SCARB1介导的卵母细胞脂代谢在BNC1突变致卵巢功能不全发生中的作用及机制研究

Premature ovarian insufficiency (POI) seriously affects patients' life quality and reproductive health. In our previous study, by investigating a large Chinese premature ovarian insufficiency pedigree and transgenic animal model study, we found BNC1 gene mutation would cause the occurrence of premature ovarian insufficiency, and the transcription of SCARB1 gene was directly regulated by BNC1. Since SCARB1 is an important gene in regulating lipid metabolism, we suppose SCARB1 mediated oocyte lipid metabolism may be involved in the BNC1 mutation induced POI. In this study, we would collect specimens from clinical POI patients, carry out animal model study and in vitro cell model study to further clarify the pathogenesis and regulation mechanism of SCARB1 mediated oocyte lipid metabolism in BNC1 mutation induced premature ovarian insufficiency. The results would help provide a theoretical basis for early intervention, treatment and genetic blockade of premature ovarian insufficiency, and have both significant scientific research value and translational medical significance.

卵巢功能不全严重影响患者生活质量及生殖健康。本课题组前期通过一个大型中国人卵巢功能不全家系发现新的卵巢功能不全致病基因突变——BNC1基因突变，通过转基因小鼠模型验证了其致病性，并初步发现SCARB1基因受到BNC1基因的转录调控，且可能与卵母细胞脂代谢异常相关。本课题拟在前期研究基础上，通过收集临床卵巢功能不全家系及散发患者的临床标本，开展动物模型、体外细胞实验，进一步明确SCARB1基因表达异常导致卵母细胞脂代谢异常并进而导致卵巢功能不全的发病机理和调控机制，为卵巢功能不全的早期干预、治疗和子代遗传阻断提供理论基础，兼具重大科研价值和转化医学意义。

卵巢功能不全以卵泡的提前耗竭为特征，导致不孕和一系列女性近远期健康风险，严重影响患者生活质量及生殖健康。然而，其具体调控机制尚不明晰，且缺乏延缓或逆转的有效策略。本课题组前期通过一个大型中国人卵巢功能不全家系发现新的卵巢功能不全致病基因突变——BNC1基因突变，并通过转基因小鼠模型验证了其致病性。在本项研究中，我们进一步通过动物模型和体外细胞实验等，确证了BNC1基因在卵巢储备维持和卵母细胞脂代谢、氧化还原稳态维持中的作用；并发现BNC1基因作为转录因子，除了直接调控脂代谢相关基因SCARB1，还通过直接调控下游NF2基因的转录，影响NF2-Hippo-YAP-TFRC/ACSL4信号通路，并最终导致卵母细胞铁死亡的发生。此外，我们还发现YAP特异性抑制剂、铁死亡抑制剂均可显著改善卵母细胞脂质过氧化水平、并显著挽救小鼠卵巢功能不全表型。研究结果明确了BNC1突变导致卵母细胞脂代谢异常和卵母细胞铁死亡并进而导致卵巢功能不全的发病机理和调控机制，发现了基于铁死亡挽救的卵巢功能不全潜在治疗新方法，为卵巢功能不全的早期干预、治疗和子代遗传阻断提供理论基础，并具有较好的临床转化价值。