环状RNA BRAP在促进子痫前期发病中的作用及其机制研究

The high incidence of preeclampsia (PE) is a serious threat to the health of pregnant women and fetus. In the previous study, we took the lead in developing and publishing the research of the circular RNA predicting PE, which was highly appraised by the colleagues. Then, the circRNA-BRAP which was significantly increased in the serum of patients with PE was studied, the study showed that silencing the circRNA-BRAP can promote the formation of vascular endothelial cells and invasion of trophoblast, which suggested that it may promote the occurrence of PE; Bioinformatics displayed that it can positively regulate the expression of HIF1 or sFLT-1, which can induce symptoms of PE rat model. Accordingly, we put forward scientific hypothesis that circular BRAP may promotes the occurrence of PE by inhibiting the infiltration of trophoblast and formation of vascular endothelial cells. In order to verify the hypothesis, we will carry out the following research: first the large sample of serum from PE is collected, then we intend to detecte the expression level of circRNA-BRAP for identifying the predictive PE value; to explore the mechanism of circRNA-BRAP high expression from transcription factor, DNA mutation and methylation ; to verificate the circRNA-BRAP biological function in vitro and in vivo model. At last, we intend to elucidate the molecular mechanism that circRNA-BRAP promoting the pathogenesis of PE according to the clinical sample. The completion of this project will help to deepen the understanding of the pathogenesis of PE and provide a new marker for the prediction of PE and the target of treatment for the clinic.

子痫前期（PE）发病率高、严重威胁孕妇和胎儿的健康。前期研究中，我们率先开展和发表了环状RNA预测PE的研究，受到同行高度评价。接着，我们对在PE患者血浆中显著上调的环状BRAP进行了实验研究，发现沉默它能促进滋养细胞浸润和内皮细胞的血管形成，提示它能促进PE的发生；生信分析显示，它能正调控HIF1和sFLT-1的表达，而后两者可诱导大鼠出现PE症状。据此，我们提出科学假设：环状BRAP通过抑制滋养细胞浸润和内皮细胞血管形成促进PE的发生。为了验证假设，我们拟开展以下研究：收集大样本PE的血浆，检测BRAP表达水平，明确其预测PE的临床价值；从转录因子、DNA突变和甲基化等探索BRAP高表达的机制；在体内外模型上验证BRAP的生物学功能，并结合临床样本阐明BRAP促进PE发病的分子机制。本项目的完成将有助于深化认识PE的发病机制，并为临床提供预测PE的新标志物和治疗的靶点。

子痫前期严重危害孕产妇及胎儿生命健康，本项目主要研究环状RNA BRAP等在子痫前期发病中的作用及其机制，以及寻找有效的子痫前期早期预测新模型。通过本国基金青年项目的支持，我们发现①CircBRAP，CircSFXN1，circCRAMP1L，SerpinA5等多个PE 早期预测新型分子标志物。② 证实CircBRAP，CircSFXN1，circCRAMP1L，SerpinA5对螺旋血管重塑或滋养细胞行为的影响。 ③ 从前体基因遗传出发，阐明EIF4A3可能引起环状 RNA BRAP 表达上调的机制。从表观遗传出发，首次揭示环状circRNA m6A修饰（比如circPAPPA2）对子痫前期的可能的作用。④ 阐明环状 RNA BRAP，CircSFXN1，circCRAMP1L，SerpinA5 可通过调控 HIF或MSP信号通路参与 PE 的发生、发展机制。同时我们联合血浆蛋白因子SerpinA5，和超声学以及临床流行病学风险因素做出了一个新的子痫前期预测模型，接着为了方便临床实验室操作方便，我们用circRNA代替临床流行病学风险因素，做出了首个血浆 circRNA和蛋白因子同时联合超声学的全新的预测模型（UtA-PI+sFLT1+circBRAP），为日后临床的筛查提供了新的简易方式且有利于提高灵敏度和特异度。在国际上首次研究了circRNA的甲基化（m6A）在子痫前期中的可能作用，并探讨了其中m6A甲基化修饰的circPAPPA2的功能，这为子痫前期的机制研究提供了一个全新的策略。总之本研究有利于日后的子痫前期机制的深入研究和临床实际运用的可能性。