SUMMARY In humans, the number of annotated long noncoding RNAs (lncRNA) is almost three times that of protein coding transcripts, yet fewer than 50 of these have been functionally characterized. A major challenge in all fields of biology is to investigate how these mysterious RNAs regulate gene expression and biological pathways, and to integrate the results of these findings into current paradigms. The field of lipoprotein metabolism and atherosclerosis has lagged behind in these efforts. We are attempting to bridge this conceptual gap by investigating the role of lncRNA in regulating cholesterol metabolism and atherogenesis. To date, the functions of lncRNAs have proven difficult to dissect, in part because unlike microRNAs, lncRNAs lack unifying features (other than length), and they can form numerous types of interactions, including RNA- RNA, RNA-DNA or RNA-protein. As such, each lncRNA studied presents new and unique challenges that require the flexibility to change course or pursue new directions as they arise. This project is thus ideal for support by the NHLBI's Outstanding Investigator Award Program. As described in this application, we have recently discovered primate-specific lncRNAs that regulate cholesterol efflux, HDL biogenesis and inflammatory signaling, and we are further characterizing their function. Our exciting findings illustrate the tremendous potential for discovery in this area. Notably, these primate-specific lncRNAs are not conserved in other mammals, highlighting the importance of further studies of human lncRNAs and their functions. We are now pursuing other novel lncRNAs and micropeptides that function in human cardiovascular health and disease, studies that will lead to better understanding of the molecular regulation of cholesterol homeostasis and atherosclerosis, as well as the identification of novel prognostic/diagnostic approaches and therapeutic targets.