LSD1通过调控颗粒细胞自噬促进卵泡优势化选择的机制研究

卵泡的优势化选择决定着卵母细胞的质量。已证实促卵泡素FSH在生长卵泡的优势化选择和有腔卵泡发育过程中发挥重要作用，但具体机制仍不完全清楚。我们发现颗粒细胞特异性敲除组蛋白去甲基化酶Lsd1的小鼠卵巢体积和有腔卵泡数量减小；Lsd1缺失下调促卵泡素受体FSHR的表达，降低颗粒细胞的自噬水平，抑制卵泡的周期性募集和优势化选择。我们推测，LSD1与Fshr基因转录起始位点结合，降低组蛋白H3K9甲基化修饰水平，促进Fshr及自噬相关基因的表达，诱导颗粒细胞自噬从而调控卵泡的周期性募集和优势化选择。本项目拟利用Foxl2-Cre、Foxl2-CreERT2、Lsd1fl/fl小鼠和LC3-EGFP-RFP自噬双标小鼠等模型，运用ChIP-seq等技术深入揭示LSD1调控生长卵泡优势化选择的表观遗传学机制，为以LSD1-FSHR信号轴为靶点开发新型卵母细胞体外成熟的药物提供理论依据。

The follicle selection determines the quality of oocyte. Follicle-stimulating hormone (FSH) has been shown to play an important role in the selection of follicles and the development of antral follicles, but the mechanism is not entirely clear. We found that conditionally knockout lysine demethylase 1A (Lsd1) in granulosa cells, the ovarian size and the number of antral follicles of mice was reduced. Lsd1 deletion down-regulates the expression of follicle-stimulating hormone receptor (FSHR), reduces the level of autophagy in granulosa cells, and inhibits the periodic recruitment of follicles. We hypothesized that LSD1 could bind to the transcription start site of Fshr, reduce the level of H3K9 methylation, promote the expression of Fshr and autophagy-related genes, induce autophagy of granulosa cells, thereby, regulate the periodic recruitment and selection of follicles. This study intends to use Lsd1fl/fl, Foxl2-Cre and Foxl2-CreERT2 as well as LC3-EGFP-RFP mouse models to explore the function of LSD1 in follicle selection. We also intend to use ChIP-seq and other techniques to further reveal the epigenetic mechanism of LSD1 in regulating the selection of follicles. Finally, the LSD1-FSHR signal axis was used as the target to develop new drugs for oocyte maturation in vitro.