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. !
Monocytes are innate immune cells with pathogenic roles in inflammatory diseases including rheumatoid arthritis and lupus nephritis. We identified the amino acid sensing pathway as a novel regulator of monocyte development and function. Understanding this mechanism will allow targeting of monocyte-mediated inflammation through therapeutic manipulation of metabolic pathways.