Mouse models for mitochondrial disorders caused by mtDNA mutations

mtDNA 突变引起的线粒体疾病小鼠模型

基本信息

批准号：
8442897
负责人：
Mikhail F Alexeyev
金额：
$ 34.13万
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 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8442897
关键词：
Adult Affect Aging-Related Process Alabama Animal Model Animals Biological Assay Book Chapters Cell Line Cells Cellular biology Chairperson Child Collection Complex Cultured Cells DNA-Directed DNA Polymerase Defect Development Disease Disease model Ensure Environment Event Faculty Funding Generations Genotype Goals Human Journals Laboratories Maintenance Medicine Methodology Methods Missense Mutation Mitochondria Mitochondrial DNA Mitochondrial Diseases Modality Modeling Morbidity - disease rate Mouse Cell Line Mus Mutagenesis Mutate Mutation NADH dehydrogenase (ubiquinone)Nature Neurosciences Nonsense Mutation Nuclear Nucleotides Outcome Patients Peer Review Phenotype Point Mutation Positioning Attribute Production Publications Publishing Reagent Reporting Research Research Personnel Resources Respiratory Chain Ribosomal RNA Risk Role Secure Source Structure Supportive care Technology Testing Transfer RNA Universities Vitamins Writing career cofactor college disease phenotype disease-causing mutation human disease member mitochondrial DNA mutation model development mortality mouse model mutant novel therapeutics outcome forecast overexpression polypeptide professor programs public health relevance research study respiratory tool

项目摘要

DESCRIPTION (provided by applicant): Mitochondrial diseases caused by mutations in the mitochondrial DNA (mtDNA) are an important source of morbidity and mortality, yet only supportive care is available to affected patients. Mouse models of human disease are instrumental in the developing and testing new therapeutic modalities. So far, the lack of characterized mouse cell lines with mtDNA mutations and technologies to produce such mutations has made impossible routine development of mouse models for the diseases caused by mtDNA mutations. Therefore, the long-term GOAL of this application is to enable routine modeling of human mitochondrial diseases in mice. We propose to achieve this GOAL through (1) refining the methodology developed in the course of preliminary studies; (2) through the use of this methodology to generate a collection of mouse cell lines (3) through the characterization of this collection by sequencing and functional assays, and (4) through the generation of transmitochondrial mice carrying mtDNA mutations generated and characterized in aims 1-3. If successful, these studies will enable routine mouse modeling of mitochondrial disease. Moreover, the outcome of aims 1-3 should generate resources, which will facilitate the structure-function studies of mammalian respiratory complexes. This outcome will also enable generation of a collection of mouse cell lines containing all possible single-nucleotide substitutions in their mtDNA. Candidate: The candidate is a new investigator who received a tenure-track Assistant Professor position in the Department of Cell Biology and Neuroscience, University of South Alabama in 2004. Since then he has authored or co-authored 23 publications in peer-reviewed journals and one book chapter. Most recently, the candidate was invited and wrote a single-author, 20-page review for FEBS journal on the role of mitochondrial DNA in aging process. The candidate's immediate career goal is to secure RO1-level funding for upcoming tenure review. The long-term career goals involve developing a vigorous research program around two main research focused in his lab: the nature of diversity of genotype-phenotype correlations in mitochondrial diseases and mechanisms for the maintenance of mitochondrial DNA integrity. Environment: College of Medicine, University of South Alabama represents a vibrant mitochondrial research environment with 10 faculty members involved in mitochondrial research. Of those, four are senior level researchers (full Professors) and 6 are junior researchers. Both the Chairman and the Vice-Chair of the applicant's Department as well as four junior faculty are mitochondrial researchers. Mitochondrial research in the applicant's Department is supported by three RO1s and one R21.

描述（由申请人提供）：由线粒体DNA（mtDNA）引起的线粒体疾病是发病率和死亡率的重要来源，但受影响的患者只能获得支持。人类疾病的小鼠模型有助于发展和测试新的治疗方式。到目前为止，缺乏具有mtDNA突变和产生此类突变技术的特征性小鼠细胞系，这使得不可能对由mtDNA突变引起的疾病的小鼠模型进行常规发展。因此，该应用的长期目标是实现小鼠人类线粒体疾病的常规建模。我们建议通过（1）完善在初步研究过程中开发的方法；（2）通过使用该方法来通过测序和功能测定来表征该集合的集合（3），以及（4）通过在AIMS 1-3中产生和表征的携带MTDNA突变的多膜骨软骨小鼠的产生。如果成功，这些研究将实现线粒体疾病的常规小鼠建模。此外，目标1-3的结果应产生资源，这将促进哺乳动物呼吸络合物的结构功能研究。该结果还将能够生成一系列小鼠细胞系，其中包含其mtDNA中所有可能的单核苷酸取代。候选人：候选人是一名新的调查员，他于2004年在南阿拉巴马大学的细胞生物学和神经科学系任职助理教授职位。从那时起，他就在同行评审期刊和一本书中撰写或共同创作了23个出版物。最近，该候选人被邀请并为FEBS杂志写了一本关于线粒体DNA在衰老过程中的作用的单作者，为20页的评论。候选人的直接职业目标是确保RO1级的资金以进行即将到来的任期审查。长期职业目标涉及在其实验室中着重于两项主要研究的剧烈研究计划：线粒体疾病中基因型 - 表型相关性的多样性和维持线粒体DNA完整性的机制。环境：南阿拉巴马大学医学院代表了一个充满活力的线粒体研究环境，有10名教职员工参与线粒体研究。其中，有四位是高级研究人员（全部教授），而6名是初级研究人员。申请人部门的董事长和副主席以及四个初级教师都是线粒体研究人员。申请人部门的线粒体研究得到了三个RO1和一项R21的支持。