。卵巢颗粒细胞异常可能影响卵母细胞代谢，导致卵母细胞成熟困难。卵巢多囊样改变是PCOS重要的病理特征之一，其特点包括：卵泡募集增加、卵泡发育停滞、小卵泡的闭锁、无优势卵泡排出和颗粒细胞增殖。近年来，随着对卵巢颗粒细胞增殖及凋亡的研究取得巨大进步，研究发现颗粒细胞异常造成卵母细胞的成熟延迟，因此在PCOS中的作用逐渐引起学者的重视。
发明内容：
本发明的目的是提供检测PGRMC1(孕激素膜受体1)含量的试剂在制备诊断和预测多囊卵巢综合征的试剂盒中的应用。
本发明通过实验发现，PCOS患者卵巢组织中平均PGRMC1蛋白的水平明显高于对照组人群(平均光密度，PCOS vs.对照：0.21±0.12,vs.0.13±0.08,P<0.01)。与对照组(n＝11例)相比，PCOS组(n＝11例)颗粒细胞中PGRMC1 mRNA平均表达水平升高(PCOS组0.22±0.11vs.对照组0.13±0.06)，两组间PGRMC1表达水平差异具有统计学意义(P＜0.05)。孕激素水平随着PGRMC1浓度水平升高而升高。
因此，本发明的第一个目的是提供检测PGRMC1(孕激素膜受体1)含量的试剂在制备诊断和预测多囊卵巢综合征的试剂盒中的应用。
优选，是检测卵巢组织孕激素膜受体1蛋白含量的试剂在制备诊断和预测多囊卵巢综合征的试剂盒中的应用。
本发明的第二个目的是提供检测卵巢颗粒细胞中孕激素膜受体1的mRNA表达水平的制剂在制备诊断和预测多囊卵巢综合征的试剂盒中的应用。
本发明的第三个目的是提供孕激素膜受体1作为PCOS患者的生物标记物在制备诊断和预测多囊卵巢综合征的试剂盒中的应用。
本发明发现PCOS患者卵巢组织中平均PGRMC1蛋白的水平明显高于对照组人群。与对照组相比，PCOS组颗粒细胞中PGRMC1 mRNA平均表达水平升高。因此可以将孕激素膜受体1作为PCOS患者的生物标记物在临床应用于诊断和预测多囊卵巢综合征，具有广阔的应用前景。
附图说明：
图1是卵巢颗粒细胞RNA电泳图；
图2是PCOS及对照组卵巢组织中PGRMC1的情况(A为PCOS组，B为对照组，放大倍数400倍，图上标尺为50μM)；
图3是PGRMC1 mRNA在PCOS患者颗粒细胞表达情况；
图4是PCOS患者卵泡液PGRMC1表达情况；
图5是PGRMC1与E2(A)及P(B)的关系。
具体实施方式：
以下实施例是对本发明的进一步说明，而不是对本发明的限制。
实施例1：PGRMC1在PCOS患者卵巢组织及卵巢颗粒细胞表达
一、材料与方法
1、临床样本的收集
收集2014年至2015年期间就诊于广东省妇幼保健院的腹腔镜下手术患者，符合鹿特丹标准的PCOS患者30例卵巢组织作为实验组，选取年龄、体重与PCOS组匹配的非PCOS患者30例卵巢组织作为对照组。两组患者均行腹腔镜下卵巢楔形切除术，取楔形切除的卵巢组织进行研究。腹腔镜手术收集卵巢组织样本时，其大小应达到整个卵巢组织的十分之一，在卵巢组织表面取一块类似金字塔样结构的组织，该组织应包括有颗粒细胞、卵泡膜细胞、卵母细胞、间质细胞等各种结构。手术将由广东省妇幼保健院具有IV类腹腔镜执业资格的妇科内分泌主任医师进行，以确保临床样本收集的准确性及代表性。
另外收集2020年12月至2021年03月我院行辅助生殖助孕治疗的PCOS及对照组患者的卵巢颗粒细胞，其中PCOS组及对照组各11例。收集样本前，征得医院伦理委员会及患者同意，伦理委员会审批号为：201401011，并与患者签署手术同意书。本研究PCOS诊断标准采用2003年欧洲人类生殖和胚胎与美国生殖医学会(ESHRE/ASRM)指定的鹿特丹诊断标准，即：①稀发排卵或无排卵；②具有高雄激素血症或雄激素过高的临床表现；③妇科超声检查提示一侧或双侧卵巢有≥12个直径2-9mm的小卵泡，或和卵巢体积增大(每侧体积≥10ml，卵巢体积按0.5×长径×横径×前后径计算)；以上3条标准符合2条，并排除其他高雄激素疾病和内分泌疾病，如先天性肾上腺皮质增生、甲状腺疾病、高泌乳素血症、库欣综合征、分泌雄激素的肿瘤、卵巢早衰等。
