小分子肽APEP1在抗子痫前期血管内皮损伤中的作用与机制研究

子痫前期是可危及母儿生命的妊娠期特有疾病，治疗手段有限。APEP1是我们借助多肽组学筛选获得的子痫前期患者血清中差异表达的新功能多肽。前期实验发现APEP1能够改善受损血管内皮细胞增殖和迁移、减少细胞凋亡，缓解模型鼠子痫前期表型，其可能机制是通过结合抗血管内皮细胞损伤因子PPARγ影响其转录调控发挥作用。本研究拟应用多种血管内皮细胞损伤模型和子痫前期动物模型，论证APEP1在恢复受损血管内皮细胞功能中的作用；以PPARγ为机制线索，通过挽救实验策略、物理学方法、荧光素酶报告基因系统、ChIP-seq技术等深入阐明APEP1与PPARγ相互作用机制以及其他可能分子机制；进一步评估APEP1毒副作用、药代动力学和给药后多组织分布特征，为远期的转化应用奠定基础。多肽具有分子量低、稳定性好、亲脂性高、易于入胞等优势，因此，本研究如获成功，有可能为子痫前期临床防治提供新的理论依据和潜在干预手段。

Preeclampsia is a potentially life-threatening condition that affects pregnant women and their babies, but until now treatment options have been limited. APEP1 is a novel unknown function polypeptide with differential expression in the serum of preeclampsia patients obtained by peptide-based screening. Our study has found that APEP1 can improve the proliferation and migration of vascular endothelial cells, decrease the apoptosis, promote the function of angiogenesis, alleviate the clinical symptoms of preeclampsia in model mice, and protect vascular endothelial cell injury. The possible mechanism is that APEP1 acts by binding to PPARγ and affects PPARγ transcriptional activity. It is well known that PPARγ is an anti-vascular endothelial cell injury factor. Further study we will propose to demonstrate the role of APEP1 in restoring damaged vascular endothelial cells. In addition, we will use Physics method and Co-IP technology to demonstrate the binding of APEP1 with PPARγ. Moreover，rescue experiment strategy， dual luciferase reporter assay and ChIP-seq will be performed to demonstrate the molecular mechanism of APEP1 through PPARγ or other possible molecules. Furthermore，we will reveal the toxic side effects, pharmacokinetics and multi-tissue distribution characteristics by evaluating multiple vascular endothelial cell injury models and pre-eclampsia animal models. Peptide has a good molecular basis for low molecular weight, good stability, good lipophilicity, easy to enter cells as a peptide drug. This study may provide a new theoretic basis for the prevention and treatment of preeclampsia, with potential drug development value.