# Harnessing molecular breaks on macrophage efferocytosis in atherosclerosis

> **NIH NIH P01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $632,206

## Abstract

Lipid-lowering approaches reduce atherosclerotic cardiovascular disease (ACVD), but significant residual risk
remains. Macrophage (Mφ) accumulation and defective phagocytic clearance of apoptotic cells (ACs) by Mφs,
i.e., defective efferocytosis, promote atherosclerotic plaque vulnerability and subsequent acute cardiovascular
events. Enhancing efferocytosis represents a potential therapeutic strategy for residual risk reduction in ACVD.
Discovering novel genes that can be harnessed to enhance efferocytosis addresses a major knowledge gap and
provides opportunities for new ACVD therapeutics. As discovered in our genome-wide CRISPR screen of
efferocytosis regulators, Pdcd6ip deficiency enhances Mφ efferocytosis, representing a novel therapeutic
opportunity in atherosclerosis and management of CVD residual risk. Preliminary data show that transplantation
of Pdcd6ip-/- mice bone marrow into atherosclerosis-prone Ldlr-/- mice increases features of plaque stability. This
PPG project will test the central hypothesis that Pdcd6ip acts as a molecular break on Mφ efferocytosis and
can be harnessed to ameliorate athero-progression or to promote athero-regression through effects on plaque
stabilization, the central theme. Integrating with Drs. Tall and Tabas, the project will assess the therapeutic
impact of Pdcd6ip inhibition on atherosclerosis with clonal hematopoiesis (CH) mutations, with implications for
inflammation-related residual risk in CH patients. Aim 1 will determine how Pdcd6ip deficiency enhances
efferocytosis in vitro in murine and human Mφs. Our data show that Pdcd6ip-/- induces cytokinesis arrest and
increased formation of polyploid Mφ that demonstrate superior capability of continuing efferocytosis, suggesting
a “super-eater” phenotype. Mononuclear Mφs with Pdcd6ip-/- also show enhanced primary efferocytosis, though
not continuing efferocytosis. We will test the hypothesis that Pdcd6ip deficiency enhances efferocytosis via both
polyploidy-dependent and -independent mechanisms. Aim 2 will determine if harnessing Pdcd6ip inhibition
enhances efferocytosis to ameliorate athero-progression or to promote athero-regression in mice. We will
determine: (A) whether Pdcd6ip deficiency ameliorates progression via converting proliferating Mφs to “super-
eater” polyploid Mφs, including in JAK2-CH mice; and (B) whether Pdcd6ip deficiency promotes regression via
enhancing efferocytosis-resolution cycle, including in DNMT3A-CH mice. Using fate-mapping and scRNA-seq,
we will also address how Pdcd6ip deficiency promotes plaque stability via Mφ and stromal cell crosstalk (with
Drs. Tall, Tabas, Reilly, Cores B&C). Aim 3 integrates the histological, clinical, transcriptomic, and spatial
transcriptomics data of biobanked human plaques in the Munich Vascular Biobank (Dr. Maegdefessel, Core C)
to prioritize potential efferocytosis regulators identified in our genome-wide CRISPR screen that are associated
with human atheroma. The prioritized genes will accelerate m...

## Key facts

- **NIH application ID:** 10849324
- **Project number:** 1P01HL172741-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Hanrui Zhang
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $632,206
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10849324

## Citation

> US National Institutes of Health, RePORTER application 10849324, Harnessing molecular breaks on macrophage efferocytosis in atherosclerosis (1P01HL172741-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10849324. Licensed CC0.

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