蛋白激酶复合体Cdk12/cyclin k调控干细胞自我更新的分子机制研究

Cdk12的具体功能目前尚不完全明确，但近年来的研究提示其调控早期胚胎发育及肿瘤发生发展等多个重要的生物学过程。本实验室已发表的数据表明Cdk12调控胚胎干细胞自我更新过程，但机理尚不明确。对胚胎干细胞自我更新及分化机理的探索既能让我们更好的理解细胞命运调控这一基本生命现象，也能为干细胞在再生医学领域中的应用提供理论依据。前期工作中，我们猜想通过鉴定Cdk12在胚胎干细胞中的蛋白底物，可以为研究其如何调控胚胎干细胞命运提供线索。通过两种独立方法的筛选，我们初步鉴定了Cdk12的蛋白底物，包括干细胞因子Esrrb等；并初步验证了Cdk12对Esrrb的调控机理和生物学意义。所拟研究中，我们将基于上述新发现，从分子、细胞和动物三个不同层面研究Cdk12在胚胎干细胞自我更新和早期发育过程中的功能；明确Cdk12-Esrrb/Foxo1调控通路；探索Esrrb和Foxo1之间的相互作用。

Recent studies including our own suggest that Cdk12 plays an important role in regulation of embryonic stem cell self-renewal and genomic stability. We previously identified Cdk12 interacts with cyclin K to maintain embryonic stem cell identity, albeit the underlying mechanisms are not known. Cdk12 executes its biological functions by phosphorylating its protein substrate. Thus, in our preliminary studies, we hypothesized that by identifying Cdk12 protein substrates in embryonic stem cells will shed light on how it controls self-renewal of these cells. To this purpose, we identified several potential Cdk12 substrates including stem cell factor Esrrb. In this proposal, we will functionally characterize the mechanisms how Cdk12 regulate stem cell identity and mammalian early development.