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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.

项目概要线粒体疾病或氧化磷酸化遗传性疾病可能是由 at 突变引起的至少 290 个基因，影响大约五千分之一的活产。除了这个严重和虽然个别罕见疾病，线粒体功能障碍可能是许多常见的衰老疾病的原因，例如帕金森病和阿尔茨海默病。申请人的长期目标是将线虫遗传学与线粒体生理学、生物化学和代谢技术来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。最近的工作已表明缺氧可能是电子传递链复合物 I 丢失的有效治疗方法，然而，缺氧拯救的精确分子机制仍然难以捉摸。在第一部分中在他的博士后培训中，申请人已经证明缺氧可以挽救另一种线粒体疾病，弗里德赖希共济失调是由铁硫簇合成基因 Frataxin 水平降低引起的。这申请人已对秀丽隐杆线虫进行了正向遗传筛选，并鉴定了五种新型遗传抑制因子 Frataxin 和复合物 I 损失。在K99/R00申请中，申请人提出（1）确定机制通过缺氧挽救复合物 I 的潜在作用，以及 (2) 表征复合物 I 的新型基因抑制因子和 Frataxin功能障碍。申请人由博士共同指导。 Gary Ruvkun 和 Vamsi Mootha 在 MGH 分子生物学系。 Ruvkun实验室将为线虫遗传提供优良的环境分析，Mootha 实验室将为候选人提供线粒体生理学方面的新科学培训（例如 NADH 和耗氧量测定）、生物化学（例如蓝色本机页面）和新陈代谢（例如稳定同位素示踪剂研究）。在 K99 阶段，申请人还将学习新陈代谢和生物化学，补充了 Mootha 实验室学到的新科学技能，并让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本线粒体生物学的见解，可能会带来减轻线粒体损伤的新治疗策略疾病。