cAMP通过HDAC6调控原始卵泡选择性激活的机制研究

卵巢中的绝大多数原始卵泡处于休眠状态，休眠的原始卵泡被有序地选择性激活对于维持雌性生育寿命的长度具有决定性作用。尽管现有与原始卵泡激活相关理论为深入认识卵泡激活机制奠定了较好的基础，但仍不能解释生理情条件下原始卵泡从卵泡库中选择性激活的机制。我们发现伴随原始卵泡激活cAMP的浓度升高；上调cAMP可促进原始卵泡激活；cAMP可能通过瞬时下调HDAC6的表达并上调NGF从而介导原始卵泡选择性激活，这提示部分原始卵泡中cAMP浓度升高可能是介导原始卵泡选择性激活的关键机制之一。为证明我们的假设，本项目拟利用光遗传学等方法分别在原始卵泡前体颗粒细胞和卵母细胞中表达cAMP、条件性敲除cAMP的合成酶Adcy3等小鼠模型，结合RNA-seq等技术来证实cAMP在原始卵泡选择性激活中的作用；阐明cAMP调控原始卵泡选择性激活的分子机制。本研究将为揭示女性生育力保持和推动辅助生殖新技术开发奠定基础。

The majority of primordial follicles in the ovary are in dormant state, the selective activation of dormant primordial follicles plays a decisive role in maintaining the length of the female's reproductive life. Although the existing theories related to primordial follicles activation have laid foundation for understanding of the mechanism about primordial follicle activation, it still cannot explain the mechanism of selective activation of primordial follicles from the follicle pool under physiological conditions.We found that the content of cAMP increases with the primordial follicles activation; up-regulating cAMP can promote the primordial follicles activation; cAMP may mediate the primordial follicles selective activation by transiently down-regulating HDAC6 and up-regulating NGF. This suggests that the increase of cAMP content in some primordial follicles may be one of the key mechanisms that mediate the primordial follicles selective activation. To prove our hypothesis, we intend to use optogenetic methods to express cAMP in primordial follicle granulosa cells and oocytes, respectively, conditionally knock out cAMP synthetase Adcy3 and other mouse models, combined with RNA-seq and other technologies. Confirming the role of cAMP in the selective activation of primordial follicles; clarifying the molecular mechanism of cAMP in regulating the selective activation of primordial follicles. This research will lay the foundation for revealing the mechanism of female fertility maintenance and promoting the development of new technologies for assisted reproduction.