miR-370-3p/miR-411-5p在原发性卵巢功能不全发病中的作用及机制研究

Primary ovarian insufficiency (POI), refers to the exhaustion of women’s ovary reserve before the age of 40 years, is one of the commonest reproductive endocrine disorders for women of child bearing age. The underlying explanation for POI remains to be elucidated in most cases. Therefore, it is necessary to explore the pathogenesis of POI from other viewpoints. The results of our previous research showed that miR-370-3p and miR-411-5p, which were up-regulated in the granulosa cells of POI patients compared with the controls, influenced the proliferation of ovarian granulosa cells and the expression of FOXO1 genes. It is presumed that dysfunction of FOXO1, regulated by miR-370-3p and miR-411-5p, participate in the development of POI. Based on the previous results, the present study focuses on the effect of miR-370-3p and miR-411-5p on the biological behaviors of granulosa cells, follicular development and ovarian function, and furthermore, illustrates the regulation of the target genes expression by miR-370-3p/miR-411-5p, aiming to clarify underlying mechanism of miR-370-3p/miR-411-5p in development of POI. The current study will certainly contribute to the demonstration of the etiology of POI from the view of epigenetics, and show great significance about early diagnosis and treatment of POI.

原发性卵巢功能不全（primary ovarian insufficiency，POI）是指女性40岁之前闭经，伴有促性腺激素升高及雌激素缺乏。POI病因高度异质，目前遗传学研究所发现的相关基因都不能解释绝大多数特发性POI的发病原因及机制。因此，非常有必要从其它角度对POI发病机制进行深入研究。我们的前期研究结果显示，POI患者颗粒细胞中表达上调的miR-370-3p/miR-411-5p能够影响颗粒细胞增殖及FOXO1基因的表达，提示它们可能参与POI的发病过程。在前期研究结果的基础上，本项目将深入研究miR-370-3p/miR-411-5p对颗粒细胞生物学行为、卵泡发育以及卵巢功能的影响并明确它们调控靶基因表达的分子机制，最终阐明它们在POI发生中的作用及机制。本研究有助于从表观遗传学角度理解与阐明POI发病机制，对于POI的早期诊断、早期治疗具有重要的理论和实践意义。

早发性卵巢功能不全（premature ovarian insufficiency，POI）临床表现高度异质，绝大多数患者病因不明确，缺乏早期诊断标志物和有效的治疗手段。我们通过高通量芯片技术，发现早期POI（biochemical POI, bPOI）患者颗粒细胞中存在大量差异表达的miRNAs和mRNAs；联合应用生物信息学分析及功能实验，首次证实miR-379-5p和miR-127-5p调控DNA损伤修复基因影响颗粒细胞功能，与POI发生密切相关，其中miR-127-5p可以作为女性卵巢储备下降的分子标志物。首次在POI中证实存在具有明确功能的小RNA，提出miRNA调控DNA损伤修复基因参与POI的致病机制假说，揭示表观遗传在POI中的重要作用，拓展了POI病因学研究方向。同时，我们首次在散发POI患者中进行CAV1、PUM1和TMEM150B基因突变筛查，并对新发突变进行功能研究，明确上述基因与POI的相关性和致病机制，进一步丰富了POI的致病谱，为育龄期女性及其后代提供遗传咨询和生育指导。此外，本项目首次证实褪黑素可以有效增加卵母细胞体外成熟率及囊胚形成率，并阐明其作用机制。该研究为褪黑素应用于辅助生殖临床提供了重要的理论依据。