生殖内分泌激素对多囊卵巢综合征（PCOS）蛋白质糖基化的调控及致病机制的研究

The incidence of polycystic ovary (PCOS) is high both in China and abroad. It is the most common cause of infertility among gynecological diseases. Although the diagnosis of PCOS is reproductive endocrine disorder (hyperantrogenism, increased estrogen and decrased progesterone, et al.) and polycystic pathology of ovary, the detailed mechanism is still unclear. Our research team has been studying reproductive biology on glycobiology for many years. Recently, we got important finding that protein glycosylation was different in the serum of PCOS patients vs. normal control female, which has not been reported before. In this study, by MALDI-TOP-MS and lectin chip analysis, to screen and confirm the charcteristic sugar chains, which will be used as glycosylation marker of PCOS to set up the new sensitive and specific serum assay for PCOS; Using clinical samples, cells and animal models to illucidate the regulatory effects of different reproductive endocrine hormones on the features and rules of glycosylation; Select the key glycotransferases which control the abnormal sugar chain biosythesis to illucidate the sugar-molecule related mechanism by regulation of enzyme gene expression and point mutation of active site. To further confirm the correlation between PCOS caused by abnormal glycosylation and infertility. The project initiates from the ergent clinical problem and proposes that abnormal glycosylation is a novel mechanism of PCOS etiology. It will apply the potential target for clinical diagnosis and treatment. It has important theoretical and practical significance.

国内外多囊卵巢综合征（PCOS）发病率高，是引起不孕症最常见的妇科疾病。尽管临床诊断为生殖内分泌激素紊乱（高雄酮、高雌激素、低孕激素等）及卵巢多囊性病理改变等，但发病机制不清楚。课题组多年开展生殖生物学的糖分子机制研究，近期有重要发现：PCOS患者和正常育龄妇女血清中蛋白质糖基化有明显差异，相关研究未见报到。课题拟利用MALDI-TOP-MS和凝集素芯片等，筛选并确证患者血清中特征糖链，并作为PCOS糖基化标志物建立灵敏特异的血清学检测新方法；利用临床样品、细胞、动物模型，研究不同生殖内分泌激素所致的PCOS糖基化变化特点和规律；选择调控异常糖链合成的关键糖基转移酶，通过酶表达调控和活性位点突变等，阐明PCOS发生的糖分子机制，并验证PCOS异常糖基化与不孕症的相关性。课题从亟待解决的临床问题出发，提出异常糖基化为PCOS病因机制的新学说，为临床诊治提供新靶点，具有重要理论和实际意义。

国内外多囊卵巢综合征（PCOS）发病率高，是引起不孕症最常见的妇科疾病。尽管临床诊断为生殖内分泌激素紊乱（高雄酮、高雌激素、低孕激素等）及卵巢多囊性病理改变等，但发病机制不清楚。本课题通过凝集素芯片、细胞因子芯片等比较PCOS患者和正常育龄妇女血清中糖链结构以及蛋白质的差异，利用临床样品、细胞、动物模型探讨激素、糖基化、细胞因子在PCOS发病过程中的作用和机制。项目得到如下结果：（1）通过凝集素芯片发现PCOS患者和正常育龄妇女血清中蛋白质糖基化有明显差异，通过ELISA、lectin blot等方法，确证患者血清及子宫内膜组织中特征糖链变化（甘露糖、岩藻糖、唾液酸），通过细胞因子芯片，筛选出正常早孕妇女与PCOS患者差异表达的血清蛋白；利用临床样品、细胞、动物模型，孕激素上调EREG和inhibin βA表达，促进卵巢颗粒细胞增殖，并抑制凋亡，可作为低孕激素PCOS患者潜在的血清学标志物；（2）子宫内膜表面N-糖基化水平与子宫内膜细胞接受态呈正相关，衣霉素抑制蛋白质N-糖基化水平抑制子宫内膜接受态，LIFR上N-岩藻糖基化水平促进子宫内膜接受态建立；（3）唾液酰基转移酶ST3Gal3通过增加子宫内膜细胞表面α2，3唾液酸化修饰促进子宫内膜接受态的建立。课题从亟待解决的临床问题出发，为临床PCOS及相关不孕症诊治提供新靶点，具有重要理论和实际意义。