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

目的1：精确研究发病机制。结果：我们首次提供了mtDNA突变与男性不育有关的证据，发表在PNAS 103: 15148-15153, 2006。目的2:mtDNA向后代的传播概况。结果：哺乳动物mtDNA是否存在重组一直存在争议。我们的研究提供了令人信服的证据，证明小鼠mtDNA很少通过制造携带异质mtDNA的小鼠来相互重组，该研究已发表在PNAS 102: 6057-6062, 2005。此外，我们发现线粒体瓶颈不是由于卵子发生早期mtDNA拷贝数急剧下降而产生的，而是由于小鼠生殖细胞中mtDNA的有效分离单位数量较少。该研究已发表在Nature Genet. 39: 386- 390,2007。目的3：发展表达呼吸缺陷的mitto小鼠的基因治疗。结果：利用核移植技术对有丝分裂小鼠受精卵进行基因治疗，首次获得成功，发表于PNAS 102: 16765-16770, 2005。

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.