# Metabolic control of monocyte development and function by amino acids

> **NIH NIH K08** · BOSTON CHILDREN'S HOSPITAL · 2022 · $173,587

## Abstract

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.
!

## Key facts

- **NIH application ID:** 10356893
- **Project number:** 5K08AR074562-04
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Pui Yuen Lee
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $173,587
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10356893

## Citation

> US National Institutes of Health, RePORTER application 10356893, Metabolic control of monocyte development and function by amino acids (5K08AR074562-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10356893. Licensed CC0.

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