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 超负荷对健康寿命的影响部分是由mTORC1(雷帕霉素复合体1的机械靶点)介导的， 一种进化上保守的营养感应蛋白，信号提示合成代谢过程增加。MTORC1 在不同的生物体中，活动与衰老和与年龄相关的疾病有直接联系 包括人类、老鼠、苍蝇和蠕虫。值得注意的是，mTORC1的遗传或药物抑制 改善几种早衰动物模型的健康和延长寿命。尽管 最近，氨基酸和生长因子激活mTORC1的分子机制得到了充分的证实 研究结果表明，过量的葡萄糖通过非常规机制刺激mTORC1信号转导 还没有完全被理解。葡萄糖代谢直接或间接地刺激 小的代谢物六磷酸肌醇(IP6)。最近的结构研究表明，IP6与 与mTOR相关的mTORC1的催化亚基。初步数据表明，IP6与mTOR结合 稳定mTOR和mTORC1的调节亚单位Raptor之间的体外联系。目标是 这项建议的目的是确定IP6在体内mTORC1信号调节中的作用并评估 靶向代谢途径的IP6合成是否能防止细胞衰老和延长寿命。 在具体目标1中，将研究IP6代谢对mTOR信号和细胞老化的影响。 IP6的合成将通过抑制催化IP6合成的两个关键激酶来进行操作 -IPMK和IPK1。此外，我们还将抑制ISYNA1，这种酶催化从头合成 从葡萄糖中提取肌醇。细胞内IP6对mTORC1/2复合体组装和稳定性的直接影响 使用不能与IP6结合的重组mTOR突变体进行检测。在《特定目标2》中，串扰 IP6代谢和mTORC1信号之间的关系将使用线虫作为模型进行遗传测试 评估寿命。将进行上位性研究以确定IPMK和IPK1如何与OF相互作用 MTORC1.抑制参与IP6合成的酶被预测为保护蠕虫免受mTORC1- 导致过早衰老。了解IP6对mTORC1信号和衰老的影响将会打开 针对这些途径以改善健康的新机会。