叉头转录因子FOXO1与线粒体常见缺失突变相互调控在老年性聋中的作用

Presbycusis is the most common functional disabling disease, the pathogenesis of which has not been clarified up to now and there is lack of effective treatment method for this reason. It has been recently reported that there is nucleus-cytoplasm shuttle mechanism about FOXO1, which participates in the regulation of apoptosis. In our previous study , we established the rat model with mimetic in inner ear and established a mimetic senescence marginal cell model. Moreover,we determined the expression and subcellular distribution of FOXO1 in inner ear cells. In this model, we found that the increase of mitochondrial DNA common deletion was accompanied by up-regulation of FOXO1, which was down-regulated after overexpression of PGC-1α, indicating that FOXO1 may play important roles in the pathogenesis of presbycusis through PGC-1α mediated nucleus-mitochondria interaction and apoptosis pathway. In this present study, we aim to investigate the role and mechanism of FOXO1 gene in mitochondrial DNA common deletion and presbycusis using the previously established mimetic aging rat model and senescence marginal cell lines by means of the techniques in epigenetics, molecular biology, cytology, audiology and morphology.

老年性聋是最常见功能性致残疾病，其发病机制迄今还不清楚，缺乏有效的治疗方法。国内外研究表明线粒体常见缺失突变（CD)与老年性聋密切相关，并可能受到核基因的调控，寻找合适的候选核调控基因是研究的关键。近来有研究表明FOXO1存在核-质穿梭机制，并参与凋亡调节。在前期研究中，我们建立了内耳拟老化大鼠模型和边缘细胞拟老化细胞系，发现FOXO1在内耳细胞的表达与亚细胞定位，CD增加伴随FOXO1表达增高，过表达PGC-1α后，FOXO1表达下降，提示FOXO1可能通过PGC-1α介导的核-线粒体相互作用和凋亡途径在老年性聋发病机制中起重要作用。本研究拟应用前期建立的内耳拟老化大鼠模型和边缘细胞衰老细胞系，通过基因转染过表达FOXO1基因或抑制FOXO1基因表达，采用表观遗传学、分子生物学、细胞学、听力学、形态学等方法研究FOXO1基因对CD及老年性聋的作用机制及可能的防治方法。

老年性聋是最常见功能性致残疾病，其发病机制迄今还不清楚，缺乏有效的治疗方法。国内外研究表明线粒体常见缺失突变（CD)与老年性聋密切相关，并可能受到核基因的调控，寻找合适的候选核调控基因是研究的关键。近来有研究表明FOXO1存在核-质穿梭机制，并参与凋亡调节。在前期研究中，我们建立了内耳拟老化大鼠模型和边缘细胞拟老化细胞系，发现FOXO1在内耳细胞的表达与亚细胞定位，CD增加伴随FOXO1表达增高，过表达PGC-1α后，FOXO1表达下降，提示FOXO1可能通过PGC-1α介导的核-线粒体相互作用和凋亡途径在老年性聋发病机制中起重要作用。本研究应用前期建立的内耳拟老化大鼠模型和边缘细胞衰老细胞系，通过基因转染过表达FOXO1基因或抑制FOXO1基因表达，发现在拟衰老大鼠听皮层，自噬水平随着年龄的增长呈现先升高后降低的趋势并且受到AMPK-mTOR-ULK1信号通路的调控。奥体普拉（oltipraz）作为Nrf-2特异性激动剂，在D-gal诱导的拟老化PC12细胞系中能显著减轻线粒体异常。推测Keap1/Nrf2信号通路可能通过影响线粒体功能参与中枢性老年聋的发生。FOXG1通过调节老年性聋动物模型大鼠毛细胞的自噬水平改变及CD变化参与老年性聋的发病过程。