抗宫腔粘连新分子：内源性多肽AIUAP的作用及机制研究

Intrauterine adhesion is a common and intractable gynecological disease. The pathological feature is endometrial fibrosis. AIUAP is an unknown endogenous peptide indentified by mass spectrometry, which is lower expressed in intrauterine adhesion tissues and TGF-β1 induced fibrosis cells. Preliminary experiment found that AIUAP could inhibit TGF-β1 induced cell fibrosis in a dose dependent manner. Pull down experiment showed that AIUAP can interact with Smad2, a factor of TGF-β1/Smad signaling pathway. So we hypothesized that AIUAP may interact with Smad2 and participate in the regulation of TGF-β1/Smad signaling pathway and inhibit the formation of intrauterine adhesion. To verify this hypothesis, we will further detect the expression of AIUAP in the IUA tissues as well as during the formation of intrauterine adhesion and further verify the inhibitory effect of AIUAP during fibrosis. Besides, we will also confirm the interaction between AIUAP and Smad2 and the mechanism of AIUAP function during fibrosis. Finally, we will also clarify the function of AIUAP during intrauterine adhesion formation in vivo. Until now, there is no report of peptide function in intrauterine adhesion. This study is of certain novelty and may provide a new clue for the prevention and treatment of intrauterine adhesion.

宫腔粘连是临床常见而棘手的妇科疾病，子宫内膜纤维化为其病理学特征。AIUAP是我们利用质谱筛选获得的、差异低表达于宫腔粘连组织和TGF-β1诱导的纤维化细胞模型、功能未知的内源性多肽。前期实验发现，AIUAP可剂量依赖性地抑制TGF-β1诱导的纤维化，利用Pull down等实验发现AIUAP可与TGF-β1信号通路下游的Smad2结合，因此我们提出了“AIUAP可能通过结合Smad2参与调控TGF-β1/Smad信号通路，抑制宫腔粘连形成”的科学假说。为论证该假说，本研究拟：进一步明确AIUAP的表达规律；分离原代子宫内膜基质细胞验证AIUAP抑制纤维化的作用；以Smad2为机制主线，探讨AIUAP通过Smad2影响纤维化的机制；在体评估AIUAP在宫腔粘连形成中的作用。目前未见多肽抑制宫腔粘连形成的报道，因此本研究具有源头创新性，如获成功，可为宫腔粘连的防治提供新的靶标。

宫腔粘连的治疗手段为粘连组织的切除及再粘连的预防及促进子宫内膜的再生。但对于重度粘连患者，现有治疗方法预后均欠佳，宫腔粘连发病机制不明，我们从内源性多肽角度来探讨了宫腔粘连的发病机制，我们利用串联质谱的方法筛选宫腔粘连组织和正常增生期子宫内膜组织中差异表达的肽，筛选出了155个前体蛋白的321个肽段差异表达，通过生物信息学分析，进一步筛选出6条差异肽，通过功能验证，AIUAP成为我们的目标内源性多肽。通过细胞实验，我们验证了AIUAP能剂量依赖性地抑制TGF-β1诱导的细胞纤维化；同时我们以Smad2为机制主线，初步探讨了AIUAP通过Smad2影响纤维化的机制。AIUAP 是我们通过多肽组学手段筛选新发现的具有抑制纤维化的内源性多肽，目前未见其他研究报道，具有源头创新性。而多肽类药物具有其毒性低、特异性高、靶向性好等独特的优势，在宫腔粘连和再粘连的预防上具有非常好的应用前景。但仍需要通过技术改进，增加多肽的稳定性，进一步通过在体实验验证其有效性。