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.
营养素通过代谢压力加速细胞衰老过程。营养素的有害影响
超负荷的健康寿命部分由mTORC 1(雷帕霉素复合物1的机制靶点)介导,
一种进化上保守的营养感应激酶,发出合成代谢过程增加的信号。mTORC1
在多种生物体中,活性与衰老和与年龄相关的疾病直接相关
包括人类、老鼠、苍蝇和蠕虫。值得注意的是,mTORC 1的遗传或药理学抑制
改善了几种早衰动物模型的健康状况并延长了寿命。虽然
氨基酸和生长因子激活mTORC 1的分子机制已经很好地建立,最近
研究结果表明,过量的葡萄糖通过非常规机制刺激mTORC 1信号传导,
还没有完全被理解。葡萄糖代谢直接或间接地刺激产生
小代谢产物肌醇六磷酸(IP 6)。最近的结构研究表明,IP 6是紧密的,
与mTOR相关,mTORC 1的催化亚基。初步数据表明,IP 6与mTOR的结合
稳定mTOR和RAPTOR(mTORC 1的调节亚基)之间的体外结合。目标
该建议的目的是建立IP 6在体内mTORC 1信号转导调节中的作用,并评估
针对IP 6合成的代谢途径是否会防止细胞衰老并促进长寿。
在具体目标1中,将研究IP 6代谢对mTOR信号传导和细胞老化的影响。
通过抑制催化IP 6合成的两种关键激酶来操纵IP 6合成
- IPMK和IPK 1。此外,我们将抑制ISYNA 1,这种酶催化从头合成的
来自葡萄糖的肌醇。细胞IP 6对mTORC 1/2复合物组装和稳定性的直接影响将在下文中讨论。
使用不能与IP 6结合的重组mTOR突变体进行检查。在具体目标2中,串扰
将使用C.作为一种模式,
评估寿命。将进行上位性研究,以确定IPMK和IPK 1如何与
mTORC 1。预测抑制参与IP 6合成的酶可保护蠕虫免受mTORC 1-
导致过早衰老。了解IP 6对mTORC 1信号传导和衰老的影响将打开
为这些途径提供新的机会,以改善健康。
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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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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