Application of disease-model mice with mutant mtDNA for precise investigation of its pathogenesis

目的1：对线粒体DNA进行精确的病因研究。结果：我们首次提供了突变的线粒体DNA与男性不育有关的证据，该证据已于2006年发表在《美国国家科学院院刊》103：15148-15153上。目的2：线粒体DNA在后代中的传递谱。我们的研究提供了令人信服的证据，表明通过创造携带异质mtDNA的小鼠，小鼠mtDNA很少相互重组，这已发表在2005年的PNAS 102：6057-6062上。此外，我们发现线粒体瓶颈并不是由于mtDNA拷贝数在卵子发生早期急剧下降所致，而是由于小鼠生殖细胞中mtDNA的有效分离单元数量较少所致，这已发表在《自然基因》上。目的3：研究呼吸缺陷有丝分裂小鼠的基因治疗方法。结果：首次报道了将核移植技术应用于有丝分裂小鼠冷冻卵子的基因治疗，该报道发表在2005年的《美国国家科学院院刊》上。

Purpose 1 : Precise investigation of pathogenesis.Results : We provided first evidence that the mutated mtDNA is responsible for male infertility, which had been published in PNAS 103 : 15148-15153, 2006.Purpose 2 : Transmission profiles of the mtDNA to following generations.Results : It has been controversial of whether there is recombination in mammalian mtDNA. Our study provided convincing evidence that mouse mtDNA rarely recombine each other by creating mice carrying heteroplasmic mtDNAs, which had been published in PNAS 102 : 6057-6062, 2005. Moreover, we showed that the mitochondrial bottleneck is not generated due to a mtDNA copy number drastic decline in early oogenesis rather to a small effective number of segregation units for mtDNA in mouse germ cells, which had been published in Nature Genet. 39 : 386-390, 2007.Purpose 3 : Development of gene therapy for mito-mice expressing respirtion defects.Results : We can provide the first report of the success of gene therapy by application of nuclear transplantation technique to firtilized eggs of mito-mice, which had been published in PNAS 102 : 16765-16770, 2005.