髓源性生长因子在端粒酶调控及老年性骨关节炎中的作用和机制研究

我国正面临老龄化的加剧，从细胞和分子水平揭示衰老疾病的机制有重要意义。端粒缩短和细胞衰老是骨关节炎重要的发病机制，通过体内端粒酶激活进而延缓间充质干细胞的衰老是防治老年性骨关节炎的新思路。我们用CRISPR/Cas9基因编辑文库高通量筛选出多个正调控端粒酶TERT转录活性的分子，首次鉴定出髓源性生长因子MYDGF能显著激活端粒酶。长期添加MYDGF能抑制间充质干细胞复制性衰老过程中TERT的转录下调和降低部分衰老标志基因的表达。已知MYDGF由滑膜、间充质干细胞等分泌并在骨关节炎患者尿液中上调。然而，MYDGF在骨关节炎发生发展中的功能未明。本课题将系统研究MYDGF对端粒酶功能和间充质干细胞衰老的影响，鉴定其受体和下游信号通路，阐明其调控端粒酶功能和间充质干细胞衰老的分子机制。进一步，利用临床样品和小鼠模型阐明MYDGF在骨关节炎中的作用，为相关衰老疾病的防治提供新的思路和靶点。

The increasing aged tendency of population makes revealing the mechanism of senile diseases from the cellular and molecular level great significant. Telomere shortening and cell senescence are important pathogenesis of osteoarthritis (OA). A novel idea of preventing and treating OA is activating telomerase in vivo to alleviate mesenchymal stem cell aging. We used CRISPR/Cas9 gene editing library to perform high-throughput screening of the molecules that positively regulate telomerase TERT transcriptional activity. We identified for the first time that myeloid-derived growth factor MYDGF could significantly activate telomerase activity. Long term applying MYDGF would alleviate the TERT mRNA decreasing and inhibit the expression of partial ageing markers during mesenchymal stem cell replicative senescence. MYDGF is known to be secreted by the synovium, mesenchymal stem cell et al and upregulated in the urine of patients with OA. However, the function of MYDGF in the onset and development of OA is unknown. This project will systemically study the effects of MYDGF on telomerase function and mesenchymal stem cell senescence, identify its receptors and downstream signaling pathway networks, to further study the molecular mechanism of MYDGF in modulating telomerase and mesenchymal stem cell senescence. Furthermore, clinical samples and mouse models will be used to clarify the role of MYDGF in OA, providing new insights and targets for aging related diseases.