# Genetic and metabolic regulation of macrophage activation at steady state

> **NIH NIH R35** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $382,902

## Abstract

Project Summary
Understanding how a cell is switched off and maintains its quiescence is fundamentally as important as how it
is activated. The long-term goal of the proposed research is to determine how cell-intrinsic processes control
and modulate activation states of macrophages in vivo. Because dysregulation and unprovoked activation of
the immune system cause a host of human diseases associated with inappropriate inflammation, deciphering
the molecular networks regulating immune activation normally is critical for addressing these health
challenges. This will lead to new knowledge and technologies needed to harness the properties of
macrophages for disease prevention and treatment. We are leveraging the unique advantages of the highly
tractable vertebrate model system, Danio rerio, for exquisite genetic manipulations, high throughput screening,
and in vivo imaging to dissect the complex relationship between intrinsic metabolic signaling and macrophage
activation.
The proposal encompasses a series of projects that collectively define essential negative regulators and their
functions for keeping the innate immune system in check to maintain a normal equilibrium in macrophages.
The starting basis of our projects stems from emerging evidence that metabolic and immune signaling
pathways intersect to shape immune activation in macrophages, and a discovery of a null mutation in an
intracellular NOD-like receptor (NLR) in zebrafish. A gene inactivation in this novel NLR, nlrc3l, causes
unprovoked macrophage activation possibly due to metabolic dysregulation. The proposal seeks to define the
network of molecular interactions of nlrc3l to understand this very important mechanism that keeps
macrophages in check under normal biological conditions. We are taking a highly integrated approach at
multiple levels-- using differential transcriptomics, proteomics, and metabolomics to inform candidate genes
and pathways that constitute possible interactors and effectors of nlrc3l, and validating interactions using
genetic mutants and biochemical studies. The proposal will also use the power of a forward genetic screen to
discover additional genes akin to nlrc3l that prevent macrophage activation at steady state that act in the same
or completely new pathways. We designed an innovative assay for the screen to assess macrophage
activation using a live-cell reporter for an activation marker irg1. Finally, the proposal will examine the influence
of lipid and glucose metabolic pathways on macrophage activation in zebrafish using genetic analyses and
chemical screening. This work will benefit from collaboration with an expert group in extending our findings to
mouse and human models. Taken together, these projects provide the important foundation for understanding
the genetic and metabolic basis of how the innate immune system is kept in check, and will impact the
direction of my lab far beyond the 5 years of MIRA funding.

## Key facts

- **NIH application ID:** 9978893
- **Project number:** 5R35GM124719-04
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Celia E Shiau
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $382,902
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978893

## Citation

> US National Institutes of Health, RePORTER application 9978893, Genetic and metabolic regulation of macrophage activation at steady state (5R35GM124719-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9978893. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*