# JMJD3 Regulates Abdominal Aortic Aneurysm Expansion

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $585,887

## Abstract

PROJECT SUMMARY/ABSTRACT
Abdominal aortic aneurysms (AAA) are a potentially lethal vascular disease that if left untreated, can progress
to aortic rupture which has a mortality rate over 80%. Equally alarming, there are currently no medical
therapies available to limit AAA growth, due in large part to a lack of understanding of the molecular
mechanisms underlying AAA development. Thus, a critical need exists to understand the mechanisms that
govern AAA expansion. One key hallmark of AAAs is inflammatory macrophage (Mφ) infiltration into the
vascular wall. We present data using human single cell RNA sequencing and murine AAA models, that the
histone demethylase, JMJD3, is increased in aortic aneurysm tissue Mφs resulting in a persistent inflammatory
Mφ phenotype with increased production of NFκB inflammatory mediators. Further, using human cells and our
experimental murine model of AAAs, we have identified that interferon-beta (IFNβ), via a janus kinase (JAK) /
signal transducer and activator of transcription (STAT) mechanism induces JMJD3 in Mφs. These results have
led to our hypothesis that IFN?/JAK/STAT signaling directly increases Jmjd3 expression in aortic tissue Mφs
and JMDJ3-mediated epigenetic modifications drive NFkB-mediated inflammatory genes that maintain an
aortic Mφ inflammatory phenotype, thereby promoting AAA development. We further postulate that Mφ
function may be restored via monocyte-Mφ-targeted inhibition of the JMJD3-mediated epigenetic modifications
resulting in the resolution of inflammation and AAA stabilization. This hypothesis will be investigated via the
following specific aims: Aim 1: Elucidate the regulation of NFκB-mediated inflammatory gene expression by
JMJD3 in human and murine AAA monocyte/Mφs. Aim 2: Determine the IFN?/JAK/STAT-mediated
mechanism(s) that regulate Mφ-specific Jmjd3 expression in human and murine AAAs. Aim 3: Examine the
therapeutic efficacy of Mφ-targeted JMJD3 inhibition on AAA expansion. In this translational approach, our
data will pave the way for the development of promising preventive therapeutic agents aimed at cell-specific
targeting of epigenetic enzymes that mediate Mφ inflammation and thereby prevent AAA expansion and
rupture.

## Key facts

- **NIH application ID:** 10231799
- **Project number:** 1R01HL156274-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Katherine Ann Gallagher
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $585,887
- **Award type:** 1
- **Project period:** 2021-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10231799

## Citation

> US National Institutes of Health, RePORTER application 10231799, JMJD3 Regulates Abdominal Aortic Aneurysm Expansion (1R01HL156274-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10231799. Licensed CC0.

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