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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

基本信息

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
项目类别：
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

项目摘要

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. !

摘要