iPS细胞端粒重编程及其稳定性维持的分子机制

项目名称： iPS细胞端粒重编程及其稳定性维持的分子机制

项目编号： No.31271587

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： 刘林

作者单位： 南开大学

项目金额： 88万元

中文摘要： 胚胎干(ES)细胞中端粒酶活性较高、端粒比成体细胞中长。端粒长度再生，对由成体细胞重编程而来的诱导多能干（iPS）细胞在长期培养、稳定扩增和大规模应用于临床非常重要。iPS细胞端粒长度存在不均一性和不稳定性，有的端粒长度与ES细胞相似，但也有些端粒较短。我们结果还表明，端粒长短明显影响小鼠多能干细胞（ES/iPS）基因组稳定性和发育多能性。但多能干细胞维持端粒长度和基因组稳定性、及发育多能性的分子调控机制仍不清楚。本课题试图详细阐明多能干细胞端粒长度调控的分子机制及其在维持基因组和表观遗传稳定性中的作用。设计了三个部分研究内容：1)iPS细胞诱导过程中端粒延长及稳定性维持机制；2)端粒在iPS/ES细胞体外长期传代增殖中的作用及调控机制；3)端粒长度与iPS细胞全基因组表观遗传重编程程度及多能性的关系。对ES/iPS细胞端粒调控机制的了解，也可能有助于认识衰老和肿瘤（干细胞）。

中文关键词： 胚胎干细胞；iPS细胞；端粒；多能性；表观遗传

英文摘要： Embryonic stem cells show longer telomeres and higher telomerase activity than somatic cells. Rejuvenation of telomere lengths is criticl for long-term survival and self-renewal of induced pluripotent stem cells (iPS) for potential large scale clinical application. We and others recently demonstrated that lengths of telomeres are heterogenous and unstable in pluripotent stem cells, some with telomere lengths similar to those of ES cells, but others shorter or longer than ES cells. We also showed that telomere lengths affect genomic stability and developmental pluripotency of ES/iPS cells. However, molecular mechanisms underlying regulation and maintenance of telomere lengths, genomic stability and pluripotency of pluripotent stem cells remain to be determined. This proposal aims at understanding mechanisms of telomere length regulation and its role in the maintenance of genomic stablility of pluripotent stem cells. To achieve these goals, we have designed three main experiments: 1) Mechanism of telomere lengthening and stability during induction of iPS cells; 2) Roles and regulation of telomeres in iPS/ES cells during long-term proliferation in vitro; and 3) Relationship of telomere lengths with epigenetic reprogramming extent and pluripotency of iPS cells. Analysis of telomere regulatory mechanisms of iPS/ES ce

英文关键词： ES cells；iPS cells；telomere；pluripotency；epigenetics