病例纳入标准为：
PCOS组①符合PCOS诊断；②年龄为18-35岁；③自愿参加本研究，并签署知情同意书。另外促排卵的患者应满足辅助生殖治疗适应症者。
对照组①没有内分泌疾病史，且月经正常病人；②年龄为18-35岁；③已知情同意、自愿参加本研究及依从性好者。
病例的排除标准：①合并有心脑血管、肝肾疾病及血栓疾病等严重原发性疾病；②怀疑或确有酗酒、吸烟或吸毒等不良嗜好的患者；③有卵巢良性或是恶性肿瘤者；④不孕的原因不明确；⑤既往有盆腔手术操作史；⑥患有甲状腺疾病、高泌乳素血症、Cushing综合征等内分泌疾病者；⑦在促排卵周期中出现卵泡过早黄素化以及早发LH峰者；⑧依从性差者，拒绝受试者，不易随访者。
所有纳入的研究对象均由妇科内分泌专业的主任医师级别者进行诊断，所有临床数据由经过专业培训的人员收集。
所有纳入对象均签署广东省妇幼保健院伦理委员会知情同意书。
符合鹿特丹标准的PCOS患者30例卵巢组织作为实验组，选取年龄、体重与PCOS组匹配的非PCOS患者30例卵巢组织作为对照组。
2、卵巢组织病理及免疫组化
2.1、组织切片制备
2.1.1、组织块石蜡包埋
将活检取出的子宫内膜组织用4％甲醛溶液固定(配置方法：40％甲醛溶液和水按1:9比例配制而成)。固定时间以12-24h为宜。将组织块放在固定的容器中用流水冲洗24h后依次用一次70％酒精、80％酒精各脱水2小时，90％酒精脱水1h，95％酒精脱水40min，无水乙醇Ⅰ脱水40min，无水乙醇Ⅱ脱水30min。并可将组织放于70％酒精中过夜。脱水后组织直接浸入二甲苯透明剂中(二甲苯Ⅰ，二甲苯Ⅱ)，每次透明为10min。而后采用56℃-58℃石蜡将组织浸入软蜡Ⅰ1h左右，再浸入软蜡Ⅱ40min；硬蜡Ⅰ40min，硬蜡Ⅱ1h。(一般浸蜡时间为3-4h)软蜡熔点为45℃-50℃，硬蜡熔点为55℃-60℃。最后把蜡液注入包埋硬具中，迅速将组织块平放入蜡液中，摆正并铺平，然后移至冷却台，使组织块同蜡液凝固在一起的过程。(硬蜡凝固定型)
2.1.2、石蜡切片
在切片前先切去标本周围过多的石蜡(此过程称为“修块”)，但也不能留得太少，否则易造成组织破坏，连续切片时分片困难。一般切片厚度为5μm。贴片时先在干净的载玻片上涂一层蛋白甘油，然后于60℃恒温箱中烘烤1-2h，直到玻片烘干；若组织剥脱可涂一层蛋清加以固定。将贴好的片放置在干净的玻片盒中，4℃冰箱保存，备用。
2.2、免疫组化部分
2.2.1、脱蜡和水化
脱蜡前，应将组织切片在室温中放置60min或60℃恒温箱中烘烤20min。然后把组织切片置于二甲苯中浸泡10min，更换二甲苯后再浸泡10min；而后分别在无水乙醇中浸泡、95％乙醇中浸泡以及70％乙醇中各浸泡5min后，用PBS洗两次，每次各5min。接着用蒸馏水或PBS配置新鲜的3％H2O2，室温封闭5～10min，PBS洗3次，每次2min。
2.2.2、包埋
抗原修复，用于福尔马林固定的石蜡包埋组织切片。煮沸热修复，电炉或者水浴锅加热，0.01M枸橼酸钠缓冲溶液(pH6.0)至95℃左右，放入组织切片加热10～15min，加热完毕用自来水冷却至室温，方能将切片取出。用PBS洗5min后，滴加5％BSA封闭液，室温封闭15分钟。甩去多余液体，不洗。而后滴加一抗，4℃过夜(4℃过夜后在室温复温45min)。第二天清晨用PBS洗3次每次2min。接着滴加聚合HRP标记抗兔子/小鼠IgG二抗，室温孵育1h。然后用PBS洗3次每次2min。
2.2.3、显色
用DAB显色试剂盒或者自配显色剂显色(镜下掌握显色程度)，观察至目的信号深背景颜色浅时立即用蒸馏水终止。先用苏木素复染20s，蒸馏水洗2次每次2min。而后把切片依次放入50％、70％、80％、90％、95％、100％乙醇中脱水，每次2min。接着将切片放入100％二甲苯10min透明。最后用中性树脂50ul封片，室温保存。
