Cell reprogramming, embryo development and genome integrity

细胞分化和重编程是研究疾病机制和开发新的细胞治疗方法的重要研究课题。体细胞核移植（Somatic cell nuclear transfer， SCNT）进入去核卵母细胞是最初用来证实分化的体细胞保留全能性的能力，并可以通过第二轮发育完全重编程的方法。******基因组损伤和内源性内源性应激可由许多内源性和外源性因素引起，包括活性氧、细胞代谢改变、外源药物和辐射。在对DNA损伤或内质网应激的反应中，细胞激活反应机制，导致细胞恢复、细胞适应或细胞停滞/死亡。虽然这些机制已经在体细胞中进行了系统的研究，但在早期发育的胚胎和核移植后的细胞重编程过程中却不为人所知。体细胞研究表明，基因组损伤和内质网应激机制是相互依存的。然而，它们对核移植后细胞发育和重编程的影响尚未研究。******我们的研究计划将研究早期胚胎发育和SCNT后细胞重编程过程中DNA双链断裂修复的分子途径。我们还将研究基因组损伤和内质网应激机制在早期发育胚胎中的相互关系，并探讨它们对细胞重编程和分化的影响。该研究将揭示胚胎早期发育中DNA损伤和/或内质网应激、SCNT后细胞重编程以及胚胎细胞稳态、命运和分化之间的联系。拟议的研究计划还将支持基础科学和应用科学以及尖端技术领域的高素质人才（HQPs）的学生培训和毕业。

Cell differentiation and reprogramming are important research topics for the study of disease mechanisms and development of new cell-based therapies. Somatic cell nuclear transfer (SCNT) into enucleated oocytes was the original method used to confirm that differentiated somatic cells retain capacity for totipotency and can be completely reprogrammed through a second round of development. ******Genome damage and ER stress can be caused by a number of endogenous and exogenous factors, including reactive oxygen species, altered cell metabolism, xenobiotics and radiation. In response to DNA damage or ER stress cells activate reaction mechanisms that will lead to cell recovery, cell adaption or cell arrest/death. Although these mechanisms have been systematically investigated in somatic cells they are not well known in early developing embryos and during cell reprograming after nuclear transfer. There is evidence from studies in somatic cells indicating that genome damage and ER stress mechanisms are interdependent. However, their effects on development and cell reprogramming after nuclear transfer were not studied.******Our research program will investigate the molecular pathways involved in the repair of DNA double-strand breaks during early embryo development and cell reprogramming after SCNT. We will also study how genome damage and ER stress mechanisms are interrelated in early developing embryos and explore their effects on cell reprogramming and differentiation. The proposed research will reveal the link between DNA damage and/or ER stress in early embryo development, cell reprogramming after SCNT, and embryo cell homeostasis, fate and differentiation. The proposed research program will also support student training and graduation of Highly Qualified Personnel (HQPs) in basic and applied sciences, and cutting edge technology.