CN116832160A - Aβ1-42在制备子痫前期治疗药物或诊断试剂盒中的用途 - Google Patents
Aβ1-42在制备子痫前期治疗药物或诊断试剂盒中的用途 Download PDFInfo
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- CN116832160A CN116832160A CN202310246837.3A CN202310246837A CN116832160A CN 116832160 A CN116832160 A CN 116832160A CN 202310246837 A CN202310246837 A CN 202310246837A CN 116832160 A CN116832160 A CN 116832160A
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- Cardiology (AREA)
Abstract
本发明涉及生物医药工程技术领域，Aβ1‑42抑制剂在制备抗子痫前期药物中的用途、Aβ1‑42抑制剂重组载体及其在制备抗子痫前期药物中的用途，还提供了检测Aβ1‑42含量的试剂在制备子痫前期诊断试剂盒中的用途，并进一步提供了抗子痫药物组合物和子痫前期诊断试剂盒。本发明基于对PE胎盘和被TM刺激的HTR‑8/SVneo细胞的研究发现Aβ1‑42在这些样本中表达较高。因此，可通过检测Aβ1‑42水平来提高PE的准确性和敏感性，为PE的治疗和管理提供更好的方案。
Description
技术领域
本发明涉及生物医药技术领域，具体涉及Aβ1-42作为靶点在制备抗子痫药物中的应用以及作为诊断标志物在诊断子痫中的用途。
背景技术
子痫前期(PE)是一种人类特有的妊娠并发症，发病率为3％-5％，严重威胁着孕妇和胎儿的生命。子痫前期(PE)是一种潜在的严重妊娠高血压疾病，其特征是在妊娠20周后诊断为新发的母体高血压，并伴有涉及一个或多个器官系统的相关终末器官损伤。近年来，虽然人们对PE的认识有了很大的进步，但对PE发生的原因和机制仍然没有准确的解释，子痫前期的病因仍然是个谜。胎盘形成受损被广泛认为是一个主要发病原因，滋养层侵入母体子宫螺旋动脉，这被认为与炎症、局部缺血/缺氧、内质网(ER)应激、氧化应激、内皮功能障碍和不平衡的血管生成有关。
最近的研究表明，PE可能是一种与蛋白质错误折叠聚集相关的疾病，错误折叠的蛋白质在PE患者的尿液、胎盘和血清中积累。Irina A发现PE和公认的蛋白质错误折叠障碍具有相同的病理生理特征，他们还发现这些错误折叠蛋白包括人β淀粉状蛋白(Aβ)。Aβ由淀粉样前体蛋白(APP)产生。人胎盘富含APP，APP酶复合物α、β和γ分泌酶水解产生Aβ肽。Aβ具有高度的低聚和自组装特性，其形成可能与APP蛋白水解过程调控的不平衡有关，但具体哪种Aβ蛋白与PE关系最为紧密，目前尚无相关研究报道。
发明内容
本发明在上述研究的基础上进行，发明人在对PE患者的研究中，发现错误折叠的蛋白具有与Aβ相同的特征，其中Aβ1-42低聚物毒性最强。
通过比较子痫前期(PE)和正常(NP)胎盘组织中Aβ1-42的表达，发现Aβ1-42在PE胎盘中表达明显高于NP，且主要位于滋养层细胞的细胞膜和细胞质中，提供了子痫前期中蛋白质错误折叠特征与Aβ1-42聚集重叠的证据。这为子痫前期的诊断提供了新的标志物，也为寻找新的治疗靶点提供了线索。
基于上述发现，本发明的目的在于提供子痫前期新的诊断标志物或新的治疗靶点。本发明对PE胎盘和被TM刺激的HTR-8/SVneo细胞的研究，发现Aβ1-42在这些样本中表达较高。因此，可通过检测Aβ1-42水平来提高PE的准确性和敏感性，为PE的治疗和管理提供更好的方案。
