The functional role of mTORC1 regulation by AMPK in cellular metabolic reprogramming

AMPK 调节 mTORC1 在细胞代谢重编程中的功能作用

• 批准号: 10705694
• 负责人: Jeanine L Van Nostrand
• 金额: $ 40万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-16 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705694
• 关键词: 5' -AMP-activated protein kinase; Alanine; Autophagocytosis; Biochemical; Cell physiology; Cells; Complex; Diabetes Mellitus; Disease; Energy consumption; Environment; FRAP1 gene; Failure; Gene Expression; Genetic Transcription; Goals; Growth; Health; Homeostasis; Human; Knowledge; Laboratories; Link; Lipids; Malignant Neoplasms; Mediator; Metabolic; Metabolic Control; Metabolic Diseases; Metabolic Pathway; Metabolic dysfunction; Metabolism; Molecular; Mus; Mutant Strains Mice; Mutation; Nutrient; Pathway interactions; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Process; Protein Synthesis Inhibition; Regulation; Research; Role; Serine; Signal Pathway; Signal Transduction; Stress; Tissues; Work; cell growth; cell growth regulation; energy balance; experimental study; functional genomics; human disease; innovation; insight; mouse model; nervous system disorder; novel; novel therapeutic intervention; programs; treatment strategy

PROJECT SUMMARY Loss of energy homeostasis is a key driver in human disease. Failure to maintain cellular energy balance results in many disease states, including diabetes, cancer, and neurological diseases. AMP-activated kinase (AMPK) is a highly conserved kinase responsible for maintaining cellular energy balance. Under conditions of low nutrients and low energy, AMPK controls the metabolic switch from an energy-consuming anabolic state to an energy-producing catabolic state at both the cellular and organismal level. Upon activation by energetic stress, AMPK phosphorylates downstream targets to arrest cell growth, regulate transcription, inhibit protein synthesis, and reprogram cellular metabolism. One of the most well-established downstream signaling pathway inhibited by AMPK is the pro-growth mechanistic Target of Rapamycin complex 1 (mTORC1) pathway. However, the functional role that mTORC1 inhibition plays in cellular metabolic reprogramming and maintaining energy homeostasis upon AMPK activation is controversial, as both AMPK-independent inhibition of mTORC1 and mTORC1-independent regulation of metabolic pathways have been described. The long-term scope of my research program is to elucidate the mechanisms that regulate energy homeostasis and refine the current understanding of how pathways exert control of metabolic reprogramming. To accomplish this long-term goal, my research group will address two major knowledge gaps in our current understanding of how mTORC1 inhibition interacts with AMPK activity to drive cellular metabolism and growth: 1) Is mTORC1 inhibition necessary for cellular metabolic reprogramming by AMPK? What aspects of cellular metabolic reprogramming require mTORC1 inhibition by AMPK? 2) How does mTORC1 inhibition and AMPK activation coordinate the regulation of processes involved in metabolic reprogramming? My extensive expertise in defining molecular mechanisms of cellular processes and using innovative mouse models makes my recently established independent laboratory an ideal environment to undertake these efforts toward a more complete understanding of AMPK signaling. We will employ novel point-mutant mice harboring specific serine-to-alanine mutations at the phosphorylation sites required for AMPK-dependent inhibition of mTORC1. Using both mouse tissues and primary cells derived from these mice, we will perform functional genomic and biochemical analyses to uncover the precise role of mTORC1 inhibition induced by AMPK activation in regulating gene expression, autophagy, and lipid synthesis, which are critical for cellular metabolic reprogramming. Together, these experiments will provide conceptual advances in how we think about AMPK and its relationship with mTORC1 and will offer mechanistic insight into how dysregulation of these pathways can lead to metabolic dysfunction and disease, which will allow us to identify new therapeutic strategies for treatment of metabolically-linked human disease.

项目摘要 能量稳态的丧失是人类疾病的关键驱动因素。无法维持细胞能量平衡 导致许多疾病状态，包括糖尿病、癌症和神经系统疾病。AMP活化激酶 AMPK是一种高度保守的激酶，负责维持细胞能量平衡。条件下 低营养和低能量，AMPK控制代谢从消耗能量的合成代谢状态转换为 在细胞和有机体水平上都是一种产生能量的分解代谢状态。在被能量激活后， 应激时，AMPK磷酸化下游靶点以阻止细胞生长，调节转录，抑制蛋白质 合成和重新编程细胞代谢。最成熟的下游信号通路之一 被AMPK抑制的是雷帕霉素复合物1（mTORC 1）途径的促生长机制靶标。然而，在这方面， mTORC 1抑制在细胞代谢重编程和维持能量中发挥的功能作用 AMPK激活后的体内平衡是有争议的，因为mTORC 1的AMPK非依赖性抑制和 已经描述了代谢途径的mTORC 1非依赖性调节。 我的研究计划的长期范围是阐明调节能量的机制 稳态和完善目前的理解途径如何发挥控制代谢重编程。 为了实现这一长期目标，我的研究小组将解决我们目前的两个主要知识差距， 了解mTORC 1抑制如何与AMPK活性相互作用，以驱动细胞代谢和生长： 1)AMPK对细胞代谢重编程是否需要mTORC 1抑制？的哪些方面 细胞代谢重编程需要AMPK抑制mTORC 1？ 2)mTORC 1抑制和AMPK激活如何协调相关过程的调节 代谢重编程 我在定义细胞过程的分子机制和使用创新的 小鼠模型使我最近建立的独立实验室成为进行这些研究的理想环境。 努力更全面地了解AMPK信号。我们将使用新的点突变小鼠 在AMPK依赖性的磷酸化位点上具有特异性的丝氨酸-丙氨酸突变， 抑制mTORC 1。使用小鼠组织和来自这些小鼠的原代细胞，我们将进行 功能基因组和生物化学分析，以揭示mTORC 1抑制诱导的确切作用， AMPK活化在调节基因表达、自噬和脂质合成中起作用，这些对细胞增殖至关重要。 代谢重编程总之，这些实验将为我们如何思考 AMPK及其与mTORC 1的关系，并将提供机制的洞察如何失调，这些 代谢途径可能导致代谢功能障碍和疾病，这将使我们能够确定新的治疗策略， 用于治疗代谢相关的人类疾病。