Mouse models for mitochondrial disorders caused by mutations in mtDNA

mtDNA 突变引起的线粒体疾病小鼠模型

基本信息

批准号：
9030551
负责人：
Mikhail F Alexeyev
金额：
$ 37.1万
依托单位：
UNIVERSITY OF SOUTH ALABAMA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9030551
关键词：
Affect Alabama Amino Acids Animal Model Animals Cell Line Collection Communities DNA DNA copy number Data Defect Development Disease Epidemiology Funding Generations Genes Goals Hereditary Disease Homologous Gene Human Leadership Leber&apos s Hereditary Optic Neuropathy Libraries Literature Lysine-Specific tRNA MELAS Syndrome MERRF Syndrome Methodology Methods Mitochondria Mitochondrial DNA Mitochondrial Diseases Modality Modeling Morbidity - disease rate Mus Mutagenesis Mutate Mutation Nuclear Nucleotides Outcome Patients Pediatric Hospitals Philadelphia Positioning Attribute Prevalence Production Protocols documentation Reporting Research Respiratory Chain Source Staging Supportive care Techniques Testing Transfer RNA Universities disease-causing mutation drug candidate effective therapy human disease innovation interest mitochondrial DNA mutation mitochondrial dysfunction mortality mouse model mutation screening next generation sequencing novel therapeutics public health relevance respiratory screening tool

项目摘要

DESCRIPTION (provided by applicant) Mitochondrial diseases caused by mutations in mitochondrial DNA (mtDNA) are a significant source of morbidity and mortality, yet only supportive care is available to affected patients. This lack of effective therapies can be partly attributed to the lack of faithful animal models for mitochondrial diseases caused by mutations in mtDNA. Two critical obstacles to the availability of mouse models of these diseases are 1) the lack of mouse mtDNA mutations homologous to those found in human disease, and 2) the lack of a method to efficiently generate such mutations. Therefore, the long-term goals of the proposed studies are 1) to overcome these obstacles in order to enable routine modeling of human diseases caused by mtDNA mutations, and 2) to provide mouse models of mitochondrial disease to the research community. In this application, we propose to leverage expertise developed at the University of South Alabama (mutagenesis of mouse mtDNA) and Children's Hospital of Philadelphia (transmitochondrial mouse models) towards generating models of human diseases caused by mutations in mitochondrially-encoded tRNA genes. Using the tools and techniques developed in the previous funding cycle and in preliminary studies, we will 1) generate an arrayed library of mouse clones carrying mutations in mtDNA, 2) use it to perform a targeted screening for mutations in tRNALeuUUR and in tRNALys, and 3) use these mutations as well as tRNA mutations isolated by us previously for the generation and characterization of transmitochondrial animals. It is anticipated that, if successful, the proposed studies will deliver a powerful impetus to mitochondrial research in general and to research on mitochondrial disease in particular by providing the mitochondrial research community with (1) mouse model(s) for mitochondrial disease caused by mutations in tRNA genes, (2) an arrayed library of mouse clones suitable for targeted screening for mtDNA mutations of interest as well as tools and protocols for generating and screening such libraries, and (3) cell line(s) carrying mouse homolog(s) of human pathogenic mtDNA mutations.

描述（由申请人提供）线粒体DNA（mtDNA）引起的线粒体疾病是发病率和死亡率的重要来源，但仅受影响的患者才能提供支持。这缺乏有效的疗法可以部分归因于缺乏由mtDNA突变引起的线粒体疾病的忠实动物模型。这些疾病小鼠模型可用性的两个关键障碍是1）缺乏与人类疾病中发现的小鼠mtDNA突变，以及2）缺乏有效产生此类突变的方法。因此，拟议的研究的长期目标是1）克服这些障碍，以实现由mtDNA突变引起的人类疾病的常规建模，以及2）为研究界提供线粒体疾病的小鼠模型。在此应用程序中，我们建议利用南阿拉巴马大学（小鼠mtDNA的诱变）和费城儿童医院（蒙脱膜软骨小鼠模型）开发的专业知识，以生成由线粒体辅导的TRNA基因突变引起的人类疾病模型。 Using the tools and techniques developed in the Previous funding cycle and in preliminary studies, we will 1) generate an arrayed library of mouse clones carrying mutations in mtDNA, 2) use it to perform a targeted screening for mutations in tRNALeuUUR and in tRNALys, and 3) use these mutations as well as tRNA mutations isolated by us previously for the generation and characterization of transmitochondrial animals.预计，如果成功的话，拟议的研究将为一般的线粒体研究带来强大的动力，并通过为线粒体研究社区提供（1）小鼠模型，以通过（1）小鼠模型为线粒体模型提供针对TRNA基因的突变和适用于trna的库的突变，（（2），（2），（2）对线粒体疾病的研究，（2）及其对小鼠的突变引起的线粒体疾病的研究，（2）产生和筛选此类文库，以及（3）携带人类致病性mtDNA突变小鼠同源物的细胞系。