Unconventional regulation of mTORC1 signaling by inositol phosphate: implications for nutrient-induced premature aging
磷酸肌醇对 mTORC1 信号传导的非常规调节:对营养诱导的过早衰老的影响
基本信息
- 批准号:10372324
- 负责人:
- 金额:$ 29.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-15 至 2022-09-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAgeAgingAmino Acids ActivationAnimal ModelBindingCaenorhabditis elegansCatalytic DomainCell AgingCellsComplexDataDiseaseDown-RegulationEnzymesEventFRAP1 geneGeneticGenetic EpistasisGenetic studyGlucoseGoalsGrantGrowth FactorHealthHumanImmune TargetingIn VitroInositolInositol Phosphate Metabolism PathwayInositol PhosphatesInterventionLate Onset Alzheimer DiseaseLinkLongevityMediatingMetabolicMetabolic PathwayMetabolic stressMetabolismModelingMolecularMolecular WeightMusMutationNutrientOrganismPathway interactionsPatientsPharmacologyPhosphotransferasesPhysiologyPhytic AcidPremature aging syndromeProcessProductionRecombinantsRegulationReportingResistanceRiskRoleSignal TransductionSingle Nucleotide PolymorphismSirolimusStudy modelsTestingTimeTissuesUp-RegulationWomanWorkdetection of nutrientdietary restrictionflyglucose metabolismhealthspanimprovedin vitro activityin vivomutantnovelpreventresponsesensorsmall molecule
项目摘要
Nutrient accelerates cellular aging processes through metabolic stress. The detrimental effects of nutrient
overload to health span are partially mediated by mTORC1 (mechanistic Target of Rapamycin Complex 1),
an evolutionarily conserved nutrient-sensing kinase that signals for increase in anabolic processes. mTORC1
activity has been directly linked to aging and age-associated diseases in a diverse range of organisms
including humans, mice, flies and worms. Remarkably, genetic or pharmacological inhibition of mTORC1
improved the health and increased the lifespan of several animal models of premature aging. Although the
molecular mechanisms for mTORC1 activation by amino acids and growth factors are well established, recent
findings indicate that excess glucose stimulates mTORC1 signaling through unconventional mechanisms that
are not completely understood. Glucose metabolism directly and indirectly stimulates the production of the
small metabolite inositol hexakisphosphate (IP6). Recent structural studies revealed that IP6 is tightly
associated with mTOR, the catalytic subunit of mTORC1. Preliminary data suggest that IP6 binding to mTOR
stabilizes the in vitro association between mTOR and RAPTOR, the regulatory subunit of mTORC1. The goal
of this proposal is to establish a role for IP6 in the regulation of mTORC1 signaling in vivo and to assess
whether targeting the metabolic pathways for IP6 synthesis will prevent cellular aging and promote longevity.
In specific aim 1, the impact of IP6 metabolism on mTOR signaling and cellular ageing will be investigated.
IP6 synthesis will be manipulated by suppression of the two critical kinases that catalyze the synthesis of IP6
– IPMK and IPK1. In addition we will suppress ISYNA1, the enzyme that catalyzes de novo synthesis of
inositol from glucose. The direct effects of cellular IP6 on mTORC1/2 complex assembly and stability will be
examined using recombinant mTOR mutants that are unable to bind to IP6. In specific aim 2, the crosstalk
between IP6 metabolism and mTORC1 signaling will be genetically tested using C. elegans as a model for
assessing longevity. Epistasis studies will be performed to determine how IPMK and IPK1 interact with of
mTORC1. Suppression of enzymes involved in IP6 synthesis are predicted to protect worms from mTORC1-
induced premature aging. Understanding the impact of IP6 on mTORC1 signaling and in aging will open up
new opportunities for targeting these pathways to improve health.
营养物质通过代谢应激加速细胞衰老过程。营养的有害影响
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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Raymond Daniel Blind其他文献
Raymond Daniel Blind的其他文献
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{{ truncateString('Raymond Daniel Blind', 18)}}的其他基金
Unconventional regulation of mTORC1 signaling by inositol phosphate: implications for nutrient-induced premature aging
磷酸肌醇对 mTORC1 信号传导的非常规调节:对营养诱导的过早衰老的影响
- 批准号:
10772905 - 财政年份:2022
- 资助金额:
$ 29.42万 - 项目类别:
Cancer cell signaling through lipids complexed to proteins
通过脂质与蛋白质复合的癌细胞信号传导
- 批准号:
8543686 - 财政年份:2012
- 资助金额:
$ 29.42万 - 项目类别:
Cancer cell signaling through lipids complexed to proteins
通过脂质与蛋白质复合的癌细胞信号传导
- 批准号:
8708521 - 财政年份:2012
- 资助金额:
$ 29.42万 - 项目类别:
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