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: 10809251
• 负责人: Estela Jacinto
• 金额: $ 0.83万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10809251
• 关键词: Affect; Aging; Amino Acids; Autoimmunity; Cell Fate Control; Cells; Complex; Diabetes Mellitus; Disease; Environment; Enzymes; Eukaryota; FRAP1 gene; Gene Expression; Growth Factor; Hexosamines; Insulin; Malignant Neoplasms; Metabolic; Metabolism; Natural Compound; Nutrient; Pathway interactions; Protein Kinase; Regulation; Role; Signal Transduction; Signaling Molecule; Sirolimus; T-Cell Development; Thymocyte Development; cell growth; 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. 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 细胞命运受细胞外和细胞内信号相互作用的影响 环境。多年来的研究揭示了如何在质量和数量上 信号触发的细胞外生长受体动员细胞内信号分子 导致基因表达变化，从而决定细胞的反应或命运。怎么会这样呢 信号影响营养新陈代谢以及营养代谢物如何反过来控制 细胞内信号、基因表达和最终细胞命运仍然很差 明白了。一种对营养物质和控制作出反应的中央信号分子 新陈代谢是mTOR。MTOR是一种非典型的丝氨酸/苏氨酸蛋白激酶，形成两种蛋白 复合体、mTORC1和mTORC2。许多研究都集中在mTORC1上， 它被天然化合物雷帕霉素抑制。MTORC1在 氨基酸的存在，促进合成代谢。与mTORC1相反， 目前对mTORC2的调控和功能知之甚少。在高等真核生物中， MTORC2被胰岛素等生长因子激活。我们的项目将阐明如何 MTORC2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。我们将重点介绍mTORC2如何调节氨基己糖 控制胸腺细胞早期发育的生物合成途径。我们的发现是 理解新陈代谢如何影响细胞分化的启示 尤其是在T细胞发育的早期。更深入地了解该法规和 更有效的治疗策略需要mTOR复合体的功能 防止在衰老和疾病期间发生的代谢异常，如 自身免疫、糖尿病和癌症。