PROJECT SUMMARY/ABSTRACT Abdominal Aortic Aneurysm (AAA) is a life-threatening vascular condition associated with high mortality rates upwards of 80% upon rupture. Vascular inflammation plays a primary role in AAA, with chronic inflammation and degradation of the extracellular matrix leading to segmental dilation of the aortic wall. However, clinical trials involving anti-inflammatory therapeutics have failed to yield meaningful results. Currently, there are no FDA- approved therapeutics to treat AAA. Our lab has demonstrated that treatment with synthetic high-density lipoprotein (sHDL) nanoparticles has a protective effect in AAA, leading to a nearly two-fold reduction in AAA incident and aortic diameter, highlighting the potential of sHDL for AAA treatment. Thus, the objective of this proposal is to determine the mechanism by which sHDL attenuates AAA pathogenesis and optimize formulation for effective treatment and delivery. We will accomplish this by 1) developing sHDL particles and determine underlying protective mechanisms against AAA in vitro. Specifically, the effects of sHDL will be assessed in vascular smooth muscle cells (VSMC), macrophages, endothelial cells. We will also 2) evaluate and optimize sHDL treatment in AAA mouse models. The successful completion of this present study will provide robust mechanistic insight into how sHDL attenuates AAA pathogenesis through its actions at VSMCs, endothelial cells and macrophages.