mTORC1调控线粒体代谢在ESCs和体细胞重编程中的作用和机制研究

mTORC1-PGC1 pathway has been shown to regulate mitochondrial metabolism and controls multiple somatic and stem cell fate, but its function and mechanism in ESCs is still elusive. Recently, it has been proved that mitochondrial related metabolites regulate ESC epigenetics and pluripotency. Our previous work showed that mTORC1-PGC1 regulates mitochondrial metabolic switch during somatic cell reprogramming, and activation of mTORC1 induces ESC differentiation. Based on these discoveries, we propose that mTORC1-PGC1 regulates the epigenetic status in ESCs and somatic cell reprogramming through controlling the mitochondrial metabolism. In this project we aim to: 1, activate mTORC1 and mitochondrial biogenesis in ESCs individually and identify the changes of key metabolite/s that regulate pluripotency; 2, investigate the corresponding epigenetic changes that contribute to pluripotency; 3, confirm these discoveries in both the early stage ESC differentiation and somatic cell reprogramming. Our discovery in this project will increase our knowledge on the interrelationship between mitochondrial metabolism, epigenetics and pluripotency, and may provide new solutions to improve ESC culture and promote reprogramming efficiency.

mTORC1-PGC1通路调控线粒体代谢并影响多种体细胞、干细胞的命运，但其在ESCs中对多能性的影响还有待进一步明确。最新研究发现线粒体代谢产物可以影响ESCs的表观遗传学修饰并参与维持多能性。我们的前期研究发现：mTORC1-PGC1调控体细胞重编程中的线粒体代谢转变；ESCs中激活mTORC1抑制多能性。综合以上证据我们提出假设：mTORC1-PGC1很可能通过线粒体代谢产物调控表观遗传学修饰，在多能性维持和重建中发挥重要作用。本课题我们将：1，在ESCs中分别激活mTORC1和线粒体发生，检测线粒体代谢产物，并确定哪些变化与多能性维持有关；2，研究这些重要代谢产物的变化引起哪些表观遗传学修饰的改变；3，在分化早期和重编程中进一步验证这些变化是否同样重要。本课题将增进我们对线粒体代谢-表观遗传学-多能性之间密切关联的认识，进而探索优化ESCs培养和提高重编程效率的新方法。

mTORC1-PGC1通路调控线粒体代谢并影响多种体细胞、干细胞的命运，但其在ESCs中对多能性的影响还有待进一步明确。最新研究发现线粒体代谢产物可以影响ESCs的表观遗传学修饰并参与维持多能性。我们的前期研究发现：mTORC1-PGC1调控体细胞重编程中的线粒体代谢转变；ESCs中激活mTORC1抑制多能性。综合以上证据我们提出假设：mTORC1-PGC1很可能通过线粒体代谢产物调控表观遗传学修饰，在多能性维持和重建中发挥重要作用。本课题我们将：1，在ESCs中分别激活mTORC1和线粒体发生，检测线粒体代谢产物，并确定哪些变化与多能性维持有关；2，研究这些重要代谢产物的变化引起哪些表观遗传学修饰的改变；3，在分化早期和重编程中进一步验证这些变化是否同样重要。本课题将增进我们对线粒体代谢-表观遗传学-多能性之间密切关联的认识，进而探索优化ESCs培养和提高重编程效率的新方法。