早期胚胎停育是导致女性不孕的重要原因之一，该疾病的发病原因及分子机制尚不明确，缺乏有效治疗手段。申请人前期通过外显子测序结合生物信息学分析，发现早期胚胎停育患者中存在KPNA7基因突变。体外实验发现突变会导致该蛋白表达水平降低，体内研究发现患者早期停育胚胎中KPNA7及转录激活相关基因表达水平下降。我们推测突变通过降低蛋白表达影响早期胚胎转录激活而致病。本研究拟在细胞层面，利用蛋白质组学手段，建立KPNA7结合蛋白库。同时利用人卵突变、siRNA敲降模型，运用单细胞测序技术，揭示KPNA7调控早期胚胎发育信号通路及转录因子。通过构建点突变小鼠模型，模拟疾病表型，验证KPNA7调控通路，全面阐明KPNA7调控早期胚胎发育分子机制及突变致病机制。最后利用小鼠模型，以其中重要通路和关键蛋白为靶标，运用相关药物培养，cRNA注射等手段对疾病的治疗进行探索，为今后开展精准医疗提供理论基础与实验依据。

Early embryonic arrest is one of the leading causes of female infertility. However, little is known about the genetic determinants and, thus potential pathogenic mechanism and treatment of this disease. In our privious study, we detected mutations in KPNA7 in patients with early embryonic arrest by use of whole-exome sequencing followed by bioinformatic analysis. Further study revealed that mutant KPNA7 was down regulated in vitro and KPNA7，as well as transcription activation-related genes were significantly down-regulated in the patients’ arrested embryos. In this project, we plan to build the KPNA7 interaction protein database using the method of proteomics on the cellular level. Find out the signal pathway and transcription factors which was mediated by KPNA7 by single-cell sequencing technique using the mutant and siRNA knockdown oocytes. Generate Kpna7 point mutation mouse models to reproduce the phenotype and to illustrate the molecular mechanism of KPNA7 mediated early embryonic development and the pathogenic mechanisms of early embryonic arrest. Lastly, based on the key factors in the KPNA7 mediated embryonic development pathway, explore the potential treatment of the disease, to provide the theoretical basis and experimental evidence for the precision treatment of the disease.