Metabolic control of monocyte development and function by amino acids

氨基酸对单核细胞发育和功能的代谢控制

• 批准号: 10356893
• 负责人: Pui Yuen Lee
• 金额: $ 17.36万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356893
• 关键词: Address; Adult; Advisory Committees; Amino Acids; Arthritis; Award; Bioinformatics; Biological; Biology; Boston; Cells; Cellular biology; Child; Childhood; Complex; Data; Development; Disease; Doctor of Philosophy; Environment; Experimental Arthritis; FRAP1 gene; Faculty; Funding; Generations; Goals; Growth; Hospitals; Host Defense; Human; Immune; Immunity; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Institutes; Joints; Licensing; Lupus; Lupus Nephritis; Mediating; Mentors; Mentorship; Metabolic; Metabolic Control; Metabolic Pathway; Metabolism; Mus; Myelogenous; Myeloid Cells; Myelopoiesis; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Natural Immunity; Participant; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Pediatric Hospitals; Phagocytosis; Phenocopy; Phenotype; Positioning Attribute; Productivity; Raptors; Regulation; Research; Research Personnel; Rheumatism; Rheumatoid Arthritis; Rheumatology; Role; Signal Transduction; Solid; Systems Biology; Technology; Testing; Therapeutic; Training; Translational Research; Woman; Work; autoimmune arthritis; c-myc Genes; chronic inflammatory disease; collaborative environment; detection of nutrient; experience; immune function; immunoregulation; in vitro Model; in vivo; insight; mTOR Inhibitor; macrophage; member; metabolome; metabolomics; monocyte; mouse model; new therapeutic target; novel; novel strategies; progenitor; ranpirnase; ras-Related G-Proteins; rheumatologist; stem cells; targeted treatment; transcriptomics; translational study

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. !

抽象的 单核细胞对于先天免疫力至关重要，但也会传播自身免疫性的炎症反应 关节炎和其他风湿病。了解单核细胞开发的基本生物学是 因此，揭示疾病发病机理并确定新的治疗靶标的中心。 PI的先前工作已经确立了中央代谢积分器MTORC1的重要作用 （雷帕霉素复合物的机械目标1）作为髓样发育的主要调节剂。单核细胞 显示了MTORC1组件猛禽的突出MTOR信号传导和破坏。 祖细胞中C-Myc的无限制激活导致小鼠的骨髓卵巢菌。但是，MTORC1集成 一系列广泛的生物输入，以及在髓样过程中导致MTORC1激活的信号 开发仍然不确定。 PI现在提供了初步数据，即通过RAGA（与RAS相关的GTP结合蛋白）传感氨基酸 a）表示获得单核细胞开发许可的MTORC1激活的关键信号。 Raga的不足 表托管猛禽缺陷小鼠的特征。这些发现建立了无法识别的联系 在营养感应和脊髓卵之间。 当前的建议将通过三个来定义氨基酸传感和髓样细胞生物学的作用 互补的特定目的。 AIM 1将表征单个氨基酸，这些氨基酸为Raga-提供输入 MTORC1在小鼠中信号单核细胞发育的途径，并对人类单核细胞进行平行研究。目标2 将通过整合转录组阐明氨基酸调节的髓样发育的机制 和代谢组学分析。 AIM 3将解决氨基酸传感对单核细胞 /巨噬细胞的影响 体外极化以及包括关节炎和狼疮在内的炎症性疾病的鼠模型。一起， 这些研究将为单核细胞的代谢调节提供新的见解，并阐明新方法 靶向炎症性疾病。 PI是MD/PHD小儿风湿病学家，其长期目标是成为独立研究者 和终身教师。拟议的研究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。这项工作将以出色的方式进行 在骨髓生物学和关节炎专家彼得·尼格罗维奇（Peter Nigrovic）的指导下，机构环境 研究和恒星咨询委员会的指导。该奖项将为PI的过渡铺平道路 给独立的研究者和髓样生物学领导者。 呢