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:
- 金额:$ 10万
- 依托单位:
- 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:
- 关键词:Acyl Carrier ProteinAffectAgingAlzheimer&aposs DiseaseAnabolismAnimalsBindingBiochemistryBioenergeticsBiogenesisBiological AssayBiologyBreathingBypassCaenorhabditis elegansCellsCellular biologyCollectionComplementComplexDNA sequencingDiseaseDisease modelDominant GenesElectrophoresisEnvironmentFerredoxinFriedreich AtaxiaFunctional disorderGene ExpressionGenesGeneticGenetic ModelsGenetic ScreeningGenetic TranscriptionGenomeGoalsHealthHereditary DiseaseHyperoxiaHypoxiaIn VitroIndividualInfant MortalityInner mitochondrial membraneIronLeadLeigh DiseaseLive BirthMeasurementMentorsMetabolicMetabolismMetalloproteasesMethylationMethyltransferaseMicroscopyMitochondriaMitochondrial DiseasesMolecularMolecular BiologyMusMutationNADHNADH dehydrogenase (ubiquinone)Nerve DegenerationNuclearNuclear RNAOrganismOxidative PhosphorylationOxygenOxygen ConsumptionPaperParkinson DiseasePatient-Focused OutcomesPhasePhysiologyPost-Transcriptional RNA ProcessingProteinsProteomeRNA StabilityRNA methylationRare DiseasesResearchSulfurSuppressor MutationsSystemTechniquesTherapeuticTracerTrainingTranslatingWorkcysteine desulfuraseeffective therapyexperimental studyfrataxingene synthesisgenetic analysisimprovedin vivoinsightmitochondrial dysfunctionmouse modelmutantnervous system disordernovelnovel therapeutic interventionpost-doctoral trainingpreventrare genetic disordersensorstable isotopetranscriptome 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。
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
申请人的长期目标是将线虫遗传学与帕金森病和阿尔茨海默病结合起来。
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。
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,在第一部分中,缺氧拯救的精确分子机制仍然难以捉摸。
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。
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Complex I损失在K99/R00申请中,申请人建议(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 MGH 的 Gary Ruvkun 和 Vamsi Mootha 博士共同指导。
分子生物学系。Ruvkun 实验室将为秀丽隐杆线虫遗传提供良好的环境。
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
在 K99 阶段,申请人还将学习新陈代谢和同位素示踪剂研究方面的课程。
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
K99/R00项目的完成将提供线粒体生物学领域的独立研究实验室。
对基本线粒体生物学的见解,可能会导致减轻线粒体的新治疗策略
疾病。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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