极体基因组移植阻断母源线粒体DNA突变的子代遗传机制

项目名称： 极体基因组移植阻断母源线粒体DNA突变的子代遗传机制

项目编号： No.81471512

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 沙红英

作者单位： 复旦大学

项目金额： 78万元

中文摘要： 以卵子纺锤体移植(ST)、受精卵原核（PNT）为支撑的线粒体置换（MR）技术虽有望改善母源性线粒体疾病患者后代线粒体功能，但无法彻底预防该遗传病发生。项目组在前期研究中发现极体基因组移植（PB1T/PB2T）制备的MR小鼠及其子一代均未检测到核供体来源的线粒体，提示PB1T/PB2T有望彻底预防该病发生(前期结果投稿《CELL》，已审稿获得修回资格)。基于此，本项目利用不同线粒体背景小鼠制备PB1T、ST、PB2T及PNT四种MR小鼠，探索两种线粒体在四种MR小鼠及其子代中的遗传特征，揭示PB1T/PB2T阻断母源性突变线粒体DNA向子代遗传的机制。在此基础上，利用助孕夫妇捐赠的人卵／受精卵制备PB1T、ST、PB2T及PNT胚胎衍生的胚胎干细胞并分化为神经元，比较两位母亲线粒体在四种神经元中的比例，以此开展MR治疗该疾病的临床前研究，为促进PBT为基础的MR技术转化为临床应用奠定基础。

中文关键词： 胚胎发育；卵母细胞；辅助生殖技术；表观遗传；转化医学

英文摘要： Although mitochondrial replacement (MR) technology, including spindle transfer (ST), pronuclei Transfer (PNT), is expected to improve mitochondria function of descendants from mother with mitochondrial disease, it can not completely prevent the occurrence of maternally inherited mitochondrial diseases. Our project team found that there were only healthy mitochondria in MR mice from first / second polor body genome transfer (PB1T/PB2T) and their first generation in previous study, suggesting PB1T/PB2T expected to completely block maternal mitochondrial genetic diseases (Paper of these results have been contributed to 《CELL》,Under Revision ). To investigate the genetic characteristics of two kinds of mitochondria from two mother and further to explore the genetic mechanism of PB1T/PB2T blocking maternal mitochondrial genetic diseases，our project prepared four kinds of MR mice from PB1T, ST, PB2T and PNT respectively. Further more, we will conduct preclinical studies of MR technology using donated the egg / zygote from assisted reproductive couples in this study. Four kinds of MR human embryonic stem cells will be derived from PB1T, PB2T, ST and PNT human embryos. Then the four kinds of ESCs will be differentiated into neurons to compare the degree of heterogeneity of two mothers mitochondria in the four kinds MR derived neurons. The results of our study will promote clinical transformation and application of PBT -based MR technology.

英文关键词： embryonic development;oocyte;Assisted reproductive technology;epigenetic;translational medicine