ABSTRACT Cardiovascular diseases are the most frequent cause of death worldwide and, given the central role of prolonged endothelial activation in vascular disease, interventions that dampen the molecular drivers of this process would have far-reaching consequences to improve human health. Still, the development of therapies to specifically target vascular inflammation requires that the mechanisms driving this process be understood at the molecular level in cells exposed to disease-relevant conditions. The long-term goal of this application is to deconstruct the molecular mechanisms that govern healthy and pathogenic endothelial cell traits in human cells so that these processes may be exploited for human health. The overall objective of this application is to investigate the molecular attributes that fine-tune how the endothelial-specific transcription factor ERG steers endothelial cell gene expression towards healthy or diseased states. Importantly, this application combines traditional molecular approaches with the power of genomics so that targeted hypotheses may be tested on the genome-wide scale. The central hypothesis is that ERG's transcriptional activity is essential for healthy endothelial cell function, and molecular interactions altering its function are direct links to vascular disease. The central hypothesis will be tested through investigation of three specific aims. The first will identify specific partners of ERG activity that depend on upstream signaling cascades present in inflammation. The second will identify direct transcription targets of ERG that perpetuate its pro- and anti-inflammatory functions. Finally, the third will identify the extent to which ERG directs endothelial cell traits downstream of two different hemodynamic waveforms that distinguish inactive from activated vascular locales in vivo. Experiments to test these hypotheses will utilize human aortic endothelial cells to maximize the translatability of the findings to human genetics research and drug development pipelines. The approach is innovative because it uses genomics to test targeted, molecular hypotheses, and because it will test novel relationships among proteins that have not been considered in vascular health and disease. The proposed work will provide molecular insights to inform the development of novel intervention strategies to improve vascular health and cardiovascular disease.