Control of RNA methylation by growth signals through the mTORC1 pathway
通过 mTORC1 途径通过生长信号控制 RNA 甲基化
基本信息
- 批准号:10277131
- 负责人:
- 金额:$ 32万
- 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:2021-09-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:A549AddressAgingAnabolismApoptosisBindingBiochemicalBiologicalBiologyBiomassCRISPR/Cas technologyCell Cycle ArrestCell ProliferationCell SurvivalCellsClinicClinicalComplexConsumptionDNA MethylationDNA Modification MethylasesDataDevelopmentDiabetes MellitusDiseaseDrug TargetingEnvironmentEnzymesEpigenetic ProcessEssential Amino AcidsExhibitsFRAP1 geneGenetic TranscriptionGlucoseGlutamineGoalsGrowthGrowth FactorHela CellsHomeostasisHumanHuman Cell LineImmunosuppressionIntronsIsotope LabelingLeadLinkLipidsMEL GeneMalignant NeoplasmsMammalian CellMeasuresMessenger RNAMetabolicMetabolic PathwayMetabolic syndromeMetabolismMethionineMethionine Metabolism PathwayMethylationMethyltransferaseModificationMolecularMutateNeurodegenerative DisordersNutrientObesityOrganPC3 cell linePathologicPathway interactionsPatientsPhosphorylation SitePhosphotransferasesPhysiologicalPositioning AttributeProcessProtein BiosynthesisProteinsProteomicsRNARNA InterferenceRNA methylationReactionRegulationReportingRibosomal RNARoleS-AdenosylmethionineSignal PathwaySignal TransductionSyndromeSystemTherapeuticTherapeutic InterventionTissuesTracerTranscriptional Regulationbasec-myc Genescell growthcell motilitychemical geneticsdietarydrug discoveryhistone methylationinhibitor/antagonistinsightmacromoleculemetabolic ratemetabolomicsmethionine adenosyltransferasemouse modelneoplastic cellnervous system disordernovelnucleotide metabolismpre-clinicalside effectstable isotopetargeted treatmenttherapeutic targettumortumor growth
项目摘要
SUMMARY
The mechanistic target of rapamycin complex 1 (mTORC1) senses and integrates diverse environmental signals
to control energy and nutrient-consuming biosynthetic processes, such as protein, lipid, and nucleotide
synthesis. mTORC1 stimulates anabolic cell growth through posttranslational and transcriptional mechanisms
leading to increased macromolecule synthesis a prerequisite to augment cellular biomass priming cells for
growth and division. In many diseases, the prominence of mTORC1 signaling reinforces the importance of
considering targeting mTORC1 signaling in several diseases including neurodegenerative disorders, diabetes,
tumor syndromes, and aging. However, direct mTORC1 targeted therapies, being conceptually and preclinically
a promising target, displayed only limited efficacy in human patients. Therefore, a better understanding of the
biology downstream of mTORC1 and the development of more effective and specific therapeutic strategies in
the treatment of mTORC1-driven diseases are needed. To achieve the biosynthetic demands accompanying
proliferation, cells must increase the transport of nutrients from the environment. Glucose, lactate, and glutamine
are the principal nutrients that promote biosynthesis and survival in mammalian cells. An emerging aspect of
nutrient utilization in aging and proliferative diseases includes the role of dietary methionine restriction, which
was recently explored in the context of obesity, metabolic syndrome, and cancer. Methionine is an essential
amino acid that is catabolized and recycled in a sequence of metabolic reactions designated as the methionine
cycle. Methionine and ATP are converted into the universal methyl donor S-adenosylmethionine (SAM) via the
methionine adenosyltransferase 2 alpha (MAT2A) enzyme. Under this proposal, we propose to study the
influence of mTORC1 signaling on S-adenosylmethionine (SAM) synthesis and the subsequent methylation
processes supporting anabolic metabolism. We have identified that mTORC1 stimulates SAM synthesis in
various cell settings through direct transcriptional control of MAT2A expression by c-MYC. We propose to
evaluate the influence of mTORC1 signaling on SAM synthesis in a variety of human cells (Specific Aim1). Will
identify the mechanisms by which mTORC1 signaling promotes RNA methylation, particularly the N6-
methyladenosine (m6A) mark. We will determine the role of m6A on RNA downstream of mTORC1 in the control
of cell growth (Specific Aim2). Furthermore, we will determine the implication of the mTORC1-MAT2A axis on
tumor growth and the potential therapeutic strategy derived from this mechanism (Specific Aim3). Thus, the
overall goal of this proposal is to decipher the molecular mechanisms by which mTORC1 controls RNA
methylation in normal and pathological settings. We anticipate that the proposed studies will yield new insights
into how SAM levels alter anabolic metabolism and will uncover therapeutic targets to perturb mTORC1-driven
diseases.
