Metabolic control of monocyte development and function by amino acids

摘要 单核细胞对先天免疫是必不可少的，但也在自身免疫中传播炎症反应。 关节炎和其他风湿病。了解单核细胞发育的基本生物学 因此，对于解开疾病的发病机制和确定新的治疗靶点至关重要。 PI之前的工作已经确立了中央代谢整合子mTORC1的重要作用 (雷帕霉素复合体的机制靶点1)作为髓系发育的主要调节因子。单核细胞 显示了突出的mTOR信号和mTORC1组件猛禽的中断 C-Myc在祖细胞中的不受限制的激活导致小鼠的骨髓生成。然而，mTORC1集成了 一系列广泛的生物输入，以及在髓系中负责mTORC1激活的信号 发展仍未确定。 PI现在提供了通过RAGA(RAS相关GTP结合蛋白)感知氨基酸的初步数据 A)代表mTORC1激活的关键信号，该信号允许单核细胞发育。RAGA缺乏症 表型复制了猛禽缺陷小鼠的特征。这些发现建立了一种未被识别的联系 营养感知和骨髓生成之间的关系。 目前的提案将通过以下三个方面定义氨基酸传感和髓系细胞生物学的作用 互补的具体目标。目标1将描述为RAGA提供输入的单个氨基酸- 小鼠单核细胞发育的信号转导通路，与人类单核细胞的平行研究。目标2 将阐明氨基酸通过整合转录调控髓系发育的机制 和新陈代谢组学分析。目标3将解决氨基酸感应对单核/巨噬细胞的影响 在体外极化和包括关节炎和狼疮在内的炎症性疾病的小鼠模型上。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 针对炎症性疾病。 PI是一名医学博士/博士儿科风湿病专家，长期目标是成为一名独立的研究人员 和终身教职员工。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。这项工作将出色地完成。 在髓系生物学和关节炎专家彼得·尼格罗维奇博士的指导下的机构环境 来自一流咨询委员会的研究和指导。这一奖项将为PI的过渡铺平道路 一位独立的调查者和一位髓系生物学的领先者。 好了！

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. !