Metabolic control of monocyte development and function by amino acids

摘要 单核细胞是先天免疫所必需的，但也在自身免疫性疾病中传播炎症反应。 关节炎和其他风湿性疾病。了解单核细胞发育的基本生物学是 因此是揭示疾病发病机理和鉴定新治疗靶点的核心。 PI先前的工作已经确定了中枢代谢整合因子mTORC 1的重要作用 （雷帕霉素复合物1的机制靶标）作为骨髓发育的主要调节剂。单核细胞 显示出显著的mTOR信号传导和mTORC 1组分的破坏，Raptor被严重破坏， 由于祖细胞中c-Myc的不受限制的激活，小鼠中的骨髓生成。然而，mTORC 1整合了 一系列广泛的生物学输入，以及负责骨髓中mTORC 1激活的信号， 发展尚未确定。 PI现在提供了通过RagA（Ras相关GTP结合蛋白）传感氨基酸的初步数据， A）代表mTORC 1激活的关键信号，该信号允许单核细胞发育。RagA缺乏 表现出猛禽缺陷小鼠的特征。这些发现建立了一种未被认识的联系 营养感应和骨髓生成之间的联系 目前的建议将通过三个方面来定义氨基酸传感和骨髓细胞生物学的作用。 互补的具体目标。目的1将表征向RagA-1提供输入的单个氨基酸。 mTORC 1通路在小鼠中信号单核细胞发育，与人单核细胞的平行研究。目的2 将通过整合转录组学阐明氨基酸调节骨髓发育的机制， 和代谢组学分析。目的3将讨论氨基酸传感对单核/巨噬细胞的影响 在体外和在炎性疾病包括关节炎和狼疮的鼠模型上的极化。在一起， 这些研究将为单核细胞的代谢调节提供新的见解，并阐明新的方法 到针对炎症性疾病。 PI是一名MD/PhD儿科风湿病学家，其长期目标是成为一名独立研究者 和终身教职拟议的学习和培训计划将为他提供翻译方面的专业知识， 研究、免疫代谢、代谢组学和生物信息学。这部作品将以精湛的 在骨髓生物学和关节炎专家Peter Nigrovic博士的指导下， 研究和指导从恒星咨询委员会。该奖项将为PI的过渡铺平道路 一位独立的研究者和骨髓生物学的领导者。 !

Abstract Monocytes are essential to innate immunity but also propagate the inflammatory response in autoimmune arthritis and other rheumatologic diseases. Understanding the basic biology of monocyte development is therefore central to unraveling disease pathogenesis and to identifying new therapeutic targets. Previous work by the PI has established an essential role of the central metabolic integrator mTORC1 (mechanistic target of rapamycin complex 1) as a master regulator of myeloid development. Monocytes displayed prominent mTOR signaling and disruption of the mTORC1 component Raptor profoundly disrupted myelopoiesis in mice due to unrestricted activation of c-Myc in progenitor cells. However, mTORC1 integrates a broad array of biological input, and the signal responsible for mTORC1 activation during myeloid development remains undefined. The PI now provides preliminary data that sensing of amino acids via RagA (Ras-related GTP-binding protein A) represents the key signal for mTORC1 activation that licenses monocyte development. Deficiency of RagA phenocopies the features of Raptor-deficient mice. These findings establish an unrecognized connection between nutrient sensing and myelopoiesis. The current proposal will define the role of amino acid sensing and myeloid cell biology through three complementary Specific Aims. Aim 1 will characterize individual amino acids that provide input to the RagA- mTORC1 pathway to signal monocyte development in mice, with parallel studies on human monocytes. Aim 2 will elucidate the mechanism of amino acid-regulated myeloid development through integrated transcriptomic and metabolomics analyses. Aim 3 will address the impact of amino acid sensing on monocyte / macrophage polarization in vitro and on murine models of inflammatory disease including arthritis and lupus. Together, these studies will provide novel insights into metabolic regulation of monocytes and illuminate new approaches to targeting inflammatory diseases. The PI is an MD/PhD pediatric rheumatologist with the long-term goal of becoming an independent investigator and tenured faculty. The proposed studies and training plan will provide him with expertise in translational research, immunometabolism, metabolomics and bioinformatics. The work will be performed in superb institutional environment with the mentorship of Dr. Peter Nigrovic, an expert in myeloid biology and arthritis research, and guidance from a stellar Advisory Committee. This award will pave the way for the PI's transition to an independent investigator and a leader in myeloid biology. !