本发明的第一方面，提供了Aβ1-42抑制剂在制备抗子痫前期药物中的用途。
所述的Aβ1-42抑制剂为任何能够降低Aβ1-42的活性、降低Aβ1-42的稳定性、抑制Aβ1-42的表达、减少Aβ1-42的有效作用时间或抑制Aβ1-42的转录活加工的物质，包括但不限于：特异性干扰Aβ1-42基因表达、加工的小干扰分子，如shRNA分子、siRNA分子、反义核苷酸等；Aβ1-42的拮抗剂、下调剂、阻滞剂、阻断剂等。优选特异性干扰Aβ1-42基因表达的小干扰RNA分子、短发夹RNA或反义核苷酸。
本发明的第二方面，提供了一种Aβ1-42抑制剂重组载体，包括表达载体以及插入设置在该表达载体上的Aβ1-42的siRNA、shRNA或反义核苷酸。
所述的载体包括病毒载体和非病毒载体。所述的“病毒载体”，包括腺病毒、腺相关病毒、慢病毒、柯萨奇病毒、单纯疱疹病毒等。所述的“非病毒载体”包括脂质体或脂类复合物、阳离子多聚物、壳聚糖聚合物及纳米粒子载体等。
与此同时，本发明也提供了该Aβ1-42抑制剂重组载体在制备抗子痫前期药物中的用途。
本发明的第三方面，提供了一种抗子痫药物组合物，包括活性组分以及药学上可接受的赋形剂、载体或稀释剂，所述活性组分为上述所述的Aβ1-42抑制剂或Aβ1-42抑制剂重组载体。
本发明的Aβ1-42抑制剂和药学上可以接受的辅料一起组成抗子痫早期药物组合物，从而更稳定地发挥疗效，这些制剂可以保证本发明公开的双特异性抗体氨基酸核心序列的构像完整性，同时还要保护蛋白质的多官能团，防止其降解(包括但不限于凝聚、脱氨或氧化)。
通常情况下，液体制剂可以在2℃-8℃条件下保存至少稳定一年，冻干制剂在30℃至少六个月保持稳定。制剂可为制药领域常用的混悬、水针、冻干等制剂。
本发明中组合物在对包括人在内的动物给药时，给药剂量因病人的年龄和体重，疾病特性和严重性，以及给药途径而异，可以参考动物实验的结果和种种情况，总给药量不能超过一定范围。
本发明的第四方面，提供了检测Aβ1-42含量的试剂在制备子痫前期诊断试剂盒中的用途。
优选的，所述检测Aβ1-42含量的试剂包括对生物样本中Aβ1-42基因具有检测特异性的引物，或者对Aβ1-42蛋白具有检测特异性的抗体。
所述生物样本选自孕妇的血液、尿液或胎盘。
本发明的第五方面，提供了一种子痫前期诊断试剂盒，分为基因诊断试剂盒和蛋白诊断试剂盒，所述基因诊断试剂盒包括对Aβ1-42基因具有检测特异性的引物，所述蛋白诊断试剂盒包括对Aβ1-42蛋白具有检测特异性的抗体。
进行诊断的方法如下：收集待检测样本，如孕妇的血液或尿液、胎盘组织等；将样本中的Aβ1-42含量进行检测；通过与正常对照组进行比较，判断Aβ1-42的含量是否高于正常水平。
本发明的有益保障及效果：
本发明提供了Aβ1-42在制备子痫前期治疗药物或诊断试剂盒中的用途，基于对PE胎盘和被TM刺激的HTR-8/SVneo细胞的研究发现Aβ1-42在这些样本中表达较高。因此，可通过检测Aβ1-42水平来提高PE的准确性和敏感性，为PE的治疗和管理提供更好的方案。
因此，本发明在子痫前期病人胎盘中检测到错误折叠蛋白(Aβ1-42)，在子痫前期的病因和诊断方面提供了新的视角和思路，也为子痫前期治疗提供了新的方案。
附图说明
图1为PE和NP胎盘组织中蛋白质的β-折叠区域的差别：A，硫磺荧光素T(ThT)检测PE组的阳性率显著高于NP组(6.14％vs 0.99％)，Aβ1-42是蛋白质β-折叠区域中的重要成分之一；B，免疫组化染色的结果显示，Aβ1-42位于滋养层细胞的细胞膜和细胞质中，主要位于绒毛外侧滋养层细胞(EVT)和绒毛膜细胞(ST)；C-D，Aβ1-42的蛋白质水平在PE中呈逐渐增加的趋势。
图2为被TM刺激的HTR-8/SVneo细胞内Aβ1-42的表达。
具体实施方式
