Genetic modulation of mitochondrial function

线粒体功能的遗传调节

基本信息

批准号：
9542442
负责人：
Michael John Palladino
金额：
$ 23.44万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9542442
关键词：
5&apos Untranslated Regions Aging Animals Antibodies Biochemical Biology Cell Nucleus Cells Chimeric Proteins Cleaved cell Code Development Disease Drosophila genus Endoribonucleases Engineering Excision Fluorescence Microscopy Gene Expression Genes Genetic Genetic Transcription Goals Health Hela Cells Human Inner mitochondrial membrane Internal Ribosome Entry Site Measures Membrane Messenger RNA Methods Mitochondria Mitochondrial Diseases Mitochondrial RNA N-terminal Nerve Degeneration Neurodegenerative Disorders Neuromuscular Diseases Nuclear PTGS2 gene Phenotype Process Proteins Publishing RNA Reporter Research Science Signal Transduction Site Syncope System Technology Testing Therapeutic Translation Initiation Translations Validation Western Blotting age related design efficacy testing experimental study fly genetic manipulation in vivo knock-down mitochondrial dysfunction monomer mutant nervous system disorder novel novel therapeutic intervention novel therapeutics oligomycin sensitivity-conferring protein overexpression prevent tool transcriptome vector

项目摘要

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.

项目摘要/摘要：线粒体的遗传控制几乎完全缺乏，然而，此类工具的效用将对生物医学科学的许多领域产生变革。开发遗传方法敲低或表达/拯救内源线粒体基因将是一个强大的研究工具但也将立即促进新疗法的开发。我们开发了新颖的载体 (mtTRES) 将 RNA 靶向线粒体并显示出其减少内源基因在动物和人类细胞中的表达。我们还开发了载体能够向线粒体表达长的编码 RNA，使我们能够执行过度表达/拯救实验。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，但也故意加工 mtTRES 表达的 RNA 并促进其有效表达。这开发在动物中遗传操纵线粒体基因表达的新方法，这将在人体细胞中得到验证，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。