CN116850292A - Sting作为作用靶点在制备防治腹膜炎症和纤维化的药物中的应用 - Google Patents
Sting作为作用靶点在制备防治腹膜炎症和纤维化的药物中的应用 Download PDFInfo
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Abstract
本发明公开了STING作为作用靶点在制备防治腹膜炎症和纤维化的药物中的应用，属于基因功能与应用领域。本发明通过负调控STING表达水平，发挥防治腹膜炎症和纤维化的作用。本发明证明了，在高糖腹膜透析液诱导的腹膜炎症和纤维化模型中，敲除STING可以抑制腹膜的炎症因子释放和炎症细胞浸润，延缓腹膜炎症和纤维化的进展；或者在小鼠模型中注入抑制剂H151，能明显抑制腹膜增厚和腹膜纤维化相关分子的表达，改善腹膜纤维化。实验结果表明，通过基因敲除或者抑制剂负调控STING表达水平，能够发挥预防、缓解或治疗腹膜炎症和纤维化的药效，本发明为腹膜透析液引起的腹膜炎症和纤维化疾病的防治及药物制备提供了新思路。
Description
技术领域
本发明涉及基因功能与应用领域，特别是涉及一种STING作为作用靶点在制备防治腹膜炎症和纤维化的药物中的应用。
背景技术
终末期肾病(End stage renal disease，ESRD)是慢性肾脏病的终末阶段，易出现各种并发症，严重危害患者生命健康，需及时进行透析治疗。腹膜透析(peritonealdialysis，PD)是ESRD患者肾替代治疗的主要治疗方案之一，具有便于开展、费用较低、保护残余肾功能等优点；然而长期的腹膜透析会导致腹膜慢性炎症和纤维化，导致腹膜功能障碍和透析效率降低。目前认为，腹膜慢性炎症是腹膜纤维化的潜在机制，腹膜透析液(PDF)内含有的高浓度葡萄糖可通过激活smad依赖性和smad非依赖性TGF-β通路、结缔组织生长因子(CTGF)信号通路、NOD样受体蛋白3(NLRP3)/白介素IL-1β、IL-6、IL-17等细胞因子相关的炎症途径，诱导腹膜慢性无菌性炎症和纤维化。抑制炎症的发生发展可以有效减轻腹膜纤维化、提高腹膜透析效率。
STING(干扰素基因刺激因子，又称TMEM173、MPYS、MITA)是一种位于内质网的衔接蛋白。STING可以检测胞质核酸，并传递激活I型干扰素反应的信号，从而在先天免疫反应中起主要调节作用。已有研究表明STING可通过激活核因子κB(NF-κB)和干扰素调节因子3(IRF3)转录信号通路启动I型干扰素的表达，在肿瘤、自身免疫病和神经系统疾病等疾病中起重要的炎症和免疫调节作用。因此，针对STING的靶向治疗在炎症相关疾病中具有潜力。然而STING在高糖透析液引起的腹膜炎症和纤维化中的作用及其潜在的调节作用尚未有任何报道。
发明内容
本发明的目的是提供一种STING作为作用靶点在制备防治腹膜炎症和纤维化的药物中的应用，以解决上述现有技术存在的问题，本发明通过基因敲除或者抑制剂负调控STING表达水平，能够发挥预防、缓解或治疗腹膜炎症和纤维化的药效，为腹膜透析液引起的腹膜炎症和纤维化疾病的防治及药物制备提供了新思路。
为实现上述目的，本发明提供了如下方案：
本发明提供STING作为作用靶点在制备防治腹膜炎症和纤维化的药物中的应用，通过负调控STING表达水平，发挥防治腹膜炎症和纤维化的作用。
进一步地，通过基因敲除或抑制剂负调控STING的表达水平。
进一步地，所述抑制剂包括H151。