以下实施例、实验例对本发明进行进一步的说明，不应理解为对本发明的限制。实施例不包括对传统方法的详细描述，如PCR方法，那些用于构建载体和质粒的方法，将编码蛋白的基因插入到这样的载体和质粒的方法或将质粒引入宿主细胞的方法。这样的方法对于本领域中具有普通技术的人员是众所周知的，并且在许多出版物中都有所描述，包括Sambrook,J.,Fritsch,E.F.and Maniais，T.(1989)Molecular Cloning：ALaboratoryManual，2ndedition，Cold spring Harbor Laboratory Press。
除非另外说明，否则百分比和份数按体积计算。除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明，具体实施方式文中所述的较佳实施方法与材料仅作示范之用。
实施例1、PE和NP胎盘组织中蛋白质的β-折叠区域比较
1、实验材料及处理
在分娩后1小时内，从胎盘母体面中心取得3个无菌状态的胎盘组织样本，每个样本大小约为1×1×1厘米，避开出血、梗死和钙化区域，用无菌PBS润洗3次；同一胎盘标本分为两组：一组标本迅速冷冻在液氮中，然后存放在-80℃，以便后续提取蛋白质和RNA；另一组标本则用4％的多聚甲醛或2.5％的戊二醛固定并进行组织学分析。所有操作尽快在冰桶上进行。
2、免疫组织化学分析
将3个PE和3个NP的胎盘组织进行石蜡包埋，并切割成10微米厚的切片；随后，将3％的过氧化氢孵育，经过5％牛血清白蛋白(BSA)预处理30分钟后，切片在4℃下孵育过夜，使用兔抗人Aβ1-42(1：1000，ab180956，Abcam)孵育；然后使用第二抗体(1:2000，ab150077，Abcam)孵育30分钟。切片用苏木精淡染后观察并拍照。每个蛋白质的实验均重复3次。
3、硫磺素T(Thioflavin T)检测
去石蜡切片首先连续浸泡在两个二甲苯改变液中，每个改变液中浸泡15分钟。用纯乙醇进行两次脱水处理，每次5分钟，然后用梯度酒精，分别为85％和75％的酒精进行脱水，每次5分钟；用水冲洗并用0.3％的硫磺素(Sigma)染色，过滤并在室温下孵育8分钟，然后用DAPI对细胞核染色。最后，切片用PBS洗涤三次并加上盖玻片。荧光显微镜用于检测和收集图像。
4、Westernblot分析
从胎盘和HTR8/SVneo细胞中提取孕期蛋白质，然后使用SDS-PAGE(10％凝胶)将蛋白质(20μg/轨道)分离，之后转移到PVDF膜(Millipore Sigma)；在室温下用5％脱脂奶阻滞1小时后，膜与Aβ1-42(Abcam，1:500)，GAPDH(Abcam，1:2500)的初级抗体在4℃过夜，然后在室温下用荧光偶联的兔抗体(Abcam，1:2000)孵育1小时。使用ChemiScope 6000(CLINX)捕获图像。
上述实验结果参见图1，硫磺荧光素T(ThT)检测结果显示，PE组的阳性率显著高于NP组(6.14％vs 0.99％)，Aβ1-42是蛋白质β-折叠区域中的重要成分之一(图1A)。免疫组化染色的结果显示，Aβ1-42位于滋养层细胞的细胞膜和细胞质中，主要位于绒毛外侧滋养层细胞(EVT)和绒毛膜细胞(ST)(图1B)；Westernblot分析结果显示，Aβ1-42的蛋白质水平在PE中呈逐渐增加的趋势(图1C-D)。
Aβ1-42在PE胎盘中表达明显高于NP，且主要位于滋养层细胞的细胞膜和细胞质中，提供了子痫前期中蛋白质错误折叠特征与Aβ1-42聚集重叠的证据。这为子痫前期的诊断提供了新的标志物，也为寻找新的治疗靶点提供了线索。
实施例2、HTR-8/SVneo细胞内Aβ1-42的表达
1、实验方法
