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，它允许我们有效地用 人诱导多能干细胞的肝细胞特性。我们还表明， 来源于先天肝脏代谢障碍患者的IPSCs可以用来模拟 培养中的代谢性肝病。在这里，我们建议使用这种方法来研究一种罕见的 称为线粒体DNA耗竭综合征3(肝脑型)(MTDPS3)的疾病 是由脱氧鸟苷激酶(DGUOK)基因突变引起的。我们建议生成 IPSC来源的肝细胞含有不同的DGUOK突变，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有影响。 最后，我们建议将这些细胞作为一个平台来识别可用于治疗的药物 MTDPS3和其他可能的线粒体DNA耗竭综合征。

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.