Study and Treatment of Mitochondrial DNA Depletion Syndrome 3 Using iPSCs

项目摘要 我们之前已经描述了一种程序，该程序允许我们有效地分化具有以下特征的细胞： 来自人诱导多能干细胞的肝细胞特征。我们还表明， 来源于具有先天性肝代谢缺陷的患者的iPSC可用于建模 代谢性肝病在这里，我们建议使用这种方法来研究一种罕见的 线粒体DNA耗竭综合征3（肝脑型）（MTDPS3）， 是由脱氧鸟嘌呤激酶（DGUOK）基因突变引起的。我们建议生成 在DGUOK中含有不同突变的iPSC衍生的肝细胞，并比较 这些突变对线粒体DNA拷贝数、线粒体活性和肝细胞功能的影响。 最后，我们建议利用这些细胞作为一个平台，以确定药物，可用于治疗 MTDPS3和潜在的其他线粒体DNA缺失综合征。

Project Summary We have previously described a procedure that allows us to efficiently differentiate cells with hepatocyte characteristics from human induced pluripotent stem cells. We have also shown that iPSCs derived from patients with inborn errors of hepatic metabolism can be used to model metabolic liver disease in culture. Here we propose to use this approach to study a rare disease called Mitochondrial DNA Depletion Syndrome 3 (Hepatocerebral type) (MTDPS3) that is caused by mutations in the Deoxyguanine Kinase (DGUOK) gene. We propose to generate iPSC-derived hepatocytes that contain different mutations in DGUOK and compare the effect of these mutations on mtDNA copy number, mitochondrial activity, and hepatocyte function. Finally, we propose to use these cells as a platform to identify drugs that can be used to treat MTDPS3 and potentially other mitochondrial DNA depletion syndromes.