FBXO31泛素化作用在早发性卵巢功能不全发病中的机制研究

早发性卵巢功能不全(POI)导致的不孕、早发绝经等严重影响女性生殖健康，卵泡消耗和闭锁加速是其主要原因。卵泡闭锁实际是卵泡颗粒细胞及卵母细胞的凋亡。我们前期研究发现POI患者血清和颗粒细胞中miR-106a水平下降，颗粒细胞FBXO31mRNA升高，FBXO31表达受miR-106a调控。结合FBXO31的泛素化作用，本研究拟围绕“FBXO31泛素化作用为中心的miRNA-基因-蛋白调控异常可能是POI发病的重要原因”这一假设，应用原代颗粒细胞和卵泡培养体系，结合POI小鼠和FBXO31敲除小鼠模型，通过在体miRNA过表达、ChIP等技术研究FBXO31对p53、MDM2等蛋白泛素化降解和p53对miR-106a转录调节，阐释以FBXO31泛素化作用为中心的miR-106a/FBXO31/p53环路调节在POI发病中的作用机制，为POI病因学研究和疾病干预提供理论基础。

Premature ovarian insufficiency (POI) is an ovarian disorder of multifactorial origin which imposes great challenges on women’s fertility and premature menopause. However, the etiology of POI remains undefined. Abnormality of granulosa cell apoptosis, inadequate primordial follicle pool, or accelerated depletion of oocytes and follicles may contribute to the pathogenesis of POI. Our previous study has showed that poor ovarian reserve was associated with decreased levels of miR-106a in serum and granulosa cells, and increased FBXO31 mRNA expression in granulosa cells, which was exactly regulated by miR-106a. FBXO31, which acts as E3 ligase, regulates the expression of various target proteins (for example, p53,MDM2) by ubiquitin-proteasome degradation. To better understand the pathogenesis of POI, in the present study, we plan to investigate the potential role of FBXO31 ubiquitination to p53 and the feedback regulation of p53 on miR-106a levels in granulosa cell apoptosis and follicle development and atresia in vitro (granulosa cell culture and follicle culture) and in vivo (POI mice model and FBXO31 knockout mice).