PROJECT SUMMARY/ABSTRACT Abdominal Aortic Aneurysm (AAA) is a primary medical concern due to the increasing prevalence and high mortality rate upon rupture. Although vascular inflammation, extracellular matrix (ECM) degradation, and subsequent vascular smooth muscle cells (VSMCs) apoptosis are pathologic features and drivers of AAA, efforts to manipulate these processes did not yet result in any effective drug therapies beyond primary prevention, creating an urgent need for new drug-based therapeutic strategies. This will be facilitated by a deeper and comprehensive understanding of the molecular and cellular mechanisms driving onset, progression, and outcomes of AAA. Chromatin remodeling altering gene expression has been linked to most pathophysiologic conditions, including atherosclerosis and diabetes, but its role in AAA remains largely unknown. The BAF60 family comprises three mutually exclusive subunits of the SWItch/Sucrose Non- Fermentable (SWI/SNF) chromatin remodeling complex. Of relevance to the cardiovascular field, they play essential roles in controlling lipid homeostasis, energy metabolism (BAF60a), granulocyte (BAF60b) and heart (BAF60c) development. We found that BAF60a, b and c are differentially expressed in human and mouse AAA tissues, suggesting a potential role of the BAF60 subunits in VSMC biology and the development of AAA. We recently reported that loss of BAF60a in VSMCs prevents experimental AAA by reducing vascular inflammation and ECM degradation in mice. Remarkably, BAF60c is the most abundant BAF60 subunit expressed in VSMC. Our preliminary data show that BAF60c is downregulated in the abdominal aortic aneurysmal tissue in both humans and mice. VSMC BAF60c knockout significantly aggravates elastase-induced AAA, and knockdown of BAF60c in human aortic smooth muscle cells reduced the SMC contractile protein expression and increased inflammatory genes and MMP9 expression. We hypothesize that VSMC-specific BAF60c attenuates AAA development by maintaining the VSMC contractile phenotype, and inhibiting vascular inflammation and ECM degradation. Using gain- and loss-of-function in HASMCs in vitro, AAA-relevant stimuli, our unique VSMC- specific BAF60c knockout and transgenic mice, two established murine AAA models in vivo, and an integrated workflow, we will (Aim 1) Demonstrate that VSMC-specific BAF60c attenuates AAA formation with attention to altered cellular profiles and intercellular cross-talk by scRNAseq and provide proof-of-concept for therapeutic targeting and (Aim 2) Determine the protective mechanisms of BAF60c in VSMC homeostasis in vitro using relevant stimuli and RNAseq, ChIP-seq and co-immunoprecipitation. This work will provide unique mechanistic insights on how various and varying risk factors translate into VSMC dysfunction leading to AAA and provide the basis for developing novel therapies for AAA.