未折叠蛋白质反应介导子痫前期发病的分子机制研究

子痫前期（PE）是妊娠期妇女特有的疾病，病因未明。我们前期发现PE胎盘组织中未折叠蛋白应答显著激活，并伴随NO相关组织炎症上调，提示未折叠蛋白质（UP）的累积与PE组织炎症之间具机制联系。目前，尚无研究报道胎盘组织中UP的定量蛋白质组，因此，上述机制不明。我们前期已完成了10例胎盘组织的UP定量蛋白质组工作。本项目中我们将根据统计功效要求临床样本量，进一步完成比较蛋白质组学工作。利用生物信息学手段预测UP组的形成是由于1）特异性E3连接酶功能异常？还是2）非特异性蛋白酶体/自噬功能障碍？我们将利用体外正常滋养层细胞模型针对上述亚假说进行机制研究，并探索干预这些机制对PE相关炎症的形成和逆转的影响和生物学意义；最后我们将回到临床样本确认这些机制的体内和临床相关性。本项目将有望为PE研究领域提供以未折叠蛋白质组的组成机制为视角的新理论和临床研究方向，并为PE靶向治疗提供潜在的新策略和实验基础。

Preeclampsia (PE) is a pregnancy-specific disorder with unknown etiologies. We have shown that unfolded protein response (UPR) is significantly activated and accompanied by the enhanced NO-relevant inflammation in PE placentas. This suggests that the accumulation of unfolded proteins is mechanistically relevant to PE associated inflammation. As there is no human placenta proteomics analyses published to date focusing on the unfolded proteins, such a mechanism remains unaddressed. We have recently established such a proteomic strategy and analyzed placenta samples from 10 individuals. In this project, we will expand the sample size per statistical power needs, and complete their proteomics analyses. With bioinformatics, we will predict/compute the mechanism of unfolded protein aggregation, following two possible directions: 1) specific and aberrant activity of certain E3 ligases, or 2) non-specific dysfunction of proteasomes/autophagy. We will use human normal trophocytes to test the two sub-hypotheses and evaluate the biological significance of the interference on such mechanisms in the formation and reversion of PE placenta inflammation. These implications will be validated with human placenta samples. This investigation has its potentials to reveal new theories on the PE research focusing on the formation mechanisms of unfolded proteome that leads to novel strategies on the target therapy of PE.