CCNB3基因突变干扰卵母细胞减数分裂进程导致反复妊娠丢失相关机制的研究

反复妊娠丢失（RPL）是一种连续发生2次及以上妊娠24周前的胎儿丢失的复杂性疾病，严重损害女性的生殖健康。其中胚胎染色体异常是其最常见且最直接的病因，然而这些异常胚胎往往是来源于染色体正常的育龄夫妇，且目前尚无明确的机制研究。本项目以这一临床现象为研究线索，综合文献研究提出合理猜想，即特定基因的致病突变会干扰卵母细胞减数分裂进程中染色体的正确分离，使得女性因胚胎异常而导致妊娠丢失的发生。本项目前期研究鉴定出CCNB3基因是参与卵母细胞减数分裂进程染色体分离的关键基因，后续拟继续收集相关样本并构建CCNB3同源基因点突变敲除小鼠模型，通过检测卵母细胞及囊胚形态、发育进程、异常染色体比例、交配子代流产表型及相关转录组学和蛋白组学的测序验证，共同探索CCNB3基因调控卵母细胞减数分裂进程中发挥的具体作用及网络调控机制。从而为后续建立RPL新型遗传诊断平台，技术开发与临床治疗提供新的指导和方向。

Recurrent pregnancy loss (RPL) is a complex disorder in which two or more consecutive fetal losses occur before 24 weeks of gestation, which seriously damages the reproductive health of women. Among them, chromosomal abnormalities in embryos are the most common and direct cause. However, the abnormal embryo is usually derived from couples of childbearing ages with normal chromosomes, and the mechanisms are not clear yet. This project takes this clinical phenomenon as the research clue and puts forward a reasonable conjecture based on literature research, that is, pathogenic mutations of specific genes will interfere with the correct separation of chromosomes in the process of oocytes meiosis, leading to recurrent pregnancy loss due to abnormal embryos. The preliminary research of this project identified the CCNB3 gene as a key gene involved in chromosome separation in the process of oocyte meiosis. In the future, we plan to continue to collect relevant samples and construct a CCNB3 homologous gene locus mutation knockout mouse model. Through the detection of oocyte and blastocyst morphology, development process, abnormal chromosome ratio, miscarriage phenotype of mating offspring, and related transcriptomics and proteomics sequencing verification, jointly explore the role of CCNB3 gene in regulating oocyte meiosis process and involved network regulation mechanisms. So as to provide new guidance and direction for the new RPL genetic diagnosis platform, technology development and clinical treatments.