癌基因诱导衰老细胞分泌的因子在体细胞重编程的机理探讨

项目名称： 癌基因诱导衰老细胞分泌的因子在体细胞重编程的机理探讨

项目编号： No.31271594

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 纪俊峰

作者单位： 浙江大学

项目金额： 80万元

中文摘要： 体细胞重编程的分子调控机制仍然大部分未知.现有的研究表明:过度表达重编程因子(其中大部分是原癌基因)产生DNA损伤反应导致细胞衰老(Oncogene-Induced Senescence, OIS).抑制OIS能显著地提高重编程效率,但是衰老细胞本身对重编程的影响未知。以前在早期肿瘤发生的研究表明OIS产生的炎症因子能够加强和接力OIS.我们的前期试验表明细胞重编程过程中IL6和IL8高表达,降低IL6可以提高重编程效率。所以本研究假设重编程过程中衰老细胞所分泌的炎症因子网络能够加强和传递衰老信号从而影响重编程。阻断其信号转导机制能够提高重编程效率。该研究拟用前期成功建立的重编程模型(Stem Cells 2012)，通过分子和细胞生物学技术研究细胞衰老分泌因子影响重编程的机制。研究发现将为重编程分子机制提供新知识,为提高重编程效率提供新的手段,并将可能为延缓细胞乃至机体衰老提供新的思路。

中文关键词： 体细胞重编程；细胞衰老；炎症因子；；

英文摘要： Overexpression of defined factors Oct4, Sox2, Klf4, cMyc or Lin28 and Nanog can reprogram somatic cells into induced pluripotent stem (iPS) cells. However, almost all these factors are oncogenes, overexpression of which activates DNA damage response and induces apoptosis or senescence, posing a barrier to reprogramming. Although oncogene-induced senescence has been shown to be a roadblock to reprogramming, the role of senescent cells during reprogramming remains unknown. During early tumorigenesis, senescent cells induced by activation of oncogene have been shown to secret inflammatory factors such as IL6 and IL8 that relay and reinforce OIS. Our preliminary results revealed the elevated expression of IL6 and IL8 during reprogramming and showed that reduced IL6 expression can increase reprogramming efficiency. Therefore, the present proposal aims to systematically characterize the identity of factors secreted by senescent cells during reprogramming and examine the molecular mechanisms by which they influence reprogramming. This study will provide new understanding of the molecular mechanisms governing reprogramming and develop novel non-viral methods to improve reprogramming efficiency. Moreover, this study may shed light on developing novel strategies to delay ageing process to prolong life span.

英文关键词： somatic reprogramming；cellular senescence；inflammatory factors；；