Identification of genetic and environmental suppressors of mitochondrial dysfunction

项目摘要 线粒体疾病或氧化磷酸化的遗传性疾病可由at 至少有290个基因，大约每5,000个活产婴儿中就有一个受到影响。除了这些严重的和 个别罕见的疾病，线粒体功能障碍可能是许多常见的衰老疾病的基础， 帕金森氏症和老年痴呆症。申请人的长期目标是将联合收割机C. elegans遗传学 线粒体生理学、生物化学和代谢技术，以鉴定新的遗传和 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 已经表明缺氧可能是电子传递链复合物I损失的有效治疗， 然而，缺氧拯救的精确分子机制仍然难以捉摸。第一部分 他的博士后培训，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，这是由铁硫簇合成基因Frataxin水平降低引起的。的 申请人已经在C.并确定了五种新的遗传抑制因子， Frataxin和复合物I损失。在K99/R 00申请中，申请人建议（1）确定机制 潜在的复合物I通过缺氧拯救，和（2）表征复合物I的新的遗传抑制因子， 共济失调。申请人由MGH的加里·鲁夫昆博士和瓦姆西·穆塔博士共同指导 分子生物学系。Ruvkun实验室将为C.线虫遗传 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 (e.g. NADH和氧消耗测定）、生物化学（例如蓝色天然页）和代谢（例如稳定的 同位素示踪研究）。在K99阶段，申请人还将进行代谢课程， 生物化学，补充了在Mootha实验室学到的新的科学技能，并允许他开始一个 线粒体生物学领域的独立研究实验室。K99/R 00项目的完成将提供 深入了解基本的线粒体生物学，并可能导致新的治疗策略，以减轻线粒体 疾病

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.