新型雌激素受体ER-α36在PCOS卵子发育成熟障碍中的作用研究

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in reproductive-age women. One of the diagnostic criteria is oligo-ovulation or chronic anovulation, but the molecular mechanism underlying follicular development disorder is not totally understood. Recently, a novel variant of ER-α was identified and cloned with a molecular weight of 36 kDa that was named as ER-α36. ER-α36 is mainly localized on the plasma membrane and mediates membrane-initiated signaling pathways. We thus hypothesized that ER-α36 may be associated with follicular development disorder of PCOS. Therefore，we will dissect the interaction between ER-α36 and EGFR, research the role of ER-α36 in EGFR/MAPK/ERK pathway, study the expression of C/EBPβ and analyze the proliferation and luteinization of granulosa cells. The present project will provide an important novel information to further understand the molecular mechanism underlying follicular development disorder and for designing new drugs for the treatment of PCOS.

多囊卵巢综合征（Polycystic ovary syndrome, PCOS）是一种常见的妇科内分泌疾病，稀发或持续无排卵为临床主要特征之一，但是其卵泡发育成熟障碍机理至今不清。雌激素受体-α36（estrogen receptor α 36，ER-α36）是最近发现和克隆的ERα 新的亚型，主要定位于细胞膜，调节胞膜起始的激酶信号通路。本课题拟通过体外培养PCOS患者颗粒细胞和建立大鼠PCOS模型，研究ER-α36与EGFR之间的相互关系；通过转染ER-α36 shRNA干扰质粒探讨ER-α36在EGFR /MAPK/ERK信号通路中的作用，分析下游基因C/EBPβ的表达及颗粒细胞的增殖与分化。为阐明PCOS卵泡发育成熟障碍的分子机制奠定基础，为PCOS的治疗提供参考。

雌激素受体-α36(ER-α36)是最近发现和克隆的ER-α 新亚型。ER-α36主要定位于细胞膜，调节胞膜起始的激酶信号通路，如MAPK/ERK、PI3K/AKT等多条信号通路，参与细胞增殖、肿瘤发生；但是在生殖系统如卵巢、子宫内膜的作用有待进一步研究。ER-α36的功能作用是研究的热点和重点。在颗粒细胞与子宫内膜细胞均发现ER-α36的表达。在本课题的支持下，初步探索了ER-α36在PCOS病人子宫内膜增生病变中的作用，发现新型雌激素受体ER-α36的低表达在PCOS病人子宫内膜增生癌变过程中起着重要作用。同时利用永生化的人KGN颗粒细胞系，发现表皮生长因子(EGF)处理KGN细胞不同时间与剂量诱导了ERK磷酸化；利用腺病毒构建ER-α36的干扰表达病毒，EGF刺激降低了ERK磷酸化。此结果表明EGF/MAPK/ERK信号通路在卵母细胞发育中起着重要作用。同时对IVF-ET技术进行了系统详细评价。