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NIH grant 1R01HL187297-01: MOF Regulates Abdominal Aortic Aneurysm Expansion
Institute: {'code': 'HL', 'abbreviation': 'NHLBI', 'name': 'National Heart Lung and Blood Institute', 'admin_org_id': '12500068', 'admin_funding_url': ''}. PI: Frank Michael Davis. Award: $785185.
Start: 2026-09-05T00:00:00.
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 acetyltransferase, MOF, is increased in aortic aneurysm tissue MΦs resulting in a persistent
inflammatory MΦ phenotype with increased production of inflammatory mediators. Further, using human cells
and our experimental murine model of AAAs, we have identified that tumor necrosis factor α (TNFα), via TNF
receptor 1 (TNFR1) and NFκB-mediated mechanism induces MOF in MΦs. These results have led to our
hypothesis that TNFα/TNFR1/NFκB signaling directly increases Mof expression in aortic tissue MΦs and MOF
increases expression of inflammatory genes that maintain an aortic pro-inflammatory MΦ phenotype,
promoting AAA expansion. We further postulate that MΦ function may be restored via monocyte-MΦ-targeted
inhibition of the MOF-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 MOF-
mediated regulation of gene expression in human and murine AAA monocyte/MΦs. Aim 2: Determine the role
of TNFα-receptor 1-mediated signaling via NFκB to drive MOF expression in MΦs in human and murine AAAs.
Aim 3: Examine the therapeutic efficacy of MΦ-targeted MOF and TNFR1 inhibition on inflammation and 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.document fetched 2026-09-13 02:46