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Identification of genetic and environmental suppressors of mitochondrial dysfunction

线粒体功能障碍的遗传和环境抑制因子的鉴定

基本信息

批准号：
10319607
负责人：
Joshua Daniel Meisel
金额：
$ 10万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10319607
关键词：
Acyl Carrier Protein Affect Aging Alzheimer&apos s Disease Anabolism Animals Binding Biochemistry Bioenergetics Biogenesis Biological Assay Biology Breathing Bypass Caenorhabditis elegans Cells Cellular biology Collection Complement Complex DNA sequencing Disease Disease model Dominant Genes Electrophoresis Environment Ferredoxin Friedreich Ataxia Functional disorder Gene Expression Genes Genetic Genetic Models Genetic Screening Genetic Transcription Genome Goals Health Hereditary Disease Hyperoxia Hypoxia In Vitro Individual Infant Mortality Inner mitochondrial membrane Iron Lead Leigh Disease Live Birth Measurement Mentors Metabolic Metabolism Metalloproteases Methylation Methyltransferase Microscopy Mitochondria Mitochondrial Diseases Molecular Molecular Biology Mus Mutation NADH NADH dehydrogenase (ubiquinone)Nerve Degeneration Nuclear Nuclear RNA Organism Oxidative Phosphorylation Oxygen Oxygen Consumption Paper Parkinson Disease Patient-Focused Outcomes Phase Physiology Post-Transcriptional RNA Processing Proteins Proteome RNA Stability RNA methylation Rare Diseases Research Sulfur Suppressor Mutations System Techniques Therapeutic Tracer Training Translating Work cysteine desulfurase effective therapy experimental study frataxin gene synthesis genetic analysis improved in vivo insight mitochondrial dysfunction mouse model mutant nervous system disorder novel novel therapeutic intervention post-doctoral training prevent rare genetic disorder sensor stable isotope transcriptome sequencing

项目摘要

Project Summary Mitochondrial diseases, or inherited disorders of oxidative phosphorylation, can be caused by mutations in at least 290 genes and affect approximately 1 in 5,000 live births. In addition to this collection of severe and individually rare disorders, mitochondrial dysfunction may underly many common diseases of aging, such as Parkinson’s and Alzheimer’s disease. The long-term goal of the applicant is to combine C. elegans genetics with techniques of mitochondrial physiology, biochemistry, and metabolism to identify novel genetic and environmental suppressors of mitochondrial dysfunction and elucidate the underlying mechanisms. Recent work has shown that hypoxia may be an effective treatment for loss of Complex I of the electron transport chain, however the precise molecular mechanism underlying the rescue by hypoxia remains elusive. In the first part of his postdoctoral training, the applicant has demonstrated that hypoxia can rescue another mitochondrial disease, Friedreich’s ataxia, which is caused by reduced levels of the Iron-Sulfur Cluster synthesis gene Frataxin. The applicant has performed forward genetic screens in C. elegans and identified five novel genetic suppressors of Frataxin and Complex I loss. In the K99/R00 application, the applicant proposes to (1) determine the mechanism underlying Complex I rescue by hypoxia, and (2) characterize the novel genetic suppressors of Complex I and Frataxin dysfunction. The applicant is jointly mentored by Drs. Gary Ruvkun and Vamsi Mootha in the MGH Molecular Biology Department. The Ruvkun lab will provide an excellent environment for C. elegans genetic analysis, and the Mootha lab will provide the candidate with new scientific training in mitochondrial physiology (e.g. NADH and oxygen consumption assays), biochemistry (e.g. blue native page), and metabolism (e.g. stable isotope tracer studies). In the K99 phase the applicant will also undertake coursework in Metabolism and Biochemistry, complementing the new scientific skillsets learned in the Mootha lab, and allowing him to start an independent research lab in the field of mitochondrial biology. Completion of the K99/R00 project will provide insights into basic mitochondrial biology and may lead to novel therapeutic strategies for mitigating mitochondrial disease.

项目摘要线粒体疾病或遗传性氧化磷酸化紊乱可由at基因突变引起。至少290个基因，大约每5,000名活产儿中就有1名受到影响。除了这一系列严重和个别罕见的疾病，线粒体功能障碍可能低于许多常见的衰老疾病，如帕金森氏症和阿尔茨海默氏症。申请者的长期目标是将线虫的遗传学与线粒体生理学、生化和新陈代谢技术以识别新的遗传和线粒体功能障碍的环境抑制因子，并阐明其潜在机制。近期工作已经表明，缺氧可能是丢失电子传输链的络合物I的有效治疗方法，然而，低氧拯救的确切分子机制仍然不清楚。在第一部分中在他的博士后培训中，申请人证明了缺氧可以拯救另一种线粒体疾病， Friedreich‘s共济失调，这是由于铁-硫簇合成基因frataxin水平降低引起的。这个申请人在线虫中进行了正向基因筛查，并确定了五个新的基因抑制因子 Frataxin和Complex I Lost。在K99/R00申请中，申请人建议(1)确定机制潜在的复合体I通过缺氧拯救，以及(2)表征复合体I和复合体I的新的遗传抑制因子 Frataxin功能障碍。申请者由MGH的Gary Ruvkun博士和Vamsi Mootha博士共同指导分子生物学系。Ruvkun实验室将为线虫的遗传提供良好的环境分析，Mootha实验室将为候选人提供新的线粒体生理学科学培训 (例如NADH和氧气消耗分析)、生物化学(例如蓝色天然PAGE)和新陈代谢(例如稳定同位素示踪剂研究)。在K99阶段，申请者还将学习新陈代谢和生物化学，补充了在Mootha实验室学到的新的科学技能，并使他能够开始线粒体生物学领域的独立研究实验室。K99/R00项目的完成将提供对基础线粒体生物学的洞察，并可能导致缓解线粒体的新治疗策略疾病。