# Processing of Apoptotic Cell-Derived Cargo by Macrophages Continues Efferocytosis and Drives Atherosclerosis Regression

> **NIH NIH K99** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $167,724

## Abstract

PROJECT SUMMARY/ABSTRACT
Atherosclerotic cardiovascular disease (CVD) is the leading cause of death in the industrialized world. Most
atherosclerotic plaques are clinically silent; however, a subset can lead to myocardial infarction, stroke, or
sudden death. Atheromas that are linked to clinical events are characterized by large necrotic cores, which result
from the defective clearance of apoptotic cells (ACs). When functioning normally, clearance of ACs, termed
“efferocytosis”, resolves inflammation. Therefore, enhancing efferocytosis in advanced lesions may stabilize
rupture-prone plaques and reduce clinical events. While the mechanisms that lead to phagocytosis of one AC
have been well-defined, individual macrophages (MΦs) must engulf many ACs, termed “continued efferocytosis”,
in vivo. Accordingly, two critical, unanswered questions are (a) how do MΦs process the cargo derived from
degrading an AC, and (b) what mechanisms are in place that cue MΦs that have previously ingested an AC to
internalize a subsequent AC. Therefore, the overall objective of this proposal is to understand the signaling and
metabolic pathways that enable the continued clearance of ACs and to harness these pathways towards a novel
treatment strategy. This proposal tests two new pathways critical for continued efferocytosis. In the first pathway,
MΦs metabolize AC-derived arginine into putrescine, through the sequential action of arginase 1 (Arg1) and
ornithine decarboxylase (ODC), to remodel the actin cytoskeleton. In the second pathway, MΦs respond to the
overabundance of AC-derived nutrients by stimulating the nutrient sensor mTORC1 to recycle vesicles to the
cell surface and supply the developing phagosome with plasma membrane. Aim 1 will explore the hypothesis
that AC-derived arginine is metabolized into putrescine and examine the mechanisms by which putrescine
regulates cytoskeletal remodeling. Aim 2 will test the hypothesis and investigate the mechanisms therein, that
the putrescine-synthesizing enzymes Arg1 and ODC drive atherosclerosis regression and inflammation
resolution. Aim 3 will explore the hypothesis that SLC38A9 senses AC-derived arginine and cholesterol to
activate mTORC1 and identify the mechanisms that drive the internalization of a second AC. This research will
be accomplished in the setting of a comprehensive career development program designed to provide the
candidate with the skills needed to become an independent scientist in cardiovascular research. During the
K99/Mentored phase of the award, the applicant will continue to gain expertise in molecular, cellular, and
biochemical approaches to study atherosclerosis regression from a mechanistic standpoint. An advisory
committee of established scientists/mentors in the fields of atherosclerosis, macrophage function, inflammation
resolution, and translational science will guide the candidate in his transition to scientific independence over the
course of the award period.

## Key facts

- **NIH application ID:** 9844497
- **Project number:** 5K99HL145131-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Arif Yurdagul
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $167,724
- **Award type:** 5
- **Project period:** 2019-01-15 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9844497

## Citation

> US National Institutes of Health, RePORTER application 9844497, Processing of Apoptotic Cell-Derived Cargo by Macrophages Continues Efferocytosis and Drives Atherosclerosis Regression (5K99HL145131-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9844497. Licensed CC0.

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