Chemerin/CMKLR1信号通路调节滋养细胞侵润与子痫前期病理发生关系的研究

The incidence of preeclampsia (PE) increased dramatically in pregnant woman with preexisting hypertension and metabolic disorder with carbohydrate and lipid conditions. Literature review found that chemerin,a novel adipokine, is upregulated in the above conditions, which could be the internal link of the above metabolic disorders induced PE and PE induced postpartum high incidence of these disease, also could be the key cause of PE. However, there is no experiment proof to date to prove the relationship of chemerin with PE development. Our preliminary data shown that chemerin is upregulated in the PE placenta, the trophoblast invasive ability increased after knockout chemerin or its receptor CMKLR1, which indicates that chemerin involve the regulation of trophoblast invasion and related to the phenomena of its high level in the PE placenta and shallow trophoblast invasion. So, in this proposal, in vitro cell culture experiments, controllable in vivo placenta- and endometrium- specific overexpression of chemerin combined with chemerin/CMKLR1 knockout were used to investigate the involvement of chemerin and CMKLR1 pathway with the disease development of preeclampsia by overexpress chemerin from different temporal (before pregnancy, early-, mid- and late- pregnancy) and spatial (placenta-, endometrium- or maternal origin) combination. In addition, the CMKLR1 inhibitor will be tried on the treatment of PE, and investigating the possibility as a treatment drug. The results from this proposal will provide new target and theory basis for preeclampsia diagnosis and treatment.

糖脂代谢紊乱、高血压等均显著提高子痫前期（PE）发病率，文献显示脂肪因子chemerin在上述疾病中表达异常，可能是诱发PE的内在关联和PE发病的关键因素，但至今尚无证据表明chemerin在PE发病中的作用。我们前期工作发现，PE患者胎盘中chemerin表达升高，并且chemerin及受体CMKLR1敲除鼠的滋养细胞侵入能力加强，提示chemerin通过CMKLR1调控滋养细胞的侵润，与chemerin在PE胎盘高表达和滋养细胞侵入浅表现象相关，在PE发病中有重要作用。因此，本研究用chemerin和CMKLR1敲除小鼠，结合体外、体内可控的胎盘和子宫内膜特异性基因过表达手段，阐明chemerin在不同时（妊娠不同时期）空（胎盘、子宫和母体）组合上过表达与PE发病的关系，并用CMKLR1抑制剂治疗PE模型，探讨CMKLR1成为PE治疗靶点的可能性，为PE的预防和诊治提供靶标和理论依据。

糖脂代谢紊乱、高血压等均显著提高子痫前期（PE）发病率，文献显示脂肪因子chemerin在上述疾病中表达异常，可能是诱发PE的内在关联和PE发病的关键因素，但chemerin在PE发病中的作用不明。通过本项目支持，我们研究发现PE患者胎盘中chemerin表达升高，通过在妊娠早期开始胎盘特异性基因过表达，明确了chemerin时空上特定过表达可以诱发小鼠出现妊娠高血压、蛋白尿、肾小球血管内皮细胞增生和胎儿发育迟缓等子痫前期样症状。并明确了治疗靶器官和治疗时间；进一步实验明确了chermin-CMKLR1信号通路参与了子痫前期病理发生的过程，明确治疗靶点；在明确治疗靶器官、时间点与靶向分子后，缺少的为胎盘靶向给药系统。因此，改变了原项目申请书中最后一项，转攻胎盘靶向药物递送系统开发。并且通过实验成功的开发出了胎盘滋养细胞特异性的纳米药物递送系统，并通过载药MTX验证了此系统胎盘给药的安全性，只对胎盘起作用，而对母体没有副作用，并且药物不能通过胎盘到达胎儿。结果表明，我们成功的建立了一个安全的胎盘特异性药物投递系统，为子痫前期动物模型的建立、防治研究以及临床防治药物开发等提供了新的参考与新手段。