表观遗传修饰蛋白HDAC6参与原始卵泡选择性激活的机制研究

原始卵泡既是雌性生殖的基本结构和功能单位也是卵泡发育的起点。休眠的原始卵泡要启动发育首先需要被激活。尽管已发现了可体外激活原始卵泡的方法，但我们对体内卵泡库中部分原始卵泡在每个生殖周期中如何被选择性激活的机制仍知之甚少。近期研究提示排卵损伤可能是原始卵泡选择性激活的机制之一，而我们前期也发现组蛋白去乙酰化酶6（HDAC6）参与了小鼠排卵损伤诱导原始卵泡选择性激活过程，但具体机制不详。为此本项目拟利用激素诱导排卵、卵巢损伤、条件性敲除Hdac6小鼠和卵巢组织体外培养等模型揭示HDAC6在排卵诱导原始卵泡选择性激活中发挥的生理功能及机制。主要内容：明确性成熟后原始卵泡选择性激活与周期性排卵活动间是否存在相关性；阐明HDAC6的表达与原始卵泡选择性激活的关系及生理机制；探索基于HDAC6设计药物来优化原始卵泡体外激活方案的可行性。本研究将为揭示女性生育力保持机制和推动辅助生殖新技术开发奠定基础。

Primordial follicles are not only the basic structural and functional unit of female reproduction, but also the starting point for follicular development. The dormant primordial follicles need to be activated before development initiation. Although methods have been found to activate primordial follicles in vitro, little is known about the mechanisms by which only limited primordial follicles are selectively activated from the follicle bank in each reproductive cycle. Recent research suggests that ovulation damage to the ovary may be one of the mechanisms of selective activation of primordial follicles. In addition, we have discovered that histone deacetylase 6 (HDAC6) is involved in the process of selective activation of primordial follicles induced by ovulation in mice. However, the specific mechanism regarding to primordial follicle selective activation remains unknown. Hence, this project intends to use various models like hormone-induced ovulation, ovarian damage, conditioned knockout Hdac6 mice and ovarian tissue in vitro to reveal the physiological functions and mechanisms of HDAC6 in the selective activation of ovulation-induced primordial follicles. We plan to achieve our goal through following ways: determining the correlations between selective activation of primordial follicles and periodic ovulation after sexual maturity; clarifying the relationship between HDAC6 expression and selective activation of primordial follicles, and try to explain its physiological mechanism; screening and evaluating potential drugs that are effective to active primordial follicles through targeting HDAC6 so as to optimize the present procedures. This study will lay the foundation for revealing the mechanism of female fertility maintenance and promoting the development of new technologies for assisted reproduction.