Adipsin/C3a在子痫前期致病机制中的作用及其作为子痫前期预警标志物的应用价值研究

Preeclampsia is seriously harmful to mother and fetus. Vascular endothelial injury plays an important role in the pathogenesis of preeclampsia, but the molecular mechanism remains unclear. In the preliminary study, our data were showed that adipsin was significantly higher in the serum of preeclampsia patients than the healthy pregnant women. Adipsin activated the complement C3 in the alternative pathway and lead to C3a was largely produced and accumulated in the circulation. On the other hand, C3aR, receptor of C3a, was highly expressed on the membrane of vascular endothelial cell. Therefore, we hypothesized that the significant elevated adipsin in the circulation of pregnant women will cause the over-activation of alternative pathway of complement and lead to the accumulation of C3a, which is able to bind to C3aR on the membrane of vascular endothelial cells, induce the down pathway and cause the damage of stability and permeability of blood vessels, and result in preeclampsia. In this study, we attempt to reveal the role and mechanisms of adipsin and C3a on vascular endothelial cell dysfunction in preeclampsia with in vitro experiment and animal model. And further, we try to explore the relationship between serum adipsin/C3a and the preeclampsia with pregnant women follow-up study. This research data will contributes to demonstrate the mechanism of vascular endothelial injury for preeclampsia involved with adipsin/C3a, explore a novel candidate target for the prevention and treatment of preeclampsia, and evaluate the clinic value of serum adipsin/C3a as a risk predict biomarker for preeclampsia. It will be greatly benefit to the prevention and treatment of preeclampsia.

子痫前期严重危害母婴健康。血管内皮损伤在其发病机制中占有重要地位，但具体的分子机制不明。我们的前期研究发现：活化补体替代途径的关键分子adipsin在子痫前期病人血液中的水平显著高于健康妊娠者。Adipsin活化补体C3将大量产生C3a，而C3a的受体C3aR在血管内皮细胞膜上高表达。据此推测：由于妊娠期血液中adipsin水平异常升高，过度活化补体导致C3a大量蓄积，C3a与受体C3aR结合，破坏血管稳定性和通透性，引起血管损伤导致子痫前期。本课题组拟通过体外细胞学实验、动物实验和临床随访研究，系统深入地研究以阐明adipsin/C3a的子痫前期血管内皮损伤机制，为子痫前期的防治寻找新的靶点，并明确血液中adipsin/C3a作为子痫前期预警标志物的应用价值，对于子痫前期的防治具有重要的科学意义和临床实践价值。

子痫前期严重危害母婴健康。血管内皮损伤在其发病机制中占有重要地位，研究参与子痫前期血管内皮损伤的关键蛋白分子及调控因素是本课题组的长期研究方向。本项目在四年的执行期内，根据项目要求和研究计划，通过体外细胞学实验、动物实验和妊娠女性临床随访研究，利用细胞生物学、免疫学和小动物磁共振检测技术和方法，系统深入地研究了adipsin/C3a对血管内皮细胞及血管的损伤作用和机理，发现补体水平改变引起血管内皮细胞上血管生成相关的细胞膜受体CD54、CD105、VEGFR1表达、血管内皮细胞增殖和血管形成能力出现改变；同时，补体水平改变导致单核细胞上C3aR、C5aR、ENG和ICAM-1表达发生改变，提示adipsin/C3a路径对血管内皮细胞的损伤作用有单核细胞的积极参与。本项目的临床随访研究发现了血液中adipsin可能是监测妊娠早期子痫前期发生风险增加的一种新型生物标志物，明确了血液中adipsin/C3a作为子痫前期预警标志物的应用价值，对于子痫前期的防治具有重要的科学意义和临床实践价值。根据研究数据整理的研究结果已发表论文3篇，获得授权发明专利1项。