总结
雷帕霉素复合物1(mTORC 1)的机制目标感测和整合不同的环境信号
控制消耗能量和营养的生物合成过程,如蛋白质、脂质和核苷酸
合成. mTORC 1通过翻译后和转录机制刺激合成代谢细胞生长
导致增加的大分子合成,这是增加细胞生物量的先决条件,
成长与分裂在许多疾病中,mTORC 1信号传导的突出加强了以下方面的重要性:
考虑在几种疾病中靶向mTORC 1信号传导,包括神经变性疾病,糖尿病,
肿瘤综合征和衰老。然而,直接mTORC 1靶向治疗,在概念上和临床前
一个有希望的靶点,在人类患者中仅显示出有限的功效。因此,更好地了解
mTORC 1下游的生物学和开发更有效和特异性的治疗策略,
需要mTORC 1驱动的疾病的治疗。为了达到生物合成的要求,
为了促进细胞增殖,细胞必须增加从环境中运输营养物质。葡萄糖、乳酸盐和谷氨酰胺
是促进哺乳动物细胞生物合成和存活的主要营养素。一个新的方面,
营养素在衰老和增殖性疾病中的利用包括饮食蛋氨酸限制的作用,
最近在肥胖症、代谢综合征和癌症的背景下进行了探索。美沙酮是必不可少的
在一系列代谢反应中被分解代谢和再循环的氨基酸,称为甲硫氨酸
周期甲硫氨酸和ATP通过腺苷酸转化为通用的甲基供体S-腺苷甲硫氨酸(SAM)。
甲硫氨酸腺苷转移酶2 α(MAT 2A)酶。根据这项建议,我们建议研究
mTORC 1信号传导对S-腺苷甲硫氨酸(SAM)合成和随后甲基化的影响
支持合成代谢的过程。我们已经确定mTORC 1刺激SAM合成,
通过c-MYC对MAT 2A表达的直接转录控制来调节各种细胞环境。我们建议
评估mTORC 1信号传导对多种人类细胞中SAM合成的影响(特异性Aim 1)。将
确定mTORC 1信号促进RNA甲基化的机制,特别是N6-
甲基腺苷(m6 A)标记。我们将在对照组中确定m6 A在mTORC 1 RNA下游的作用。
细胞生长(特定Aim 2)。此外,我们将确定mTORC 1-MAT 2A轴对
肿瘤生长和源自该机制的潜在治疗策略(特异性Aim 3)。因此
这项计划的总体目标是破译mTORC 1控制RNA的分子机制
甲基化在正常和病理情况下。我们预计,拟议的研究将产生新的见解
SAM水平如何改变合成代谢,并将揭示干扰mTORC 1驱动的治疗靶点。
疾病
项目成果
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{{ truncateString('Issam BEN-SAHRA', 18)}}的其他基金
Control of RNA methylation by growth signals through the mTORC1 pathway
通过 mTORC1 途径通过生长信号控制 RNA 甲基化
- 批准号:
10469579 - 财政年份:2021
- 资助金额:
$ 32万 - 项目类别:
Control of RNA methylation by growth signals through the mTORC1 pathway
通过 mTORC1 途径通过生长信号控制 RNA 甲基化
- 批准号:
10630233 - 财政年份:2021
- 资助金额:
$ 32万 - 项目类别:
Regulation of de novo purine synthesis by the MAPK/ERK pathway
MAPK/ERK 途径对嘌呤从头合成的调节
- 批准号:
10539252 - 财政年份:2020
- 资助金额:
$ 32万 - 项目类别:
Regulation of de novo purine synthesis by the MAPK/ERK pathway
MAPK/ERK 途径对嘌呤从头合成的调节
- 批准号:
10321274 - 财政年份:2020
- 资助金额:
$ 32万 - 项目类别:
Regulation of de novo purine synthesis by the MAPK/ERK pathway
MAPK/ERK 途径对嘌呤从头合成的调节
- 批准号:
10078280 - 财政年份:2020
- 资助金额:
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Linking Oncogenic Signaling to Tumor Metabolism
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- 批准号:
9477858 - 财政年份:2015
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