IL-22/IL-22受体信号通路在卵巢早衰发生发展中的作用及机制

Premature ovarian failure (POF), the representative and final stage of diminished ovarian reserve, is one of the commonest diseases responsible for female infertility. Neither reliable biomarkers to predict its occurrence or effective treatment have been discovered. Since the etiology of majority of POF patients remain unknown, how to identify high- risk population beforehand become necessary. It is presumed that POF might be the result of interaction of endogenous genetic defects and exogenous stimulating factors. Previous studies suggest that autoimmune imbalance may be involved in POF. However, the mechanism is elusive. Our preliminary data revealed that the level of serum IL-22 was significantly higher in the idiopathic POF group compared with controls, and IL-22 receptor complex (IL-22R1 / IL-10R2) were expressed in human ovary and granulosa cells. It has been reported that the binding of IL-22 with its receptor complex could activate the downstream signaling pathways of JAK-STAT and MAPK. Therefore, our results suggest that IL-22/IL-22Rs signaling pathway may participate in the development of POF. There is no related report at present. Based on previous results, we will explore the molecular mechanism of IL-22/IL-22 receptor signaling pathway on ovarian function by studies both in vitro and in vivo. The results will provide new clues to clarify the contribution of autoimmune oophoritis for the etiology of POF. The project would be helpful for clinical diagnosis, prevention, interference, and treatment, especially for women with diminished ovarian reserve.

以卵巢早衰（Premature Ovarian Failure, POF）为代表的生育力降低是妇科内分泌领域的常见病、棘手病，是导致女性不孕不育的重要原因之一。既无可靠的标记物预测其发生，也无有效的治疗措施，POF的病因研究及识别高风险人群十分必要。本课题组前期研究首次发现IL-22在POF患者中显著升高，卵巢和颗粒细胞均表达IL-22受体，推测IL-22/IL-22Rs信号通路异常可能参与POF的发生。目前尚无IL-22与卵巢功能的相关报道。本课题组拟在前期研究的基础上，借助体外实验和动物模型，从卵巢激素合成、细胞增殖凋亡、其他炎性因子协同、JAK-STAT/MAPK/PI3K-AKT信号通路等方面，深入探讨IL-22/IL-22受体信号通路异常影响卵巢功能的分子机制，明确免疫性卵巢炎在POF发生发展中的作用，为POF临床诊断、分型、干预和病情跟踪提供依据。

卵巢早衰（POF）又称为原发性卵巢功能不全（POI），是导致女性不孕不育的常见妇科内分泌疾病。目前尚无准确预测指标和有效的治疗手段，病因研究以识别高风险人群尤为必要。POI病因高度异质性，细胞免疫异常可能参与致病，但具体机制尚不明确。本项目对POI病例异常淋巴细胞亚群及炎性细胞因子进行筛选和验证，从体外细胞实验和体内小鼠模型首次发现Th1/Treg失衡及高促炎性细胞因子通过影响颗粒细胞功能继而导致POI发生。在大样本POI病例中进行自身免疫抗体检测，发现抗肾上腺皮质抗体AAA的阳性率明显增高，提示自身免疫异常参与了POI发病，AAA可以作为预测和诊断卵巢自身免疫异常的标记物。首次对大规模POI病例进行病因分类及临床特征分析，发现不同病因的POI患者临床表型有显著差异，为临床POI患者的病因诊断、生育指导和遗传咨询提供重要参考和依据。首次对大样本不孕女性进行甲状腺自身免疫与卵巢储备、ART生育结局及子代健康的分析，发现TAI能够影响卵巢储备功能，与卵巢储备正常的女性子代先天畸形发生率增加相关，为临床ART助孕甲状腺自身免疫的评估及诊疗提供了理论依据。因此，本研究对POI免疫学病因进行了初步而系统地探讨，为自身免疫性POI的临床诊断和干预提供依据，为POI免疫学病因探讨及机制研究提供线索。