跨膜型TNF-α诱导颗粒细胞凋亡引起卵泡闭锁的分子机制研究

Granulosa cells is related to follicular development，granulosa cell apoptosis directly affect the developmental potential of oocyte. Tumor necrosis factor-α exists transmembrane form (tmTNF-α) and secretory form (sTNF-α), TNF receptors exists TNFR1 and TNFR2. sTNF-α can mediate both survival and apoptosis signaling pathways via TNFR1. In granulosa cells, sTNF-α can promote granulosa cell proliferation by activate the NF-κB and increase XIAP synthesis. Our preliminary results show that, tmTNF-α induce cell death while sTNF-α promote proliferation in the original granulocytes of mice. We speculated that tmTNF-α may induce follicular atresia by promoting granulosa cell apoptosis. In this project, we shall investigate (1) tmTNF-α mediated the molecular signal transduction of granular cell; (2)Obverse the relationship between the expression of tmTNF-α and the apoptosis of granule cells during the development of follicles.The results of this project provide experimental evidences and a new clue for treatment of follicular atresia and has important guiding significance in increase pregnancy rate and infertility.

颗粒细胞和卵泡发育的命运有关，颗粒细胞的凋亡状态直接影响相应卵母细胞的发育潜能。TNF-α分为跨膜型（tmTNF-α）和分泌型（sTNF-α）两种，TNF受体也可分为TNFR1和TNFR2两种，sTNF-α可通过TNFR1介导生存和凋亡两种信号途径，文献报道，在颗粒细胞中，sTNF-α可与TNFR1结合激活NF-κB，XIAP合成增加，促进颗粒细胞增殖。我们前期结果证实，在小鼠原代颗粒细胞中，sTNF-α促进其增值，而tmTNF-α则对其有杀伤作用。我们推测tmTNF-α可能通过促进颗粒细胞凋亡，诱导卵泡闭锁。本研究拟研究：（1）tmTNF-α介导颗粒细胞信号转导的分子机制；（2）观察小鼠卵泡发育过程中，tmTNF-α的表达与颗粒细胞凋亡发生发展的关系。本研究结果为治疗颗粒细胞凋亡引起的卵泡闭锁提供新的靶点与线索,对治疗不孕,提高妊娠率有重要的指导意义。

颗粒细胞和卵泡发育的命运有关，颗粒细胞的凋亡状态直接影响相应卵母细胞的发育潜能。TNF-α分为跨膜型（tmTNF-α）和分泌型（sTNF-α）两种，TNF受体也可分为TNFR1和TNFR2两种，sTNF-α可通过TNFR1介导生存和凋亡两种信号途径，文献报道，在颗粒细胞中，sTNF-α可与TNFR1结合激活NF-κB，XIAP合成增加，促进颗粒细胞增殖。我们的前期研究结果表明，在小鼠原代颗粒细胞中，sTNF-α促进其增殖，而tmTNF-α则对其有杀伤作用。本项目进一步阐明tmTNF-α介导颗粒细胞信号转导的分子机制；即tmTNF-α可通过TNFR1募集STAT1及DISC分子介导细胞凋亡，同时tmTNF-α可通过TNFR2募集并降解TRAF2，使信号通路由生存走向凋亡。本研究结果为治疗颗粒细胞凋亡引起的卵泡闭锁提供新的靶点与线索,对治疗不孕,提高妊娠率有重要的指导意义。