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.