MAF1 Function and Metabolic Inefficiency
MAF1 功能和代谢低效
基本信息
- 批准号:9688658
- 负责人:
- 金额:$ 4.61万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-21 至 2018-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAmino AcidsAnimalsAnti-Obesity AgentsAutomobile DrivingBiochemicalCell RespirationCellsCellular StressCitric Acid CycleClinicalCodeComplementConceptionsConsumptionDNA Polymerase IIIDataDietDrug TargetingEnergy MetabolismEngineeringEquilibriumEukaryotaExhibitsFutile CyclingGene DeletionGene ExpressionGenesGenetic RecombinationGenetic TranscriptionGlycolysisGoalsGrantHealthHepaticHumanIn VitroKnock-in MouseKnock-outKnockout MiceKnowledgeLifeLinkLipidsLipolysisLiverLongevityLoxP-flanked alleleMammalian CellMeasurementMeasuresMediatingMetabolicMetabolic PathwayMetabolismMethodsModelingMolecularMolecular AnalysisMusMutationNucleotidesNutrientNutritionalObesityObesity associated diseaseOpen Reading FramesPathway interactionsPentosephosphate PathwayPhenotypePolyaminesPopulationProcessProkaryotic CellsProteinsRNARNA Polymerase IIRNA Polymerase IIIRecombinantsRegulator GenesReportingRepressionResearchResistanceRiboseRibosomal RNARoleSingle-Gene DefectStressTestingThinnessTissuesTracerTranscriptTranscription Repressor/CorepressorTransfer RNATranslationsUntranslated RNAYeastscostexperimental studygenome-widehydrophilicityimprovedinorganic phosphateinsightmetabolic phenotypemouse modelnon-alcoholic fatty liver diseasenovelnucleotide metabolismobesity treatmentpostnatalreduced food intakeresistance generibosome profilingstable isotopetherapeutic targettranscriptomeyoung adult
项目摘要
Project Summary
MAF1 is a conserved nutrient- and stress-sensitive repressor of gene transcription. Best known for its
role as a master regulator of RNA polymerase III transcription in yeast, MAF1 has also been shown to affect
the expression of select genes transcribed by RNA polymerase II in mammalian cells. MAF1 repression of
RNA polymerase III regulates the synthesis of transfer RNAs, 5S rRNA and other abundant non-coding RNAs
that together account for ~15% of total RNA in every cell. Thus, MAF1 function is thought to be important for
metabolic economy. Recent dramatic proof of this view was provided by the finding that mice with a whole
body knockout of Maf1 are lean and profoundly resistant to diet-induced obesity and non-alcoholic fatty liver
disease. Maf1 KO mice are metabolically inefficient, have increased energy expenditure and have an extended
lifespan indicative of improved health. The current understanding is that increased RNA pol III transcription in
every tissue places such a demand on the energetically expensive synthesis of nucleotides that it alters the
balance between energy utilization and storage. Thus, the long term goal of this project is to determine how the
absence of MAF1 changes gene expression and metabolism to alter metabolic efficiency and energy
expenditure. Aim I of this proposal will examine how gene expression has been altered in key metabolic
tissues of Maf1-/- mice by transcriptome and ribosome profiling and by investigating tRNA population effects on
translation efficiency and fidelity. Aim II will determine the metabolic changes underlying the increased energy
expenditure of Maf1-/- mice by targeted metabolite profiling. These studies will focus on central metabolic
pathways and will be complemented by stable isotope measurements of whole body lipolysis and flux through
the pentose phosphate pathway, processes that we hypothesize are associated with the enhanced supply and
consumption of metabolic energy in the mice. Aim III will investigate the role of RNA pol III transcription in
driving energy expenditure in Maf1-/- mice through unrestrained synthesis of highly abundant non-coding
RNAs, including transfer RNA and non-specific transcription. Nascent elongating transcript sequencing will
locate and quantify RNA pol III molecules genome-wide and a new mouse model will be created to suppress
Maf1 KO phenotypes that result directly or indirectly from elevated RNA pol III transcription. Finally, the studies
in aim IV will determine whether loss of MAF1 in young and adult mice via inducible and systemic Cre-
mediated recombination increases metabolic inefficiency. These experiments are expected to support the
concept that the postnatal function of MAF1 is critical for metabolic economy while providing a powerful
demonstration of the potential of MAF1 as an anti-obesity drug target.
项目摘要
MAF1是一种保守的营养和胁迫敏感的基因转录抑制因子。最出名的是其
作为酵母中RNA聚合酶III转录的主要调节者,MAF1也被证明影响
RNA聚合酶II转录的精选基因在哺乳动物细胞中的表达。MAF1基因的抑制作用
RNA聚合酶III调节转移RNA、5S rRNA和其他丰富的非编码RNA的合成
它们加在一起占每个细胞总RNA的15%。因此,MAF1功能被认为对
新陈代谢经济。最近对这一观点的戏剧性证明是因为发现老鼠有一个完整的
身体敲除Maf1基因的人很瘦,对饮食引起的肥胖和非酒精性脂肪肝有很强的抵抗力
疾病。Maf1 KO小鼠代谢效率低下,能量消耗增加,并有较长的
寿命表明健康状况有所改善。目前的理解是,增加的RNA PolIII转录
每个组织都对能量昂贵的核苷酸合成提出了这样的要求,以至于它改变了
能源利用和储存之间的平衡。因此,这个项目的长期目标是确定如何
MAF1的缺失会改变基因表达和代谢,从而改变代谢效率和能量
支出。这项提案的目的一将研究关键代谢中的基因表达是如何改变的
通过转录组和核糖体图谱以及通过研究tRNA群体对Maf1/-小鼠组织的影响
翻译效率和保真度。AIM II将确定能量增加背后的代谢变化
Maf1-/-小鼠通过靶向代谢物图谱的消耗。这些研究将集中在中枢代谢方面
途径,并将补充稳定的同位素测量的全身脂肪分解和通量通过
磷酸戊糖途径,我们假设的过程与增加的供应和
小鼠体内代谢能量的消耗。AIM III将研究RNA PolIII转录在
通过高度丰富的非编码蛋白的自由合成来驱动MAF1-/-小鼠的能量消耗
RNA,包括转移RNA和非特异性转录。新生的延长的文字记录测序将
在全基因组范围内定位和量化RNA PolIII分子,并将创建一种新的小鼠模型来抑制
Maf1 KO表型,直接或间接由RNAPolIII转录升高所致。最后,研究
在Aim IV中,将确定在幼年和成年小鼠中,MAF1的丢失是否通过诱导的和系统性的CRE-
介导性重组会增加代谢效率。这些实验预计将支持
MAF1的出生后功能对代谢经济至关重要,同时提供了一种强大的
MAF1作为减肥药物靶点的潜力展示。
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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IAN M WILLIS的其他文献
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{{ truncateString('IAN M WILLIS', 18)}}的其他基金
Studies on RNA polymerase III-related leukodystrophy
RNA聚合酶III相关脑白质营养不良的研究
- 批准号:
10735229 - 财政年份:2023
- 资助金额:
$ 4.61万 - 项目类别:
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