Nampt-NAD+-SIRT4调控早发性卵巢功能不全卵泡过度激活的作用及机制研究

卵泡过度激活和卵巢储备功能下降是临床早发性卵巢功能不全（POI）导致女性不孕的重要原因，但其发病机制未明。报道称NAD+水平与卵巢储备功能、雌性生育力呈显著正相关；Nampt是NAD+生成的关键限速酶，可激活NAD+依赖的SIRT4主导卵泡过度激活的潜在调控作用。申请人前期通过提升POI小鼠卵巢NAD+水平，显著延缓原始卵泡过度激活并提高其生育力，且NAD+水平与Nampt和SIRT4的表达上调呈正相关，推测NAD+水平与POI卵泡过度激活和生育力减退互为因果。本项目拟应用POI小鼠、SIRT4敲除小鼠和体外培养卵巢，全面分析卵巢NAD+水平与卵泡过度激活的作用关系；采取组织学、胚胎学、分子生物学等方法，从分子、细胞与整体水平阐明并揭示Nampt-NAD+-SIRT4调控POI卵泡过度激活的分子机制，为人为干预控制原始卵泡过度激活、改善POI患者卵泡丢失和生育力提供新的治疗策略和药物靶点。

Excessive activation of follicles and diminished ovarian reserve are the important causes of clinical premature ovarian insufficiency (POI) resulting in female infertility, with its pathogenesis remains unknown. Reports have showed that there was an obviously positive correlation between NAD+ level and ovarian reserve, as well as female fertility. Nampt is the key rate-limiting enzyme for NAD+ production, which can activate NAD+-dependent SIRT4 to dominate the potential regulation of excessive follicular activation. Our previous studies have found that the excessive activation of primordial follicles and fertility of POI mice were significantly improved along with the elevated level of NAD+ in the ovary. Meanwhile, the expression of Nampt and SIRT4 in the ovary revealed a positive correlation with the level of NAD+, which can be speculated that the level of NAD+ is strongly linked with the excessive activation follicles and the decline of fertility in POI. In this proposal, the relationship between ovarian NAD+ level and excessive activation of follicles will be analyzed comprehensively by using POI model mice, SIRT4 gene knockout mice and ovaries cultured in vitro. Furthermore, the molecular mechanism of Nampt-NAD+-SIRT4 in regulating the excessive activation of follicles in POI can be fully elucidated in the molecular, cellular and overall levels, which by adopting the methods of histology, embryology, molecular biology and so on. This study will provide new therapeutic strategies and drug targets for human intervention in controlling the excessive activation of primordial follicles and improving follicular loss, as well as the fertility of POI patients.