# Critical Mediators of Inflammation Resolution and Immune Memory in Atherosclerosis

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $581,486

## Abstract

PROJECT SUMMARY
Despite major medical advances, cardiovascular disease remains the major cause of morbidity
and mortality worldwide. Even with aggressive risk factor control, nearly 50% of patients suffer
recurrent cardiac events and this “residual risk” has been attributed to excessive inflammation.
Recent work has demonstrated that atherosclerosis is also characterized by the failure of
inflammation resolution. The resolution program is regulated by the production of specialized
pro-resolving lipid mediators (SPMs) and the efficient clearance of apoptotic cells (efferocytosis)
from tissue. Advanced atherosclerotic plaques have higher numbers of apoptotic cells, larger
necrotic cores, and an imbalance of pro-inflammatory:pro-resolving mediators compared with
early lesions, all of which are suggestive of failed resolution. Strategies that boost resolution and
break the cycle of chronic inflammation promote plaque stability. Therefore, the identification of
novel targets that mediate this process is of critical importance. Our preliminary data have
identified Ca2+/Calmodulin-Dependent Protein Kinase IV (CaMK4) as a central regulator of both
inflammation and resolution. Uniquely, CaMK4 appears to play an important role in the
development of innate immune memory in macrophages, which enhances their pro-
inflammatory responses to atherogenic stimuli. Therefore, we hypothesize that CaMK4 is a
critical mediator of immune memory and that immune training impairs resolution through a
CaMK4-dependent mechanism. We will test our hypothesis through the following aims:
Specific Aim 1 will test the hypothesis that myeloid-CaMK4 impairs resolution as a mechanism
by which it promotes atheroprogression.
Specific Aim 2 will explore the mechanism by which CaMK4 promotes oxLDL training of
myeloid progenitors and macrophages in order to augment their inflammatory cytokine
production.
Specific Aim 3 will test the hypothesis that targeting CaMK4 in advanced atherosclerosis can
promote regression of plaque.

## Key facts

- **NIH application ID:** 10280701
- **Project number:** 1R01HL159487-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** AMANDA C DORAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $581,486
- **Award type:** 1
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10280701

## Citation

> US National Institutes of Health, RePORTER application 10280701, Critical Mediators of Inflammation Resolution and Immune Memory in Atherosclerosis (1R01HL159487-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10280701. Licensed CC0.

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