进一步地，通过负调控STING表达水平，改善腹膜的增厚、胶原沉积和新生血管的生成，以及降低炎症因子和纤维化分子的表达水平，发挥防治腹膜炎症和纤维化的作用。
进一步地，所述腹膜炎症和纤维化包括腹膜透析液引起的腹膜炎症和纤维化。
本发明还提供一种预防、改善或治疗腹膜炎症和纤维化的药物，包含有效剂量的STING抑制剂H151。
进一步地，所述药物还包含药学上可接受的载体。
进一步地，所述载体包括赋形剂、乳化剂和表面活性剂中的一种或多种。
本发明公开了以下技术效果：
本发明证明了，在高糖腹膜透析液诱导的腹膜炎症和纤维化模型中，敲除STING可以抑制腹膜的炎症因子释放和炎症细胞浸润，延缓腹膜炎症和纤维化的进展；或者在小鼠模型中注入抑制剂H151，能明显抑制腹膜增厚和腹膜纤维化相关分子的表达，改善腹膜纤维化。实验结果表明，通过基因敲除或者抑制剂负调控STING表达水平，能够发挥预防、缓解或治疗腹膜炎症和纤维化的药效，本发明为腹膜透析液引起的腹膜炎症和纤维化疾病的防治及药物制备提供了新思路。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，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为STING敲除小鼠和对照组小鼠腹膜中STING表达水平；A：Western blotting图；B：表达水平统计图；C：免疫荧光检测图；
图2为STING缺失改善PDF诱导的腹膜病变结果；A：HE和Masson染色图；B：腹膜厚度统计图；
图3为各组小鼠炎症因子表达状况；A：IL-1β；B：IL-18；C：TNF-α；D：MCP-1；
图4为各组小鼠纤维化表型相关分子表达状况；A：Western blotting图；B：COL1A1表达水平统计图；C：FN1表达水平统计图；D：α-SMA表达水平统计图；
图5为STING抑制剂H151对腹膜增厚和纤维化表型相关分子的改善结果；A：HE和Masson染色图；B：腹膜厚度统计图；C：Western blotting图；D：COL1A1表达水平统计图；E：FN1表达水平统计图；F：α-SMA表达水平统计图。
具体实施方式
现详细说明本发明的多种示例性实施方式，该详细说明不应认为是对本发明的限制，而应理解为是对本发明的某些方面、特性和实施方案的更详细的描述。
应理解本发明中所述的术语仅仅是为描述特别的实施方式，并非用于限制本发明。另外，对于本发明中的数值范围，应理解为还具体公开了该范围的上限和下限之间的每个中间值。在任何陈述值或陈述范围内的中间值，以及任何其他陈述值或在所述范围内的中间值之间的每个较小的范围也包括在本发明内。这些较小范围的上限和下限可独立地包括或排除在范围内。
除非另有说明，否则本文使用的所有技术和科学术语具有本发明所述领域的常规技术人员通常理解的相同含义。虽然本发明仅描述了优选的方法和材料，但是在本发明的实施或测试中也可以使用与本文所述相似或等同的任何方法和材料。本说明书中提到的所有文献通过引用并入，用以公开和描述与所述文献相关的方法和/或材料。在与任何并入的文献冲突时，以本说明书的内容为准。
在不背离本发明的范围或精神的情况下，可对本发明说明书的具体实施方式做多种改进和变化，这对本领域技术人员而言是显而易见的。由本发明的说明书得到的其他实施方式对技术人员而言是显而易见得的。本发明说明书和实施例仅是示例性的。
关于本文中所使用的“包含”、“包括”、“具有”、“含有”等等，均为开放性的用语，即意指包含但不限于。
本发明中，所述的腹膜炎症和纤维化主要指长期腹膜透析引起无菌性炎症和随之发生的腹膜纤维化。
