miR-181a调控Foxo1乙酰化修饰在颗粒细胞凋亡及卵泡发育中的机制研究

颗粒细胞凋亡加速卵泡闭锁，是构成临床卵巢早衰的重要原因。已知转录因子Foxo1是导致颗粒细胞凋亡的重要分子，但其作用机制不明。我们证实卵巢早衰病人血清中异常增高的miR-181a具有抑制颗粒细胞增殖作用。最近又发现miR-181a明显促进小鼠颗粒细胞凋亡和Caspase 3的活化。过表达miR-181a促进Foxo1的乙酰化和核聚集。miRNA靶基因生物信息学分析发现蛋白去乙酰化酶Sirt1为miR-181a的靶基因。推测miR-181a靶向作用于Sirt1，增加Foxo1蛋白的乙酰化修饰，促进颗粒细胞凋亡，加速卵泡闭锁，是导致卵巢早衰发生的重要机制。本研究将重点从Foxo1蛋白乙酰化修饰角度探讨miR-181a对颗粒细胞凋亡的影响；并利用miR-181a卵巢敲入小鼠模型整体实验研究miR-181a对卵泡发育的影响。期望阐明miR-181a在颗粒细胞凋亡及卵泡自主发育中的作用与机制。

Apoptosis of granulosa cells leading to accelerated follicular atresia is a possible mechanism for premature ovarian failure (POF). Previous studies indicated that transcription factor Foxo1 is a crucial regulator of mouse granulosa cell (mGC) apoptosis. However, the mechanisms that regulate mGC apoptosis remain unclear. Our studies demonstrated that the level of miR-181a in the blood of patients with POF was much higher than in normal females and miR-181a significantly suppresses mGC proliferation. We also found miR-181a promotes mGC apoptosis and caspase-3 activation. Moreover, Foxo1 acetylation and nuclear accumulation were induced in response to overexpression of miR-181a in mGC. Using the online miRNA target gene prediction program miRanda, we found that Sirt1 is potential miR-181a target. So, our hypothesis on the possible mechanism for POF is that miR-181a promotes mGC apoptosis by targeting Sirt1 and modulating Foxo1 acetylation. We will further to address the mechanism of mGC apoptosis and follicular atresia through miR-181a-mediated Foxo1 acetylation in vitro and in miR-181a knock-in mice model. Our study might be elucidating of the molecular control of granulosa cell apoptosis and follicular development by miR-181a.