# CaMK4 as a Critical Mediator of Inflammation Resolution and Trained Immunity

> **NIH NIH F31** · VANDERBILT UNIVERSITY · 2024 · $34,295

## Abstract

PROJECT SUMMARY
Atherosclerotic cardiovascular disease (CVD) is the leading cause of death globally. Despite conventional lipid-
lowering therapies to treat CVD, nearly 50% of patients suffer recurrent cardiac events that is attributed to
excessive inflammation. Recent work from our group and others has demonstrated that failed resolution of a
chronic inflammatory response is an important driver of inflammation seen in atherosclerotic plaques that result
in clinical events. The resolution program is orchestrated by the efficient clearance of apoptotic cells (ACs) and
the production of anti-inflammatory agonists known as specialized pro-resolving lipid mediators (SPMs). Notably,
continual efferocytosis, which entails the successive uptake of ACs by individual macrophages in settings where
cell death is rampant, is necessary to resolve inflammation. Advanced atherosclerotic plaques are characterized
by large necrotic cores, caused by inefficient efferocytosis, and an imbalance of pro-inflammatory to pro-
resolving mediators compared to early lesions, suggestive of failed resolution. Our primary aim for project is to
uncover the endogenous cues that underlie dysregulated inflammation resolution seen in atherosclerosis.
Intriguingly, recent publications suggest macrophages can have a memory-like response called “trained innate
immunity”. In response to an inflammatory stimulus such as oxidized low density lipoproteins (oxLDL), innate
immune cells undergo metabolic and epigenetic reprogramming that primes them to a ‘hyperactive’ state, where
they can more rapidly mount an augmented secondary response. Hyper-responsiveness upon activation by a
second innate stimuli ultimately boosts bacterial and viral immunity but may be detrimental for chronic diseases
like atherosclerosis. Our preliminary data identified Ca2+/Calmodulin-Dependent Protein Kinase IV (CaMK4) as
regulator of both resolution and innate immune memory. Our preliminary data suggests that CaMK4 supports
the proinflammatory phenotypes seen in innate immune memory in part due to its negative regulation on
efferocytosis. Based on these findings, we hypothesize that myeloid CaMK4 is a critical mediator of immune
memory and that immune training impairs resolution through a CaMK4-dependent mechanism. Aim 1 will test
the hypothesis that trained immunity impairs continual efferocytosis in myeloid cells, promoting
atheroprogression. Aim 2 will explore the role of CaMK4 in the development of trained immunity through its
negative regulation of important resolution genes.

## Key facts

- **NIH application ID:** 10826961
- **Project number:** 1F31HL172670-01
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Azuah Lucrecia Gonzalez
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $34,295
- **Award type:** 1
- **Project period:** 2024-06-29 → 2027-06-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10826961

## Citation

> US National Institutes of Health, RePORTER application 10826961, CaMK4 as a Critical Mediator of Inflammation Resolution and Trained Immunity (1F31HL172670-01). Retrieved via AI Analytics 2026-06-24 from https://api.ai-analytics.org/grant/nih/10826961. Licensed CC0.

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