# SETDB2 regulates Abdominal Aortic Aneurysms

> **NIH NIH F32** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $83,392

## Abstract

PROJECT SUMMARY/ABSTRACT
During abdominal aortic aneurysm (AAA) formation, pathological vascular remodeling is driven by macrophage
(Mφs) infiltration, and the mechanisms regulating macrophage-mediated AAA development remain undefined. In
the normal aortic wall, a balance exists between matrix metalloproteinases (MMPs), which function to break
down the aortic wall, and tissue inhibitors of matrix metalloproteinases (TIMPs), which prevent the actions of
MMPs on the aortic wall. However, in a pathologic setting, an imbalance occurs between the MMPs and TIMPs
in favor of MMP activity, resulting in AAA development. Although epigenetic mechanisms have been shown to
regulate Mφ phenotype in tissues, the regulation of these epigenetic pathways in aortic tissue remains unknown.
Our preliminary data identifies that SETDB2, a histone methyltransferase that selectively methylates histone 3
at lysine 9, decreases gene transcription and is increased in murine and human AAA Mφs. Further, we found
that JAK1/STAT3 signaling may regulate Setdb2 in aortic Mφs. Considering these findings, we hypothesize
that SETDB2 drives AAA formation through a JAK/STAT signaling pathway which shifts Mφs towards a
decreased TIMP production, favoring unregulated MMPs and AAA development. This hypothesis will be
investigated through the following specific aims: 1) Determine the JAK/STAT/SETDB2-mediated mechanism(s)
that regulate Mφ-specific Timp1-3 expression in human and murine AAAs 2) Examine the therapeutic efficacy
of Mφ-specific JAK/STAT/SETDB2 inhibition on AAA expansion. In this translational approach, our data will pave
the way for the development of promising preventative 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:** 10873676
- **Project number:** 5F32HL167534-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Tyler Michael Bauer
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $83,392
- **Award type:** 5
- **Project period:** 2023-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873676

## Citation

> US National Institutes of Health, RePORTER application 10873676, SETDB2 regulates Abdominal Aortic Aneurysms (5F32HL167534-02). Retrieved via AI Analytics 2026-05-30 from https://api.ai-analytics.org/grant/nih/10873676. Licensed CC0.

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