本发明中，所述的STING基因：人类STING(Gene ID：340061)，位于5号染色体q31.28，含有8个外显子。编码了含有379个氨基酸、分子量为42.2kDa的蛋白。
本发明中，实验动物和饲养条件如下：STING敲除小鼠(STING-/-)购自Jackson实验室(货号：025805)。饲养于武汉大学人民医院实验动物中心SPF级环境中(许可证号：SYXK(鄂)2020-0027)，维持温度22℃，相对湿度70％，明暗环境每12小时自动转换。小鼠可自由获得水和食物。实验严格按照武汉大学人民医院实验动物中心实验动物管理规定进行，所有动物实验均得到武汉大学伦理委员会审核批准。
本发明以野生型C57BL/6小鼠和相同背景的STING基因敲除小鼠(STING-/-)为实验对象，通过腹腔内注射含高糖的腹膜透析液获得腹膜纤维化小鼠模型，进行了腹膜形态学评价、STING表达和炎症表型、纤维化表型的研究。结果表明，对照组小鼠中，腹膜未见明显病变。而在实验组中，PDF能明显导致腹膜病变，表现为腹膜的增厚、胶原沉积以及新生血管的生成。STING的缺失可以明显改善腹膜的增厚和新生血管的生成，减轻IL-1β、IL-18、MCP-1、TNF-α等炎症因子的表达。同时STING的缺失也可明显减轻PDF诱导的COL1A1、FN1、α-SMA等纤维化相关分子的表达。SITNG抑制剂H151能明显抑制腹膜增厚和腹膜纤维化相关分子的表达。具体研究如下：
实施例1STING-/-小鼠的鉴定
选择8周龄、体重19g至24g的纯合STING敲除小鼠(STING-/-)为突变型，以C57BL/6J为背景的WT小鼠作为野生型。
使用南京Vazyme公司的小鼠基因鉴定试剂盒(PD104-01)提取待鉴定小鼠的DNA，PCR扩增后通过琼脂糖凝胶电泳进行鉴定。具体步骤如下：剪取待鉴定小鼠尾巴约3mm，放入l.5mL EP管中，根据说明书，按小鼠数量配制组织消化液，充分混匀后使用。向每个含有样本的EP管中加入100uL新鲜组织消化液，55℃金属浴中消化30min，随后将样本置于95℃水浴中孵育5min以灭活消化液中的蛋白酶。12000rpm离心5min，取上清液作为PCR模板。上下游引物序列如表1所示，最后通过琼脂糖凝胶电泳鉴定所需基因。
表1
为确定STING敲除小鼠是否构建成功，本发明通过Western blotting和免疫荧光检测STING的表达。与对照组相比，STING敲除小鼠腹膜中STING表达显著降低，证明构建成功(图1)。
实施例2小鼠腹膜纤维化模型构建和取材
1.实验动物分组：
基因敲除实验：将12只野生型小鼠和12只突变型小鼠平均分配至实验组和对照组。实验组小鼠每日于腹腔注射腹膜透析液(4.25％葡萄糖，H20023569,Baxter,USA)，剂量为100mL/kg；对照组注射等量的生理盐水；实验周期为6周。
药物实验：选择24只野生型小鼠平均分配至实验组、对照组和模型组，实验组和模型组小鼠每日于腹腔注射腹膜透析液(4.25％葡萄糖，H20023569,Baxter,USA)，剂量为100mL/kg；对照组注射等量的生理盐水；同时实验组小鼠注射SITNG抑制剂H151(7mg/kg/day,MedChemExpress,China)，实验周期为6周。
2.取材：麻醉小鼠，将皮肤与皮下组织分离，暴露小鼠腹壁肌肉。沿小鼠两侧肋弓下缘、腰椎左右缘、髂骨上缘剪开，将小鼠腹膜连同腹壁肌肉一并取出。组织固定于4％多聚甲醛中。隔夜固定后，将腹膜用滤纸小心包好，放入包埋框后流水冲洗，然后按照下列步骤包埋切片：脱水→透明→浸蜡→包埋→切片(3μm)→摊片→晾干后备用。
