ABSTRACTCardiovascular diseases are the most frequent cause of death worldwide and given the central role ofprolonged endothelial activation in vascular disease interventions that dampen the molecular drivers of thisprocess would have far-reaching consequences to improve human health. Still the development of therapiesto specifically target vascular inflammation requires that the mechanisms driving this process be understood atthe molecular level in cells exposed to disease-relevant conditions. The long-term goal of this application is todeconstruct the molecular mechanisms that govern healthy and pathogenic endothelial cell traits in humancells so that these processes may be exploited for human health. The overall objective of this application is toinvestigate the molecular attributes that fine-tune how the endothelial-specific transcription factor ERG steersendothelial cell gene expression towards healthy or diseased states. Importantly this application combinestraditional molecular approaches with the power of genomics so that targeted hypotheses may be tested on thegenome-wide scale. The central hypothesis is that ERG's transcriptional activity is essential for healthyendothelial cell function and molecular interactions altering its function are direct links to vascular disease. Thecentral hypothesis will be tested through investigation of three specific aims. The first will identify specificpartners of ERG activity that depend on upstream signaling cascades present in inflammation. The second willidentify direct transcription targets of ERG that perpetuate its pro- and anti-inflammatory functions. Finally thethird will identify the extent to which ERG directs endothelial cell traits downstream of two differenthemodynamic waveforms that distinguish inactive from activated vascular locales in vivo. Experiments to testthese hypotheses will utilize human aortic endothelial cells to maximize the translatability of the findings tohuman genetics research and drug development pipelines. The approach is innovative because it usesgenomics to test targeted molecular hypotheses and because it will test novel relationships among proteinsthat have not been considered in vascular health and disease. The proposed work will provide molecularinsights to inform the development of novel intervention strategies to improve vascular health andcardiovascular disease.