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基于细胞的疗法的重要研究课题。体细胞核移植（SCNT）到去核卵母细胞是最初的方法，用于确认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。 基因组损伤和内质网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、外源性物质和辐射。响应于DNA损伤或ER应激，细胞激活将导致细胞恢复、细胞适应或细胞停滞/死亡的反应机制。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并不清楚。体细胞研究的证据表明，基因组损伤和ER应激机制是相互依赖的。然而，没有研究它们对核移植后发育和细胞重编程的影响。 我们的研究计划将研究在早期胚胎发育和SCNT后细胞重编程过程中参与DNA双链断裂修复的分子途径。我们还将研究基因组损伤和ER应激机制如何在早期发育的胚胎中相互关联，并探索它们对细胞重编程和分化的影响。拟议的研究将揭示早期胚胎发育中DNA损伤和/或ER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和应用科学以及尖端技术领域的高素质人才（HQP）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.