3、卵巢颗粒细胞和卵泡液收集
在超声引导下穿刺抽取PCOS及对照患者卵泡，留取清亮卵泡液5-10ml，以3000g离心10分钟，分别收集上层清亮的卵泡液及下层卵巢颗粒细胞。收集卵泡液样本至于15ml冻存管中，并储存在-80℃的超低温冰箱中，以待行ELISA检测PGRMC1；收集下层的卵巢颗粒细胞于RNase-free 1.5ml Ep管里，立即进行mRNA提取。共收取27例卵泡液，PCOS组13例，对照组14例；离心所得颗粒细胞共22例，PCOS组及对照各11例。
4、mRNA提取
(1)离心后的卵巢颗粒细胞，加入1ml Trizol试剂，室温裂解10分钟；
(2)加入200μl氯仿，剧烈振荡上充分混匀，室温静置3分钟；
(3)在4℃、12000rpm条件下离心15分钟。样品离心后分为3层：下层无机相，中间和上层为无色水相，RNA位于上层水相中。取上层水相500ml移到新的RNase-free 1.5ml Ep管内；
(4)在Ep管中加入500ml的异丙醇，轻轻地颠倒混匀，室温下静置10分钟；
(5)在4℃、12000rpm条件下髙速离心10分钟，然后弃除管中上清液，管底见白色沉淀；
(6)RNA沉淀的清洗：加入预冷的1ml 75％的酒精，轻轻混匀，充分洗涤白色沉淀；
(7)7500rpm，4℃离心5分钟，弃上清，于超净台内干燥5-10分钟，待酒精挥发干后，每孔加30-40ul的无RNA酶的水，充分溶解mRNA。
5、RNA浓度检测及RNA琼脂电泳
取1μl RNA样本，于Nanodrop ND-1000测定mRNA浓度以及OD260/280比值；取2μlRNA样本行琼脂电泳，以鉴定所提取的RNA完整性，剩余mRNA保存于-20℃，以备后续的逆转录使用。详见图1。
6、cDNA合成
第一步：
反应体系：
在PCR仪中65℃孵育5分钟，然后立即浸入冰中。
第二步：
反应体系：
将第二步反应体系加入到上一步中，在PCR仪中25℃孵育5分钟，然后42℃孵育60分钟，70℃孵育5分钟，-20℃保存备用。
7、RT-qPCR检测PGRMC1 mRNA表达：
总RNA的提取以及mRNA逆转录成cDNA。QPCR采用20μl反应体系：cDNA 1μl、Primer11μl、Primer2 1μl、Mix 10μl、free-water 7μl。PCR循环参数：50℃UPG酶激活2分钟、95℃预变性5分钟；95℃变性15秒、55℃退火30秒,72℃延伸1min，39个循环。表达水平用2-△Ct表达。PCR引物使用Primer Premier5.0软件设计，由上海生工生物有限公司合成(表1)，以GAPDH作为内参。
表1引物设计
8、统计学方法
釆用SPSS25.0分析软件进行数据分析：连续型变量采用均数±标准差表示，所有资料均符合正态分布。用Leneve检验两组的方差齐性，两组方差平齐使用t检验比较组间差异，方差不齐实用t'检验，率的比较用χ2检验。显著性水平α＝0.05(双侧)，当P<0.05时提示差异有统计学意义。
二、试验结果
1、PGRMC1在PCOS患者卵巢组织中表达升高
收集两组患者(PCOS组30例，对照组30例)的卵巢组织，PCOS患者卵巢组织中平均PGRMC1蛋白的水平明显高于对照组人群(平均光密度，PCOS vs.对照：0.21±0.12,vs.0.13±0.08,P<0.01)，如图2所示。
2、PGRMC1 mRNA在PCOS患者卵巢颗粒细胞表达升高
与对照组(n＝11例)相比，PCOS组(n＝11例)颗粒细胞中PGRMC1 mRNA平均表达水平升高(PCOS组0.22±0.11vs.对照组0.13±0.06)，两组间PGRMC1表达水平差异具有统计学意义(P＜0.05)。具体指标及统计学情况见表2及图3。
表2 PGRMC1 mRNA在PCOS患者卵巢颗粒细胞表达差异
