HIF-1α介导SOX17抑制纺锤体装配检查点相关基因Mps1调控滋养细胞功能的机制研究

母胎界面滋养层细胞增殖能力下降和染色体不稳定性严重影响早期妊娠结局。申请人前期原创发现：核转录因子SOX17在早孕流产绒毛组织中高表达，并在宫内低氧环境下抑制滋养层细胞的增殖，调控其周期。究其原因，为HIF-1α能够介导SOX17转录激活，使其表达异常升高，细胞染色体不稳定性增加。后续机制挖掘提示：SOX17可能通过结合Mps1抑制SAC的激活，致滋养细胞有丝分裂发生障碍，最终导致早孕自然流产的发生。本项目拟在前期工作基础上，阐释HIF-1α/SOX17/Mps1信号轴各成员的调控和互作方式，并用结合位点缺失的突变体验证其对滋养细胞功能的调控影响。进一步地，利用动物实验获得体外、体内双重证据。最后，组织样本中检测HIF-1α/SOX17/Mps1信号轴各成员的表达,与临床因素做单因素/多因素相关性和治疗效果与再流产风险分析，揭示新分子靶点的临床转化意义。

Decreased proliferation and chromosomal instability of trophoblast cells at the maternal-fetal interface seriously affect the outcome of early pregnancy. The applicant’s originally discovered that the nuclear transcription factor SOX17 was highly expressed in the villi tissues of spontaneous abortion. At the meantime, SOX17 inhibited the proliferation of trophoblast cells and regulated cell cycle under an intrauterine hypoxic environment. The reason may be that HIF-1α could mediate the transcriptional activation of SOX17, and increased the risk of cell chromosomal instability. Subsequent mechanism discoveries suggested that SOX17 might inhibit the activation of SAC by combining with Mps1, causing mitosis dysfunction of trophoblast cells, and ultimately leading to spontaneous abortion in early pregnancy. Based on the previous work, this project intends to explain the regulation and interaction of each member of the HIF-1α/SOX17/Mps1 signal axis and use mutants with missing binding sites to verify their regulatory effects on trophoblast function. Furthermore, animal experiments are used to obtain the double evidence in vitro and in vivo. Finally, the expression of each member of the HIF-1α/SOX17/Mps1 signal axis was examined in tissue samples, single-factor/multi-factor correlation with clinical factors, treatment effect and re-abortion risk analysis were performed to reveal the clinical transformational significance of new molecular targets.