一种新型内源性多肽AEDPPE用于修复子痫前期血管内皮细胞损伤的应用基础研究

The damage of endothelial cells is the central part of the pathogenesis of preeclampsia (PE). By means of peptidomics, we found AEDPPE, a newly discovered endogenous polypeptide with unknown functions and a low expression in the serum of preeclampsia patients. Our previous study finds that AEDPPE has low molecular weight, good stability, good lipotropy, and an easy access to the cells and their nucleus. Moreover, it can restore the proliferation of the injured endothelial cells and inhibit the cell apoptosis. Furthermore, PE rats injected with AEDPPE showed noticeable recovery from thendothelial cell injuries, indicating that AEDPPE has the potential therapeutic effect on PE. Further pull-down experiments reveal that PARP-1 is a possible target of AEDPPE. and over-activation of PARP-1 can lead to dysfunction and necrosis of endothelial cells, suggesting that AEDPPE may exert its biological activity by affecting the function of PARP-1 .The purposes of this study are fourfold: 1) to evaluate the correlation of AEDPPE and PE by virtue of clinical resources; 2) to evaluate the feasibility of AEDPPE as a drug for PE by revealing the toxicity, pharmacokinetics and multi-tissue distribution after administration; 3) to argue the role of AEDPPE in restoring the function of endothelial cells by utilizing various models of injury and PE animals；4） to thoroughly illuminate the molecular mechanism of AEDPPE via physical methods and the strategy of rescue experiments with PARP-1 as the mechanism clue。 This study will hopefully provide a new opportunity for PE treatment.

AEDPPE是我们借助多肽组学发现的、低表达于子痫前期（PE）患者血清、功能未知的一条内源性多肽。前期发现，AEDPPE具有恢复受损血管内皮细胞增殖、抑制细胞凋亡的功能，在体注射AEDPPE可显著改善PE模型大鼠血管内皮损伤，提示有望成为PE治疗的新手段；Pull-down 实验揭示PARP-1为其可能作用靶标，已证实抑制PARP-1表达可用于治疗子痫前期导致的内皮细胞受损，提示AEDPPE可能通过影响PARP-1功能发挥作用。本研究拟临床评估AEDPPE含量与内皮细胞损伤、PE发生的关系；揭示AEDPPE的毒副作用、药代动力学和给药后组织分布特征，评估其作为PE药物治疗的可行性；应用多种血管内皮细胞损伤模型和PE动物模型，论证AEDPPE作为PE治疗手段的可能性；以PARP-1为机制线索，通过物理学方法和挽救实验策略，深入阐明AEDPPE的分子机制。本研究有望为PE治疗提供新契机。

项目背景：子痫前期是妊娠期特有的疾病，可引发孕妇多脏器功能损害、脑水肿、胎儿生长受限等，是导致孕妇和胎儿病死率最高的疾病之一。目前临床除拉贝洛尔、硝苯地平等极少数药物相对安全外，其余均对母胎存在毒副作用[4]；在治疗措施极度缺乏的今天，终止妊娠仍然是最终手段，而新生儿因孕龄小给个人、家庭和社会带来极重负担。因此，积极寻找健康、有效的子痫前期治疗药物十分迫切。血管内皮细胞损伤是子痫前期发病的中心环节。子痫前期患者滋养细胞浅着床,导致胎盘灌注不足、缺氧缺血等，引起胎盘源性毒性因子产生、血管内毒性物质和炎性介质增多，进而造成全身血管内皮损伤。进一步受损血管内皮细胞释放的舒血管因子减少、缩血管因子增多，引发血管收缩、血管通透性增加，最终导致高血压、蛋白尿等一系列子痫前期的临床症状。AEDPPE是我们通过多肽组学技术筛选到的一条在正常与重度子痫前期患者血浆（或胎盘）样本中差异表达的多肽。 主要研究内容：1.血浆来源的多肽AEDPPE对子痫前期脐静脉内皮细胞的保护作用极其机制。2.多肽AEDPPE对子痫前期滋养细胞的保护作用及其机制。 重要结果：1.血浆来源的多肽AEDPPE显著改善子痫前期血管内皮功能及动物模型的症状。2.胎盘来源的多肽AEDPPE显著改善子痫前期滋养细胞功能及动物模型的症状。 关键数据极其科学意义：AEDPPE是一种内源性多肽，其细胞毒性低，可显著改善子痫前期血管内皮细胞和滋养细胞模型的功能，保护由脂多糖诱导的子痫前期样大鼠模型的症状，AEDPPE对细胞功能和大鼠子痫前期样症状的改善表明其可能成为治疗子痫前期的新药物。