PROJECT SUMMARY The majority of the 18 million worldwide cardiovascular deaths are thought to be due to atherosclerosis, perhaps the single most devastating pathologic process affecting mankind. The recent surge in metabolic disturbances will ensure that atherosclerosis will not just fade away. This application addresses substantial knowledge gaps and capitalizes on recent discoveries from our group and new preliminary evidence suggesting that long noncoding RNAs (lncRNAs) influence the development of atherosclerosis and cardiometabolic abnormalities. The objective of this proposal is to 1) define the contributions of lncRNAs in cardiometabolic diseases, 2) improve our understanding of recurrent relationships between lncRNA conservation and function and 3) test the efficacy of lncRNA-based therapeutic strategies in cardiovascular disease. Aligned with goals of this application our multicenter collaborative group has collective expertise in lncRNA biology, atherosclerosis and metabolic disease, epigenomic profiling methodologies, and dissecting gene-phenotype relationships in human disease. The overarching hypothesis of this proposal is that there may be lncRNAs with roles in lipid metabolism that are yet to be characterized and when targeted with context specificity they can mitigate disease phenotypes in relevant models. Using an integrative screening platform combing mouse and human studies, we identify novel lncRNA involved in hepatic lipid metabolism, develop a robust pipeline that prioritizes lncRNA functional discovery, and introduce new tools for lncRNA in vivo perturbations. Aim 1, will determine role of macrophage lncRNAs in atherosclerosis and explore opportunities for lncRNA-based therapeutics targeting lesions. In Aim 2, we investigate the function of lncRNAs in hepatic lipid metabolism and test for evidence of cross-species functional conservation despite sequence evolution. These studies are expected to shed fundamental insight into the significance of noncoding gene regulation in cardiometabolic control and provide a framework for lncRNA-based therapeutics in cardiovascular disease. In summary, this discovery-oriented proposal will fill substantial knowledge gaps in the fields of atherosclerosis and lncRNA biology.