AQP8调控颗粒细胞自噬和卵泡闭锁的作用及机制

Follicular atresia is controlled by programmed cell death (PCD). However, it remains unknown how autophagy, as a distinctive PCD, takes part in the process of granulosa cell death and follicular selection. Aquaporin-8 (AQP8) is highly expressed in granulosa cells. We have previously found that AQP8 knockout mice have more number of ovulation and litter size, which is possibly due to reduced apoptosis of granulosa cells leading to decreased atresia. Further study indicated that autophagy level is significantly decreased in AQP8 knockout granulosa cells. During follicular atresia, higher level of hydrogen peroxide (H2O2) has been observed in mouse granulosa cells. Because AQP8 can transport H2O2, we speculate that AQP8 participates in autophagy and atresia via mediating the transportation of H2O2 into granulosa cells. To test the hypothesis, we plan to investigate the role of AQP8-mediated H2O2 transport in granulosa cell autophagy and programmed cell death using AQP8 knockout mouse model. The study will provide novel insights into the molecular mechanisms of follicular atresia and ovary deficiency.

卵泡闭锁是卵泡发育过程中的关键环节之一，直接决定着排卵数目，而卵泡的闭锁受颗粒细胞程序死亡直接调控。近年来一些研究显示自噬可能参与颗粒细胞程序死亡和卵泡闭锁，但是其分子机制尚不明确。有研究表明卵泡液内活性氧（ROS，主要是过氧化氢）含量受到严格控制，过量ROS进入颗粒细胞会引起氧化应激导致细胞程序性死亡。申请人初步研究发现AQP8敲除小鼠卵泡颗粒细胞自噬与凋亡水平降低，并且野生型小鼠卵泡闭锁过程中颗粒细胞过氧化氢（H2O2）浓度显著升高。鉴于AQP8具有转运H2O2功能并且在卵泡颗粒细胞高表达，我们推测AQP8介导H2O2转运可能是调控颗粒细胞自噬和卵泡闭锁的重要机制。本课题拟利用AQP8敲除小鼠模型深入研究AQP8介导H2O2转运在颗粒细胞自噬和卵泡闭锁中的作用及调控机制，为卵巢功能不足相关疾病的防治提供新策略。

卵泡闭锁是卵泡发育过程中的关键环节之一，直接决定着排卵数目，而卵泡的闭锁受颗粒细胞程序死亡直接调控。近年来一些研究显示自噬可能参与颗粒细胞程序死亡和卵泡闭锁，但是其分子机制尚不明确。有研究表明卵泡液内活性氧（ROS，主要是过氧化氢）含量受到严格控制，过量ROS进入颗粒细胞会引起氧化应激导致细胞程序性死亡。本项目研究发现AQP8敲除小鼠卵泡颗粒细胞自噬与凋亡水平降低，野生型小鼠卵泡闭锁过程中颗粒细胞自噬水平、AQP8表达与H2O2浓度显著升高。体外实验证实AQP8具有转运过氧化氢（H2O2）功能，且过量H2O2能够导致卵泡颗粒细胞发生自噬，表明AQP8介导H2O2转运可能是调控颗粒细胞自噬和卵泡闭锁的重要机制。本课题利用AQP8敲除小鼠模型深入研究AQP8介导H2O2转运在颗粒细胞自噬和卵泡闭锁中的作用及调控机制，为卵巢功能不足相关疾病的防治提供新策略。