GM130在多囊卵巢综合征排卵障碍中的作用机制研究

Polycystic ovary syndrome(PCOS) is the most common endocrinopathy in women of reproductive age characterized by ovulation disorders. Ovulation is a unique biological process that is precisely orchestrated by hormonal regulatory loops and intraovarian regulatory connections operating between theca–granulosa–cumulus cells and the oocyte. Studies have reported ovarian granulosa cells lack a typical Golgi apparatus in PCOS rat model, and destruction of the Golgi apparatus can block the oocyte growth and development. However, the role of Golgi and its molecular functions in ovulation, especially in the pathogenesis of PCOS, has rarely been studied. Our preliminary data showed that GM130 knockout mice displayed typical ovulation disorders, polycystic ovary and excess androgen，while oocyte-specific knockout mice without these phenotypes. Also, GM130 expression is decreased in granulosa cells of PCOS patients. Therefore, we hypothesize that GM130 may be involved in the regulation of ovulation by affecting Golgi functions of somatic cells rather than oocytes. In this project we will use different mouse models to systematically study the role of GM130 in ovulation and its molecular mechanisms. At the same time, we will look for and evaluate some molecules that can modulate GM130. Combined with clinical specimens, we will try to clarify the cause and role of abnormal GM130 expression in PCOS patients and to find effective strategies for PCOS treatment.

多囊卵巢综合征（PCOS）是以排卵障碍为主要特点的常见妇科内分泌疾病。排卵过程是卵巢多种细胞高度有序协同作用的结果，有研究报道PCOS大鼠模型的卵巢颗粒细胞中缺乏高尔基体结构，破坏高尔基体可影响卵母细胞的生长发育成熟。但关于高尔基体及其分子标志物在排卵过程中的作用，尤其是在PCOS发病中的作用仍未可知。我们前期研究发现高尔基体经典标志物GM130全敲小鼠无排卵，雄激素升高，促排卵用药后仍无排卵且卵巢呈多囊样改变，类似人PCOS表型；而卵母细胞特异性敲除小鼠排卵未见异常；此外PCOS患者颗粒细胞中GM130表达降低。故推测GM130可能通过影响体细胞高尔基体功能参与调控排卵。本项目将利用该基因全敲及条件性敲除小鼠，系统研究GM130在排卵中的作用及其分子机制，寻找药物靶标，并结合临床标本检测，探讨解决排卵障碍的干预措施。

多囊卵巢综合征（PCOS）的临床表现之一是排卵障碍，卵母细胞成熟及排卵需要卵巢内多种细胞协同参与。有研究报道PCOS大鼠模型卵巢颗粒细胞中高尔基体结构破坏，卵母细胞成熟受阻。体外敲降高尔基体的经典标志物GM130同样会导致卵母细胞成熟障碍，主要表现为极体排出异常。因此，本项目立项之初是为探讨GM130在PCOS排卵障碍中的分子作用机制，找寻干预途径，并结合临床探讨解决PCOS排卵障碍的干预措施。我们发现GM130在PCOS患者颗粒细胞中表达降低，且GM130全敲小鼠不孕，自然状态下排卵障碍，用药物诱导方可排卵，该表现与临床PCOS患者相似。为进一步解析GM130在卵泡发育及排卵中的作用，我们先后分别构建了卵母细胞特异性敲除小鼠（GM130-ooKO）和颗粒细胞特异性敲除小鼠（GM130-gcKO，FOXL2-Cre和SF1-Cre两种），但发现不论卵母细胞敲除还是颗粒细胞敲除，均未影响排卵及生育，说明GM130全身敲除小鼠不孕并非通过卵母细胞或颗粒细胞单方面直接作用，其导致不孕的原因仍待于进一步研究。本课题丰富了对GM130在卵母细胞成熟及排卵中的认识，为后续相关研究提供了指引。