ZNF217在多囊卵巢综合征卵泡闭锁及排卵障碍中的作用及机制

Polycystic ovary syndrome (PCOS) is a complex reproductive endocrine disease characterized by oligo/anovulation, hyperandrogenism and polycystic ovary. The mechanism underlying the follicular development and ovulation dysfunction of PCOS is not completely understood. As a transcriptional factor, zinc finger gene 217 (ZNF217) is a candidate gene for PCOS according to a previous genome-wide association study (GWAS). Thus, ZNF217 may play a role in the PCOS onset but without any evidence. Our study firstly detected the decreased ZNF217 expression in the granulosa cells (GCs) of both PCOS patients and PCOS-like rat model. Additionally, we also demonstrated that ZNF217 might contribute to the follicular atresia and ovulation dysfunction through the regulation to thrombospondin 1(TSP-1), a disintegrin and metalloproteinase with thrombospondin motifs 1(ADAMTS1) and other downstream factors in the GCs. However, the mechanism still needs to be investigated. Therefore, our study focused on the role of ZNF217 in the development of PCOS via DHEA induced PCOS rat model, ovarian ZNF217-shRNA treated rats and GCs of PCOS patients for the first time. We hope to confirm the relationship between ZNF217 and PCOS, furthermore the causative mechanism, which could provide a new strategy for the diagnosis and treatment for PCOS.

多囊卵巢综合征（PCOS）是育龄期女性最常见的生殖内分泌疾病，卵泡发育及排卵异常造成PCOS患者月经紊乱及不孕，困扰众多育龄期女性，但发病机制至今仍不明确。本研究团队早期通过汉族PCOS人群的GWAS研究发现，锌指转录因子217（ZNF217）是PCOS潜在的致病基因，但究竟是否存在相关性及具体机制未曾报道。申请人前期研究显示PCOS患者颗粒细胞及PCOS大鼠模型卵巢中ZNF217表达降低，且在颗粒细胞中敲低ZNF217出现卵泡闭锁及排卵关键基因表达的异常，提示ZNF217的降低与PCOS卵泡闭锁及排卵障碍关系密切。因此，本项目拟以我们近期的重要发现为基础，通过PCOS患者临床标本、体外细胞实验及模式动物，探讨ZNF217的降低是否通过影响卵泡闭锁及排卵障碍促进PCOS的发生发展，为进一步明确PCOS的发生机制及寻找PCOS的临床诊断和干预新靶点提供理论基础。

多囊卵巢综合征（PCOS）是育龄期女性最常见的生殖内分泌疾病，排卵障碍和胰岛素抵抗是PCOS重要的临床表现，影响育龄期女性生育力的同时造成糖尿病等远期并发症的发生增加，困扰众多女性，然而，PCOS的临床表现及发病机制复杂，至今仍未明确。本项目聚焦锌指转录因子217（ZNF217）在PCOS卵泡发育及胰岛素抵抗中的作用。通过DHEA诱导的PCOS大鼠模型及临床样本研究证明PCOS患者颗粒细胞存在ZNF217表达的降低，进一步通过COX2调控PGE2的合成，参与PCOS慢性炎性反应的发生发展，最终影响卵泡发育异常和排卵障碍。除了卵泡发育异常外，ZNF217还参与PCOS胰岛素抵抗的发生发展，通过高通量数据生物信息学分析发现，ZNF217受到m6A调控关键酶METTL3及FTO的调控，进一步通过下游ARID1A等参与胰岛素信号通路及GSK3β的调节，影响胰岛素信号通路及糖代谢。除了ZNF217外，生物钟核心节律基因BMAL1也可以通过调控NAMPT参与PCOS胰岛素抵抗的发生发展。本项目聚焦PCOS的排卵障碍及胰岛素抵抗，通过关键靶基因ZNF217探索其影响排卵障碍及胰岛素抵抗的具体机制，且本项目组进一步延伸探索了生物钟节律这个重要的环境因素及核心节律基因在PCOS胰岛素抵抗中的作用，对于解析PCOS的发病机制及PCOS的早期预防奠定了基础，为PCOS临床诊疗提供新的靶点。对于提高育龄期PCOS患者的生育力，减少远期并发症的发生具有重要的社会意义，且符合当前增加生育力、减少糖尿病、冠心病等慢性疾病发生的社会需求。

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