Genetic modulation of mitochondrial function

项目摘要/摘要： 线粒体的遗传控制几乎完全缺乏，然而，这种工具的实用性 将给生物医学科学的众多领域带来变革。开发遗传方法来 敲除或表达/挽救内源性线粒体基因将是一个强大的研究工具 而且还将立即使新疗法的开发成为可能。我们已经开发出了小说 靶向RNA到线粒体的载体(MtTRES)，并显示出它们能够减少 内源性基因在动物和人类细胞中的表达。我们还开发了载体 能够将编码的长RNA表达到线粒体上，从而使我们能够 过度表达/救援实验。我们建议利用线粒体靶向 核糖核酸内切酶作为减少内源基因表达的替代方法，但也 随意处理mtTRES表达的RNA，促进其高效表达。这个 开发基因操作动物线粒体基因表达的新方法， 它将在人类细胞中得到验证，将对衰老、线粒体等领域产生广泛影响 生物学和神经退行性疾病研究。

Project Summary/Abstract: Genetic control of mitochondria is nearly completely lacking, however, the utility of such tools would be transformative to numerous fields of biomedical science. Developing genetic methods to knockdown or express/rescue endogenous mitochondrial genes would be a powerful research tool but would also immediately enable the development of novel therapies. We have developed novel vectors (mtTRES) that targeted RNAs to mitochondria and shown their ability to reduce the expression of endogenous genes in animals and human cells. We have also developed vectors capable of expressing long, coding RNAs to mitochondria allowing us to perform overexpression/rescue experiments. We propose to utilize mitochondrial-targeted riboendonucleases as an alternative method to reduce expression of endogenous genes but also to willfully process mtTRES expressed RNAs and facilitate their efficient expression. The development of novel methods to genetically manipulate mitochondrial gene expression in animals, which will be validated in human cells will have a broad impact on the fields of aging, mitochondrial biology and neurodegenerative disease research.