SUMMARY Despite therapeutic advances, cardiovascular disease (CVD) remains the leading cause of death worldwide. There is thus an urgent need for innovation in CVD research and drug development. One class of molecules thought to hold particular promise is noncoding RNA, the importance of which was largely unrecognized until the last decade. The human genome is estimated to encode between 30,000 and 60,000 long noncoding RNAs (lncRNA), far more than the number of protein coding transcripts, and yet the vast majority remain unstudied. LncRNAs have been shown to play critical roles in genome organization and orchestration of gene expression in normal cellular function and disease. Discerning lncRNAs with regulatory functions in cardiovascular health and disease, and dissecting their molecular mechanisms is a paramount priority, and challenge, for the field. Using a systems biology approach that relies on human tissues and animal models, clinical data, predictive bioinformatics and deep molecular phenotyping, we have identified a conserved cis-acting lncRNA, which we have named CASLR, that is highly expressed in human and mouse atherosclerotic plaques. In this proposal, we aim to decipher the molecular mechanisms by which this novel lncRNA regulates inflammatory gene expression, and innate immune responses that drive atherosclerosis progression and ultimately plaque rupture, which can lead to myocardial infarction or stroke. Our studies will use novel mouse models and innovative 3-dimensional human vascular explants to test the impact of CASLR inhibition on atherosclerotic inflammation and plaque burden. Collectively, the proposed investigation into lncRNA CASLR will advance our knowledge of inflammatory mechanisms of atherosclerotic cardiovascular disease and its complications, and provide foundational studies for the design of new therapeutic strategies.