Regulation of mitochondrial homeostasis through retrograde signaling
通过逆行信号调节线粒体稳态
基本信息
- 批准号:9924614
- 负责人:
- 金额:$ 44.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-01 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:3T3-L1 CellsAddressAdipocytesApoptoticBindingBiochemicalBiogenesisCaenorhabditis elegansCell LineageCell NucleusCellsCellular Metabolic ProcessChromatinCommunicationCuesDataDefectDevelopmentDiseaseEpigenetic ProcessEquilibriumEukaryotic CellExcisionGPS2 geneGene ActivationGene ExpressionGenesGenetic TranscriptionGenomeGoalsHela CellsHistonesHomeostasisHomologous GeneInsulin ResistanceLeadMaintenanceMammalian CellMammalsMediatingMediator of activation proteinMetabolicMetabolic DiseasesMetabolismMitochondriaMitochondrial DiseasesMitochondrial ProteinsMolecularNeurodegenerative DisordersNon-Insulin-Dependent Diabetes MellitusNuclearNutrientNutritionalPathway interactionsPersonal SatisfactionPlayProteomicsRegulationRoleSignal PathwaySignal TransductionStressStructural ModelsTechniquesTranscriptional ActivationTranslatingUbiquitin-Conjugating EnzymesUbiquitinationYeastsactivating transcription factor 1basecell typecofactorcommon cellular transcription factor ATFexperimental studyflexibilitygenome-wideglobal run on sequencinghuman diseaseinhibitor/antagonistmitochondrial dysfunctionnovelpreventprogramspromoterrecruitresponsesensortherapeutic targettranscriptome sequencing
项目摘要
PROJECT SUMMARY / ABSTRACT
Because the majority of mitochondrial proteins are encoded in the nuclear genome,
mitochondrial biogenesis and maintenance of mitochondrial homeostasis ultimately
depend on nuclear transcription being regulated in response to mitochondrial damage
and to changes in cell metabolism or nutrients availability. However, the pathways
controlling mitochondria-to-nucleus communication in mammalian cells are still largely
unknown. Here, we propose to investigate the hypothesis that the transcriptional
cofactor GPS2 regulates mitochondrial homeostasis as a direct mediator of
mitochondrial retrograde signaling in mammalian cells with the following Aims: i)
Characterize the role of GPS2 in promoting transcriptional activation of nuclear-encoded
mitochondrial genes; ii) Dissect the regulation of GPS2 shuttling between mitochondria
and nucleus and define the gene programs regulated upon translocation; iii) Elucidate
the role of GPS2 retrograde translocation in regulating mitochondrial homeostasis. To
achieve these goals, we will use a combination of biochemical techniques, genome wide
ChIPseq/RNAseq experiments and open-ended proteomic approaches to dissect the
molecular mechanism underlying GPS2-mediated regulation of mitochondrial gene
expression in the nucleus and elucidate the regulatory strategies that control GPS2
retrograde translocation both in conditions of mitochondrial stress and during the
differentiation of specialized cell lineages. Overall, successful completion of the studies
outlined in this application will: 1) identify a novel player in the regulation of mitochondrial
gene expression and elucidate the molecular mechanism of its transcriptional activity, 2)
dissect the first direct pathway of mitochondrial retrograde signaling in mammalian cells,
and 3) reveal an unexpected regulatory strategy for integrating stress and metabolic
signaling within the cell through inhibition of non-proteolytic ubiquitination.
项目总结/摘要
因为大多数线粒体蛋白质是在核基因组中编码的,
线粒体的生物合成和维持线粒体的稳态,
依赖于线粒体损伤时核转录的调节
以及细胞代谢或营养物质可用性的变化。然而,路径
在哺乳动物细胞中,控制细胞核与细胞核之间的通讯仍然主要是
未知在这里,我们建议调查的假设,转录
辅助因子GPS 2调节线粒体稳态,作为
哺乳动物细胞中的线粒体逆行信号传导,目的如下:
表征GPS 2在促进核编码的转录激活中的作用。
线粒体基因; ii)剖析GPS 2在线粒体之间穿梭的调节
和细胞核,并定义易位后调节的基因程序; iii)阐明
GPS 2逆行转位在调节线粒体稳态中的作用。到
为了实现这些目标,我们将使用生物化学技术,全基因组
ChIPseq/RNAseq实验和开放式蛋白质组学方法来剖析
GPS 2介导线粒体基因调控的分子机制
在细胞核中的表达,并阐明控制GPS 2的调控策略
在线粒体应激条件下和在细胞凋亡过程中,
特化细胞谱系的分化。总体而言,顺利完成研究
本申请中概述的方法将:1)鉴定在线粒体DNA的调节中的新的参与者,
基因表达,并阐明其转录活性的分子机制,2)
剖析哺乳动物细胞中线粒体逆行信号传导的第一个直接途径,
和3)揭示了一种意想不到的整合压力和代谢的调节策略
通过抑制非蛋白水解泛素化在细胞内进行信号传导。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('VALENTINA PERISSI', 18)}}的其他基金
Coordination of PAR and Ub signaling in mitochondria
线粒体中 PAR 和 Ub 信号传导的协调
- 批准号:
10623889 - 财政年份:2023
- 资助金额:
$ 44.56万 - 项目类别:
Regulation of mitochondrial homeostasis through retrograde signaling
通过逆行信号调节线粒体稳态
- 批准号:
10133090 - 财政年份:2018
- 资助金额:
$ 44.56万 - 项目类别:
Ubiquitin-dependent regulation of inflammation and insulin resistance
炎症和胰岛素抵抗的泛素依赖性调节
- 批准号:
9243244 - 财政年份:2014
- 资助金额:
$ 44.56万 - 项目类别:
Ubiquitin-dependent regulation of inflammation and insulin resistance
炎症和胰岛素抵抗的泛素依赖性调节
- 批准号:
9040938 - 财政年份:2014
- 资助金额:
$ 44.56万 - 项目类别:
Role of the NCoR corepressor complex in the development of insulin resistance
NCoR 辅阻遏物复合物在胰岛素抵抗发展中的作用
- 批准号:
8149970 - 财政年份:2010
- 资助金额:
$ 44.56万 - 项目类别:
Role of the NCoR corepressor complex in the development of insulin resistance
NCoR 辅阻遏物复合物在胰岛素抵抗发展中的作用
- 批准号:
8328959 - 财政年份:2010
- 资助金额:
$ 44.56万 - 项目类别:
Role of the NCoR corepressor complex in the development of insulin resistance
NCoR 辅阻遏物复合物在胰岛素抵抗发展中的作用
- 批准号:
8138837 - 财政年份:2010
- 资助金额:
$ 44.56万 - 项目类别:
Role of the NCoR corepressor complex in the development of insulin resistance
NCoR 辅阻遏物复合物在胰岛素抵抗发展中的作用
- 批准号:
7300065 - 财政年份:2007
- 资助金额:
$ 44.56万 - 项目类别:
Role of the NCoR corepressor complex in the development of insulin resistance
NCoR 辅阻遏物复合物在胰岛素抵抗发展中的作用
- 批准号:
7456334 - 财政年份:2007
- 资助金额:
$ 44.56万 - 项目类别:
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