# Mechanisms of foamy monocyte formation in atherosclerosis

> **NIH NIH F31** · AUGUSTA UNIVERSITY · 2023 · $47,694

## Abstract

PROJECT SUMMARY
Atherosclerosis, the underlying cause of heart attack, stroke and peripheral arterial disease, is the leading cause
of death in the United States. A better understanding of the pathomechanisms of atherosclerosis is critical to
identify more effective therapeutic strategies to treat atherosclerosis. Recent studies demonstrated that majority
of the circulating monocyte pool in patients with atherosclerosis are lipid-laden foamy monocytes and
pharmacological depletion of foamy monocytes in hypercholesterolemic mice attenuates atherosclerosis
development. Although these studies suggest that monocyte uptake of plasma LDL is a therapeutic target in
atherosclerosis, the mechanism of foamy monocyte formation is currently unknown. Preliminary studies
demonstrate for the first time that chemical stimulation of macropinocytosis promotes native LDL uptake, leading
to foamy monocyte formation in vitro. Moreover, pharmacological inhibition of macropinocytosis and genetic
deletion of the macropinocytosis regulator, NHE1, selectively in myeloid cells attenuates atherosclerosis
development in hypercholesterolemic mice. The central hypothesis of this proposal is that stimulation of
macropinocytosis promotes monocyte lipid uptake and foamy monocyte formation. Aim 1 will test the hypothesis
that physiologically relevant stimulators of macropinocytosis increase foamy monocyte formation in vitro. We will
assess the ability of human primary and THP1 monocytes to uptake lipids in the presence or absence of
physiologically relevant macropinocytosis stimulators and pharmacological inhibitors. The relative contribution
of scavenger receptor-mediated lipid uptake vs. macropinocytosis will be quantified using monocytes from wild
type, CD36-/-, SRA-/- and CD36-/-/SRA-/- mice. Finally, we will assess phenotypic and functional changes in foamy
monocytes relevant to the pathogenesis of atherosclerosis. Aim 2 will test the hypothesis that myeloid cell-
specific deletion of the macropinocytosis regulator, NHE1, inhibits foamy monocyte formation in vivo. Monocytes
from NHE1f/f Lysm Cre+ and littermate Cre- mice injected with AAV8-PCSK9 will be isolated and analyzed for lipid
content, inflammatory cytokine secretion, inflammatory markers, and adhesion ability. Additionally, we will use
wild type and CD36-/-/SRA-/- mice to assess the effect of a repurposed FDA-approved drug that inhibits
macropinocytosis in attenuating circulating foamy monocyte levels. This project will allow me to develop new
technical skills, gain expertise in conducting rigorous, hypothesis-driven research and improve my independent
skills. The project will be conducted under the mentorship of Dr. Gabor Csanyi and Dr. Neal Weintraub in the
Vascular Biology Center at the Medical College of Georgia, Augusta University, which has a rich history of
successful pre- and post-doctoral training. The proposed project is for 3 years of funding with the aims divided
amongst the 3 years of funding, culminatin...

## Key facts

- **NIH application ID:** 10707022
- **Project number:** 5F31HL162498-02
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** WonMo Ahn
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $47,694
- **Award type:** 5
- **Project period:** 2022-08-17 → 2025-08-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10707022

## Citation

> US National Institutes of Health, RePORTER application 10707022, Mechanisms of foamy monocyte formation in atherosclerosis (5F31HL162498-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10707022. Licensed CC0.

---

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