实施例2：PGRMC1在PCOS患者卵泡液中的表达
一、研究方法
1、研究对象
收集的卵泡液的方法、病例的纳入及排除标准详见“实施例1的研究方法”。
该研究获广东省妇幼保健院医院伦理委员会批准，所有纳入患者均签署知情同意书。
2、指标测定方法及实验方法
2.1、收集所有研究对象的人体基本参数同实施例1
2.2、促排方案及收集卵泡液方法详见“实施例1中的研究方法中促排方案、收集卵泡及颗粒细胞”。
2.3、取卵数及获卵数：取卵当日，在阴道超声引导下用双腔取卵针逐个抽吸卵泡，记录双侧卵巢抽吸卵泡个数，即卵泡数；获卵数为在获得卵泡数中经冲洗后获得有卵子的卵泡数。获卵率的计算：获卵率＝获卵数/卵泡数。
2.4、ELISA试剂盒测定PCOS和对照患者卵泡液中PGRMC1的测定。本实验采用人PGRMC1酶联免疫分析。试剂盒取出应在室温平衡15-30分钟后方可使用。
(1)标准品的稀释：按照下列表3在进行稀释。
表3标准品的稀释
(2)加样：分别设空白孔(空白对照孔不加样品及酶标试剂，其余各步操作相同)、标准孔、待测样品孔。在酶标包被板上标准品准确加样50μl，待测样品孔中先加样品稀释液40μl，然后再加待测样品10μl(样品最终稀释度为5倍)。加样将样品加于酶标板孔底部，尽量不触及孔壁，轻轻晃动混匀。
(3)温育：用封板膜封板后置37℃温育30分钟。
(4)配液：将30倍浓缩洗涤液用蒸馏水30倍稀释后备用
(5)洗涤：小心揭掉封板膜，弃去液体，甩干，每孔加满洗涤液，静置30秒后弃去，如此重复5次，拍干。
(6)加酶：每孔加入酶标试剂50μl，空白孔除外。
(7)温育：操作同3。
(8)洗涤：操作同5。
(9)显色：每孔先加入显色剂A50μl，再加入显色剂B50μl，轻轻震荡混匀，37℃避光显色10分钟。
(10)终止：每孔加终止液50μl，终止反应(此时蓝色立转黄色)。
(11)测定：以空白孔调零，450nm波长依序测量各孔的吸光度(OD值)。测定应在加终止液后15分钟以内进行。
3、统计学方法
釆用SPSS25.0分析软件进行数据分析：多组间使用单因素方差分析，后进行LSD多重检验分析两两组间差异；两连续变量用Pearson相关分析，采用散点图绘制连续型变量之间的关系图，采用线性拟合绘制相关性曲线。使用GraphPad Prism绘制相关统计图。
4、试验结果
4.1、PGRMC1在PCOS患者卵泡液中表达升高
PCOS组(n＝14例)比对照组(n＝13例)平均PGRMC1浓度水平明显升高(PCOS组1289.75±1206.5vs.531.8±221.56ng/ml)，两组间差异具有统计学意义(P＜0.05)。详见表4及图4。
表4 PCOS患者卵巢卵泡液中PGRMC1表达情况
在取卵前一天检测取卵患者雌二醇(Estradiol，E2)和孕激素((progesterone，P)E2，对PGRMC1与E2及P进行Pearson相关性分析，发现PGRMC1浓度水平与排卵前E2及P的线性相关无统计学意义(P＞0.05)，但根据绘制散点图可见PGRMC1与P存在正相关，孕激素水平随着PGRMC1浓度水平升高而升高。详见表5及图5。
表5卵泡中PGRMC1浓度与E2及P相关性分析
注r表示Pearson相关系数。
Claims (4)
1.检测孕激素膜受体1含量的试剂在制备诊断和预测多囊卵巢综合征的试剂盒中的应用。
2.根据权利要求1所述的应用，其特征在于，是检测卵巢组织孕激素膜受体1蛋白含量的试剂在制备诊断和预测多囊卵巢综合征的试剂盒中的应用。
3.检测卵巢颗粒细胞中孕激素膜受体1的mRNA表达水平的制剂在制备诊断和预测多囊卵巢综合征的试剂盒中的应用。
4.孕激素膜受体1作为PCOS患者的生物标记物在制备诊断和预测多囊卵巢综合征的试剂盒中的应用。
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