mTORC2 signaling in metabolism and cell fate

mTORC2 信号在代谢和细胞命运中的作用

• 批准号: 10609270
• 负责人: Estela Jacinto
• 金额: $ 3.87万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10609270
• 关键词: Affect; Aging; Amino Acids; Autoimmunity; Cells; Complex; Diabetes Mellitus; Disease; Environment; Enzymes; Eukaryota; FRAP1 gene; Gene Expression; Growth; Growth Factor; Hexosamines; Insulin; Malignant Neoplasms; Metabolic; Metabolic Pathway; Metabolism; Nutrient; Pathway interactions; Protein Kinase; Proteomics; Regulation; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Sirolimus; T-Cell Development; Thymocyte Development; extracellular; nutrient metabolism; protein complex; receptor; response; therapeutically effective

ABSTRACT Cell fate is influenced by the interplay of signals from the extracellular and intracellular environment. Studies over the years have revealed how the quality and quantity of signals triggered extracellular growth receptors mobilize intracellular signaling molecules leading to gene expression changes that dictate cell responses or fate. How such signals affect nutrient metabolism and how nutrient metabolites in turn control intracellular signaling, gene expression and ultimately cell fate remains poorly understood. A central signaling molecule that responds to nutrients and controls metabolism is mTOR. mTOR is an atypical Ser/Thr protein kinase that forms two protein complexes, mTORC1 and mTORC2. Numerous studies have focused on mTORC1, which is inhibited by the natural compound, rapamycin. mTORC1 is active in the presence of amino acids and promotes anabolic metabolism. In contrast to mTORC1, the regulation and functions of mTORC2 are poorly understood. In higher eukaryotes, mTORC2 is activated by growth factors such as insulin. Our project will elucidate how mTORC2 is involved in determining cell fate via its role in metabolic reprogramming during nutrient fluctuations. We will focus on how mTORC2 regulates the hexosamine biosynthetic pathway to control early thymocyte development. In this project, we will conduct quantitative proteomics to define alterations in metabolic and signaling pathways that occur when mTORC2 signaling or hexosamine pathway is modified. Our findings have implications for understanding how metabolism impacts cellular differentiation particularly in early T cell development. A deeper understanding of the regulation and functions of the mTOR complexes is needed for more effective therapeutic strategies against metabolic aberrations that occur during aging and diseases such as autoimmunity, diabetes and cancer.

摘要 细胞命运受到细胞外和细胞内信号相互作用的影响 环境多年来的研究表明， 信号触发细胞外生长受体动员细胞内信号分子 导致基因表达的变化，决定细胞的反应或命运。有多少信息 信号影响营养代谢以及营养代谢物如何反过来控制 细胞内信号传导、基因表达和最终的细胞命运仍然很差 明白一种响应营养和控制的中央信号分子 代谢是mTOR。mTOR是一种非典型的Ser/Thr蛋白激酶， 复合物，mTORC 1和mTORC 2。许多研究都集中在mTORC 1， 它被天然化合物雷帕霉素抑制。mTORC 1在 存在的氨基酸和促进合成代谢。与mTORC 1相比， 对mTORC 2的调节和功能知之甚少。在高等真核生物中， mTORC 2被生长因子如胰岛素激活。我们的项目将阐明 mTORC 2通过其在代谢重编程中的作用参与决定细胞命运 在营养波动期间。我们将重点关注mTORC 2如何调节氨基己糖 控制早期胸腺细胞发育的生物合成途径。在这个项目中，我们将 进行定量蛋白质组学，以确定代谢和信号传导的变化 当mTORC 2信号传导或己糖胺通路被修饰时发生的通路。我们 这些发现对于理解新陈代谢如何影响细胞 特别是在早期T细胞发育中。深入了解 需要mTOR复合物的调节和功能，以更有效地 针对衰老过程中发生的代谢畸变的治疗策略， 自身免疫、糖尿病和癌症等疾病。