实施例3腹膜纤维化小鼠模型形态学的观察
1.HE染色
1.1.脱蜡：55℃烘烤30min→二甲苯5min×3次→无水乙醇1min→95％酒精1min→70％酒精1min→ddH2O 1min
1.2.染色：苏木素溶液(Beyotime，C0105S)，5min→水洗1min→1％盐酸-酒精溶液1-3s→水洗1min→Scott液(碳酸氢钠0.35g，硫酸镁2g，ddH2O 100mL)1min→水洗1min→伊红溶液(Beyotime，C0105S)3-5min→ddH2O洗去浮色→70％酒精1s→95％酒精1s→100％酒精30s×3次→二甲苯2min×3次→立即封片→通风橱内吹干。所有显微图像均由正置显微镜(Olympus，日本)记录。
2.Masson染色
2.1.脱蜡：按实施例3中1.1的步骤进行
2.2.染色：Weigert苏木素5min→1％酸性乙醇分化液10s→蒸馏水10s→蓝化液(0.1％氨水)10s→丽春红1min→水洗10s→0.2％冰醋酸1min→1％磷钼酸1min→2％甲苯蓝→0.2％冰醋酸20s×3次→95％乙醇20s→无水乙醇1min×3次→二甲苯1min×3次→封片。所有显微图像均由正置显微镜(Olympus，日本)记录。
结果表明，基因敲除实验中，对照组小鼠的腹膜未见明显病变。而在实验组中，腹膜透析液(peritoneal dialysis fluids，简称PDF)能明显导致腹膜病变，表现为腹膜的增厚、胶原沉积以及新生血管的生成。STING基因缺失以后，腹膜胶原沉积明显改善，未见明显的新生血管。表明了STING缺失可以明显改善PDF诱导的腹膜病变(图2)。
实施例4小鼠炎症指标表型的检测
1.qPCR检测
1.1.Trizol提取总RNA：用镊子小心将腹膜与腹壁肌肉分离，将腹膜转移如1.5mlEP管中并迅速用液氮研磨仪粉碎。然后按下列步骤提取总RNA：每50mg样品加入1ml Trizol→充分均浆1-2min→12000rpm/min离心5min，弃沉淀→每1ml Trizol加入200μl氯仿，振荡混匀15s，室温放置10min→12000rpm/min离心15min→吸取上层水相，移至另一EP管中，按每1ml Trizol加入0.6ml异戊醇，混匀放置室温5-10min→12000rpm/min离心15min→按每1ml Trizol加入1ml 75％乙醇，温和振荡，悬浮沉淀。
1.2.qPCR：使用One Step TB Green Prime Script Kit试剂盒(Taraka,Japan)进行RT-PCR，使用CFX96 Touch(Bio-Rad,USA)进行定量分析。
最后，将目标基因的相对水平归一化为GAPDH进行分析。qPCR引物如表2所示。
表2
2.免疫组织化学染色和免疫组织荧光：
2.1.脱蜡：按实施例3中1.1的步骤进行。
2.2.免疫组织化学染色：在柠檬酸缓冲液(0.01mol/L,pH6.0)微波修复抗原10min→3％H2O2室温避光孵育20min封闭内源性过氧化物酶→PBS清洗5min→5％BSA阻断1hr→一抗孵育过夜→PBS清洗5min×3次→对应二抗孵育60min→辣根酶标记链酶卵白素，37℃，15min→DAB显色后，自来水冲洗10min→苏木素复染3min→自来水冲洗返蓝10min，75％盐酸酒精分色→水冲洗10min→梯度酒精脱水、二甲苯透明→封片。所有显微图像均由正置显微镜(Olympus，日本)记录。
2.3.抗体种类与浓度见表3.
