颗粒细胞自噬性死亡使卵泡闭锁，导致卵巢储备功能下降（DOR），进而发展为卵巢早衰。叉头框蛋白FOXO3a是调控自噬的关键因子，前期我们发现ERβ、FOXO3a及自噬相关基因在DOR患者颗粒细胞中表达增加，敲低ERβ后颗粒细胞中FOXO3a以及自噬相关基因的表达随之下降，但其调控自噬的机制不明。因此，我们将在颗粒细胞中用siRNA敲除和过表达ERβ后，利用染色质免疫共沉淀（CHIP）和荧光素酶实验等确定ERβ与FOXO3a基因的结合力，验证其在转录水平和转录后修饰水平对FOXO3a表达的调控，及FOXO3a介导的ERβ对自噬的调控作用；通过自噬诱导剂和抑制剂明确ERβ通过诱导自噬来调控颗粒细胞死亡；构建DOR小鼠模型，论证ERβ对卵巢储备功能的调控及其抑制剂在保护卵巢功能中的作用机制。最终明确ERβ—FOXO3a—颗粒细胞自噬性死亡—卵巢储备功能下降的机制，为其成为DOR的治疗靶点提供证据。

Autophagic death of granulosa cells will lead to follicular atresia, which further causes decreasing ovarian reserve (DOR) and premature ovarian failure (POF). Forkhead box O3 (FOXO3a) is considered to be the key factor regulating autophagy. Our previous data showed that the expression of ERβ, FOXO3a and autophagy associated genes were increased in the granulosa cells of the patients of DOR. Meanwhile, transfection with siERβ decreased the levels of the FOXO3a and autophagy associated genes, but the specific mechanism of ERβregulation of autophagy remains poorly understood. Therefore, we will inhibit or activate ERβ in granulosa cells, and underlying mechanism of ERβ governing FOXO3a gene expression at both transcriptional and post-transcriptional levels. Then gene knockdown and overexpression were employed to determine the involvement of ERβ during autophagy via FOXO3a. Further, we will use selective autophagy inducers and inhibitors to investigate whether ERβ leads to the apoptosis of granulosa cells by inducing autophagy. Finally, DOR mouse model was constructed to demonstrate the regulation of ERβ on ovarian reserve function and the involvement of ERβ inhibitor in the protection of ovarian reserve function. Proving this hypothesis will elucidate the mechanism of high expression of ERβin DOR from the perspective of autophagy, and provide a better understanding of ERβ as the molecular marker and therapeutic target of DOR.