人类胎盘滋养细胞系HTR-8/SVneo，是从早期妊娠的侵袭性绒毛外层细胞(EVT)中分离出来的，具有侵袭等活性。它具有许多与人类原代滋养细胞相似的特征，并已成为研究胎盘功能和妊娠相关疾病的有用工具。经典的内质网应激诱导剂Tunicamycin(TM)在剂量反应研究中使用了2.50和5.0μg/mL。
人胎盘滋养层细胞株HTR8/SVneo从上海中桥新洲生物技术有限公司获得。
TR8/SVneo滋养层细胞株在含有10％胎牛血清(Invitrogen)和1％青霉素的RPMI1640培养基中，在37℃和5％CO2的湿度控制培养箱中培养。进行实验前，HTR8/SVneo细胞在六孔板中种植2mL培养基，密度为2×105个细胞/mL，进行48小时的前处理。在应用tunicamycin(TM)(ab120296，Abcam)处理之前，细胞在无血清培养基中清洗两次。用于剂量反应研究的TM剂量为2.50和5.0μg/mL。DMSO和空白组作为对照组。
2、ELISA分析
使用人类淀粉样蛋白Aβ1-42ELISA试剂盒(比色法)，按照制造商的方案定量测量经TM处理的HTR8/SVneo细胞上清液中分泌的Aβ1-42肽。简要而言，用适量的预冷PBS轻轻洗涤细胞，并使用胰蛋白酶解离；将细胞悬浮液收集到离心管中，并在1000×g下离心5分钟；去掉培养基，用预冷PBS洗涤3次。对于每1×106个细胞，加入150-250μL的预冷PBS以保持细胞悬浮状态。重复冻融过程，直到细胞完全裂解。在4℃下以1500×g离心10分钟。使用ELISA试剂盒分析上清液中Aβ1-42的水平。使用设置为450nm的微孔板读数器测定每个孔的光密度(OD值)。
ELISA结果参见图2，Aβ1-42的表达在TM组中增加，并随着剂量的增加而增加。因此，可通过检测Aβ1-42水平来提高PE的准确性和敏感性，为PE的治疗和管理提供更好的方案。
以上已对本发明创造的较佳实施例进行了具体说明，但本发明创造并不限于所述实施例，熟悉本领域的技术人员在不违背本发明创造精神的前提下还可做出种种的等同的变型或替换，这些等同的变型或替换均包含在本申请权利要求所限定的范围内。
Claims (10)
1.Aβ1-42抑制剂在制备抗子痫前期药物中的用途。
2.根据权利要求1所述的用途，其特征在于：所述Aβ1-42抑制剂为抑制或沉默Aβ1-42基因或降低Aβ1-42蛋白活性或稳定性的物质。
3.根据权利要求2所述的用途，其特征在于：
其中，所述抑制或沉默Aβ1-42基因的物质为干扰Aβ1-42基因表达的小干扰RNA分子、短发夹RNA或反义核苷酸。
4.一种Aβ1-42抑制剂重组载体，其特征在于，所述重组载体包括表达载体以及插入设置在该表达载体上的Aβ1-42的siRNA、shRNA或反义核苷酸。
5.根据权利要求6所述的Aβ1-42抑制剂重组载体，其特征在于：
其中，所述表达载体为质粒载体、粘粒载体、噬菌体载体或病毒载体。
6.检测Aβ1-42含量的试剂在制备子痫前期诊断试剂盒中的用途。
7.根据权利要求6所述的用途，其特征在于，所述检测Aβ1-42含量的试剂包括对生物样本中Aβ1-42基因具有检测特异性的引物，或者对Aβ1-42蛋白具有检测特异性的抗体。
8.根据权利要求6所述的用途，其特征在于：
其中，所述生物样本选自孕妇的血液、尿液或胎盘。
9.一种抗子痫药物组合物，其特征在于，包括活性组分以及药学上可接受的赋形剂、载体或稀释剂，所述活性组分为权利要求1～3任一项所述的Aβ1-42抑制剂或权利要求4所述的Aβ1-42抑制剂重组载体。
10.一种子痫前期诊断试剂盒，其特征在于，分为基因诊断试剂盒和蛋白诊断试剂盒，所述基因诊断试剂盒包括对Aβ1-42基因具有检测特异性的引物，所述蛋白诊断试剂盒包括对Aβ1-42蛋白具有检测特异性的抗体。
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