表3
结果表明，免疫组化显示PDF导致了巨噬细胞(标记物F4/80)和中性粒细胞(标记物Ly6b)的浸润，同时上调了炎症因子IL-1β、IL-18、MCP-1、TNF-α的表达。STING的缺失可以明显改善PDF诱导的腹膜炎症细胞浸润和炎症因子表达(图3)。
实施例5小鼠纤维化表型的检测
1.Westernblotting
1.1.腹膜总蛋白提取：用镊子小心将腹膜与腹壁肌肉分离，将腹膜用RIPA裂解液裂解→15000g离心15min→收集上清，加入5×loading buffer后95℃金属浴5min。
1.2.Western blotting检测蛋白表达：配制10％SDS-PAGE凝胶→取20μL蛋白样本及5μL预染蛋白Marker上样、进行电泳，浓缩胶电泳电压为90V，分离胶电泳电压为120V→溴酚蓝指示剂到达凝胶底部时结束电泳→制作电转“三明治”夹层，放入装有电转液的电转槽中，在低温下，使用200mA固定电流转印90min→TBS漂洗PVDF膜5min×3次→5％脱脂牛奶室温封闭1h→TBST漂洗PVDF膜5min×3次→4℃一抗孵育过夜→TBST漂洗PVDF膜5min×3次→二抗室温孵育1hr→TBST漂洗PVDF膜5min×3次→Bio-Rad扫膜成像仪对条带进行扫描，Bio-Rad公司软件分析条带的灰度。利用image J测定灰度并统计。
1.3.抗体及浓度见表4。
表4
结果表明：纤维化表型相关分子COL1A1、FN1、α-SMA等分子在对照组中表达较少。PDF可以明显诱导COL1A1、FN1、α-SMA等纤维化相关分子的表达。而STING的缺失可明显减轻PDF诱导的纤维化相关分子的表达(图4)。
同样对药物实验的实验组、模型组和对照组小鼠进行腹膜形态学染色和纤维化表型的检测，实验结果如图5，结果表明：STING抑制剂H151能抑制腹膜增厚和抑制纤维化表型相关分子COL1A1、FN1、α-SMA分子表达，对小鼠PDF引起的腹膜炎症和纤维化具有改善治疗作用。
综上所述，本发明以STING转基因小鼠为基础，或者在腹膜纤维化小鼠模型中注入H151，验证STING的表达与腹膜纤维化的关系。结果表明：STING敲除或注射STING抑制剂均能抑制腹膜炎症的发生发展，抑制腹膜纤维化的表现。证明了抑制STING能改善治疗小鼠腹膜透析液引起的腹膜炎症和纤维化。
以上所述的实施例仅是对本发明的优选方式进行描述，并非对本发明的范围进行限定，在不脱离本发明设计精神的前提下，本领域普通技术人员对本发明的技术方案做出的各种变形和改进，均应落入本发明权利要求书确定的保护范围内。
Claims (8)
1.STING作为作用靶点在制备防治腹膜炎症和纤维化的药物中的应用，其特征在于，通过负调控STING表达水平，发挥防治腹膜炎症和纤维化的作用。
2.根据权利要求1所述的应用，其特征在于，通过基因敲除或抑制剂负调控STING的表达水平。
3.根据权利要求2所述的应用，其特征在于，所述抑制剂包括H151。
4.根据权利要求1所述的应用，其特征在于，通过负调控STING表达水平，改善腹膜的增厚、胶原沉积和新生血管的生成，以及降低炎症因子和纤维化分子的表达水平，发挥防治腹膜炎症和纤维化的作用。
5.根据权利要求1所述的应用，其特征在于，所述腹膜炎症和纤维化包括腹膜透析液引起的腹膜炎症和纤维化。
6.一种预防、改善或治疗腹膜炎症和纤维化的药物，其特征在于，包含有效剂量的STING抑制剂H151。
7.根据权利要求6所述的药物，其特征在于，所述药物还包含药学上可接受的载体。
8.根据权利要求7所述的药物，其特征在于，所述载体包括赋形剂、乳化剂和表面活性剂中的一种或多种。
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