Bmi1调控Wnt信号通路参与内耳成体干细胞干性维持机制的研究

Presbycusis is one of the most important characters of senescence. The more aged people there are, the higher incidence rate of presbycusis is. The epigenetic regulation of somatic stem cell is one of the research hot spots of presbycusis nowadays. Stem cell is the cell which can be self-renewing and differentiated. Recent studies have shown that Lgr5-positve supporting cells are somatic stem cells which hasve stemness in the inner ear and are respected not only to the sensory cell self-renew in the inner ear but also to the hair cell regeneration. Lgr5 is one of the target genes in Wnt signal pathway which was reported to be involved in the regulation of stem cells aging. The polycomb group (PcG) family Bmi1, acting downstream of the hedgehog pathway, plays an essential role in the self-renewal of stem cells, and functions in the epigenetic silencing of genes governing self-renewal, differentiation, and proliferation. Therefore, we hypotheses that Bmi1 may have a close relationship with Wnt signal in the mechanism of senescence. However, there are few studies to reveal their relationship. Our project concentrates on both aspects of senescence mechanisms and regulation of signal pathway of inner ear sensory stem cell stemness, with aging mice and transgenic mice, by regulating expression level of associated molecules to study on the internal progress of inner ear somatic stem cell self-renewing and external intervention studies, which will provide evidence of theory and directions of Presbycusis prevention and treatment.

老年性耳聋是机体衰老的重要标志之一，随着我国老龄人口的增多，老年性耳聋发病率逐年增高。成体干细胞干性的表观遗传学调控机制是衰老研究的一大热点。干细胞是指具有自我更新和分化能力的细胞，研究表明内耳中Lgr5阳性的支持细胞是具有干性的成体干细胞，与内耳细胞的自我更新及毛细胞再生密切相关。Lgr5是Wnt信号通路的重要分子，已证实Wnt信号通路参与了干细胞衰老的调控；Bmi1属于PcG家族，是成体干细胞重要的表观遗传调节因子，也是维持干细胞自我更新所必需的信号分子，因此我们推测Bmi1与wnt信号分子在调控衰老方面必然有着密不可分的联系，而迄今为止两者的相互作用关系却鲜有报道。本项目拟从衰老机理及调控内耳听觉干性细胞信号通路两方面入手，利用自然衰老小鼠及转基因早衰小鼠模型，通过调控相关信号分子的表达，研究影响内耳成体干细胞自我更新的内在程序与外部干预措施，为老年性耳聋的防治提供理论依据和研究思路

老年性耳聋是机体衰老的重要标志之一，随着我国老龄人口的增多，老年性耳聋发病率逐年增高。成体干细胞干性的表观遗传学调控机制是衰老研究的一大热点。干细胞是指具有自我更新和分化能力的细胞，研究表明内耳中Lgr5阳性的支持细胞是具有干性的成体干细胞，与内耳细胞的自我更新及毛细胞再生密切相关。Lgr5是Wnt信号通路的重要分子，已证实Wnt信号通路参与了干细胞衰老的调控；Bmi1属于PcG家族，是成体干细胞重要的表观遗传调节因子，也是维持干细胞自我更新所必需的信号分子，因此我们推测Bmi1与wnt信号分子在调控衰老方面必然有着密不可分的联系，而迄今为止两者的相互作用关系却鲜有报道。我们的研究工作主要包括了以下几个方面：.1. 研究了Bmi1基因敲除抑制新生小鼠耳蜗支持细胞和Lgr5+前体细胞增殖能力和成球能力，Bmi1基因敲除抑制Wnt信号通路表达水平，Bmi1基因敲除通过下调Wnt信号通路抑制新生小鼠耳蜗支持细胞增殖，Bmi1基因参与新生小鼠耳蜗H3k27me3介导的组蛋白修饰。本课题研究结果有助于进一步了解哺乳动物耳蜗前体细胞增殖的机制，对耳蜗受损后刺激毛细胞再生提供新的思路。.2. 研究了Wnt信号通路调控与毛细胞再生的关系.3. 研究了内耳毛细胞神经细胞再生的关系.4. 建立了耳蜗毛细胞体外培养模型以及类器官模型，有助于进一步的研究。.本项目将为内耳毛细胞再生及发育提供依据。