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
• 负责人: Raymond Daniel Blind
• 金额: $ 18.84万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10772905
• 关键词: Acceleration; Address; Affect; Age; Aging; Amino Acids Activation; Animal Model; Binding; Caenorhabditis elegans; Catalytic Domain; Cell Aging; Cells; Complex; Data; Disease; Down-Regulation; Enzymes; Event; FRAP1 gene; Genetic; Genetic Epistasis; Genetic study; Glucose; Goals; Grant; Growth Factor; Health; Human; Immune Targeting; In Vitro; Inositol; Inositol Phosphate Metabolism Pathway; Inositol Phosphates; Intervention; Late Onset Alzheimer Disease; Link; Longevity; Mediating; Metabolic; Metabolic Pathway; Metabolic stress; Metabolism; Modeling; Molecular; Molecular Weight; Mus; Mutation; Nutrient; Organism; Pathway interactions; Patients; Phosphotransferases; Physiology; Phytic Acid; Premature aging syndrome; Process; Production; Recombinants; Regulation; Reporting; Resistance; Risk; Role; Signal Transduction; Single Nucleotide Polymorphism; Sirolimus; Study models; Testing; Tissues; Up-Regulation; Woman; Work; detection of nutrient; dietary restriction; feeding; fly; glucose metabolism; healthspan; improved; in vitro activity; in vivo; mutant; novel; pharmacologic; prevent; response; sensor; small molecule

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.

营养素通过代谢应激加速细胞衰老过程。营养素的有害影响 健康跨度超载部分由 mTORC1（雷帕霉素复合物 1 的机械靶标）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 活性与多种生物体的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，mTORC1 的遗传或药理学抑制 改善了几种过早衰老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 mTORC1 的分子机制已得到充分确立，最近 研究结果表明，过量的葡萄糖通过非常规机制刺激 mTORC1 信号传导， 都没有完全理解。葡萄糖代谢直接和间接刺激葡萄糖的产生 小代谢物肌醇六磷酸 (IP6)。最近的结构研究表明，IP6 紧密结合 与 mTOR（mTORC1 的催化亚基）相关。初步数据表明 IP6 与 mTOR 结合 稳定 mTOR 和 RAPTOR（mTORC1 的调节亚基）之间的体外关联。目标 该提案的目的是确定 IP6 在体内 mTORC1 信号传导调节中的作用并评估 针对 IP6 合成的代谢途径是否可以预防细胞衰老并延长寿命。 在具体目标 1 中，将研究 IP6 代谢对 mTOR 信号传导和细胞衰老的影响。 IP6 的合成将通过抑制催化 IP6 合成的两种关键激酶来控制 – IPMK 和 IPK1。此外，我们还将抑制 ISYNA1，这种酶催化从头合成 来自葡萄糖的肌醇。细胞 IP6 对 mTORC1/2 复合物组装和稳定性的直接影响将是 使用无法结合 IP6 的重组 mTOR 突变体进行了检查。在具体目标 2 中，串扰 IP6 代谢和 mTORC1 信号传导之间的关系将使用秀丽隐杆线虫作为模型进行基因测试 评估寿命。将进行上位性研究以确定 IPMK 和 IPK1 如何与 mTORC1。抑制参与 IP6 合成的酶预计可以保护蠕虫免受 mTORC1- 诱发过早衰老。了解 IP6 对 mTORC1 信号传导和衰老的影响将会开启 针对这些途径来改善健康的新机会。