15d-PGJ2介导颗粒细胞自噬途径调控PCOS患者卵泡发育的机制研究

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder in women of reproductive age, accompanied with follicular dysplasia, hyperandrogenism, obesity and disturbance in glucose and lipid metabolism. Faced with the unspecified pathogenesis and limited therapeutic effect of PCOS，a recent study provided evidence for a potential role of autophagy disorders in PCOS in which autophagy may be an important molecular event in the pathogenesis of PCOS. Compared to controls, we found significant changes in serum and follicular fluid of arachidonic acid and its several metabolites (i.e. eicosanoids) existed in patients with PCOS and obesity. One of the eicosanoids, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is defined as an endogenous ligand of PPARγ. The level of 15d-PGJ2 is associated with follicular development in patients with PCOS and obesity. Consistent with this, the decrease of 15d-PGJ2 might be related with the marked activation of autophagy in ovarian tissue of PCOS rats, which has not been reported. Given this knowledge gap, we sought to determine: (1) the differences of arachidonic acid/eicosanoids levels in PCOS patients with different clinical phenotypes, and the potential marker of follicular development; (2) the effect of 15d-PGJ2 on autophagy in granulosa cells and the follow-up influences in follicular development in PCOS rats model; (3) the detailed signal pathway of 15d-PGJ2 in autophagy process of granulosa cells and its dependence on PPARγ. The expected results would provide a new perspective and therapeutic approach to improve the metabolic disorders and reproductive abnormality of PCOS.

多囊卵巢综合征（PCOS）是育龄期妇女的常见病，临床异质性强，多伴有卵泡发育异常、高雄、肥胖和糖脂代谢紊乱等，但发病机制未明、治疗手段和效果有限。新近研究表明，颗粒细胞自噬途径可调控卵泡发育，是PCOS潜在的一个重要发病机制。我们发现相较于正常对照，合并肥胖的PCOS患者花生四烯酸和下游多个类二十烷酸水平差异显著；动物学实验除验证上述结果外，还提示PPARγ的内源性配体15d-PGJ2、卵巢组织自噬异常激活与卵泡发育异常三者存在关联，目前未有相关报道。由此，我们拟通过临床、动物和细胞学研究，阐明不同表型的PCOS患者花生四烯酸/类二十烷酸的代谢变化，筛选影响卵泡发育的类二十烷酸标记物；探索15d-PGJ2调节PCOS大鼠颗粒细胞自噬的分子机制及其与卵泡发育的关系，明确该作用是否依赖PPARγ，从而为进一步阐明PCOS的发病机制，更好地改善PCOS的代谢紊乱和生殖异常提供新的理论依据。

多囊卵巢综合征（PCOS）是育龄期妇女的常见病，临床异质性强，除伴有糖脂代谢紊乱、肥胖、高雄、卵泡发育异常等，还常合并生殖障碍，严重影响女性健康，但其发病机制未明、治疗手段有限且治疗效果不理想。近些年研究表明颗粒细胞自噬活性变化可影响卵泡发育，在PCOS发病中起着重要作用。本课题中，我们在临床研究中发现不同体脂分布的PCOS患者血清和卵泡液中脂肪酸代谢谱系存在差异，其中花生四烯酸下游代谢产物的变化尤为显著；此外，经COX途径代谢的数个花生四烯酸衍生物与胰岛素抵抗和高雄相关，我们进一步筛选得到了PCOS致病的脂质标记物，包括PGE2、PGF2α、PGJ2和TXB2，其中PGE2和PGJ2与优胚率显著相关。15d-PGJ2是花生四烯酸下游的一个重要代谢产物，作为PPARγ的内源性配体参与了体内多个代谢过程。在动物实验中，15d-PGJ2可改善PCOS小鼠模型的体重、血糖、胰岛素抵抗和睾酮等内分泌与代谢指标，进一步研究发现15d-PGJ2可经由mTOR途径改变PCOS小鼠卵巢组织的自噬活性，进而影响颗粒细胞的功能和卵泡发育，上述结果在后续体外实验中也得到进一步验证，且发现15d-PGJ2调节自噬活性作用不依赖于PPARγ。综上，本课题的研究成果为进一步阐明PCOS的发病机制，更好地改善PCOS的代谢紊乱和生殖异常提供了新的防治靶点。