Systems analysis of mitochondrial genome maintenance in physiological context
Systems analysis of mitochondrial genome maintenance in physiological context
批准号:
10898255
负责人:
Samantha C Lewis
金额:
$8.84万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-09-15 至 2027-08-31
关键词:
ATP Synthesis PathwayAllelesAnimalsBiologyCell physiologyCellsCellular biologyChromosomesComplexDiseaseEukaryotic CellFosteringGenetic TranscriptionGenomeGoalsHealthHeritabilityHomeostasisHumanInvertebratesLiteratureMaintenanceMalignant NeoplasmsMetabolic DiseasesMicroscopyMissionMitochondriaMitochondrial DNAMitochondrial Respiratory Chain DeficienciesModelingMolecularNerve DegenerationOrganellesOxidative PhosphorylationPathway interactionsPhysiologicalProcessProteinsProteomicsRNAResearchSomatic CellSystems AnalysisTissuesUnited States National Institutes of HealthWorkexperimental studyhuman diseaseinsightmitochondrial DNA mutationmitochondrial dysfunctionmitochondrial genomemutantnew therapeutic targetnovelsegregation
中文摘要
项目说明/摘要
线粒体DNA(MtDNA)编码对细胞功能至关重要的RNA和蛋白质。然而,
在动物细胞中调节线粒体DNA合成和分离的途径并不是很好
明白了。这项工作的目标是确定线粒体DNA的蛋白质成分
类核复合体,研究线粒体复制和动力学是如何协调的
来维持线粒体DNA类核的分离和丰度,并探索
体细胞中针对突变mtDNA的选择机制。这些实验
将为维持必要的线粒体提供基本的见解
动物细胞中的染色体以及维持过程是如何调控的,潜在地导致了
发现和表征调控线粒体DNA遗传的新途径
疾病等位基因。我们将使用活细胞和整个动物的尖端显微镜,
蛋白质组学和单细胞转录分析,以询问分子功能
与维持线粒体DNA完整性有关的候选蛋白质。这些实验将
调和线粒体生物学文献中的不一致之处,提供对
线粒体DNA拷贝数控制的机制,并发现新的途径,调节
线粒体功能障碍的组织特异性表现。
英文摘要
Project Description/Summary
Mitochondrial DNA (mtDNA) encodes RNAs and proteins critical for cell function. However, the
pathways that regulate mtDNA synthesis and segregation in animal cells are not well
understood. The goals of this work are to identify the protein components of mitochondrial DNA
nucleoid complexes, to investigate how mitochondrial replication and dynamics are coordinated
to homeostatically maintain mtDNA nucleoid segregation and abundance, and to probe the
mechanisms underlying selection against mutant mtDNAs in somatic cells. These experiments
will provide fundamental insights into the maintenance of the essential mitochondrial
chromosome in animal cells and how maintenance processes are regulated, potentially leading
to the discovery and characterization of novel pathways that regulate the inheritance of mtDNA
disease alleles. We will employ cutting-edge microscopy of living cells and whole animals,
proteomics, and single cell transcriptional analyses to interrogate the molecular functions of
candidate proteins implicated in the maintenance of mtDNA integrity. These experiments will
reconcile inconsistencies in the mitochondrial biology literature, provide fundamental insight into
the mechanisms of mtDNA copy number control, and identify novel pathways that regulate the
tissue-specific manifestations of mitochondrial dysfunction.
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会议论文
Systems analysis of mitochondrial genome maintenance in physiological context
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批准号:10500906
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项目类别:
-
资助金额:$37.02万
-
财政年份:2022
-
负责人:Samantha C Lewis
-
依托单位:
Systems analysis of mitochondrial genome maintenance in physiological context
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批准号:10701776
-
项目类别:
-
资助金额:$38.77万
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财政年份:2022
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负责人:Samantha C Lewis
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依托单位:
Systems analysis of mitochondrial genome maintenance in physiological context
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批准号:10816224
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项目类别:
-
资助金额:$1.47万
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财政年份:2022
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负责人:Samantha C Lewis
-
依托单位:
Molecular mechanisms of mtDNA inheritance
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批准号:10085799
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项目类别:
-
资助金额:$24.9万
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财政年份:2018
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负责人:Samantha C Lewis
-
依托单位:
Molecular mechanisms of mtDNA inheritance
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批准号:10371889
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项目类别:
-
资助金额:$24.9万
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财政年份:2018
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负责人:Samantha C Lewis
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依托单位:
Systems Analysis of Mammalian Mitochondrial DNA Segregation
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批准号:8831988
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项目类别:
-
资助金额:$5.24万
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财政年份:2015
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负责人:Samantha C Lewis
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依托单位:
海外基金