ABSTRACTAtherosclerosis is the primary pathobiology underlying ischemic heart disease (IHD) which is the leading causeof morbidity and mortality worldwide. Atherosclerosis occurs in-part through inflammation-induced abnormalitiesof endothelial cells (EC) including decreased barrier function endothelial-to-mesenchymal transition andaberrant angiogenesis. EC state transitions in atherosclerosis are thus novel therapeutic targets however thecell state transitions remain largely uncharacterized. Existing single cell (sc) RNA datasets of humanatherosclerosis provide unprecedented opportunity to identify novel EC activation states that populate humanplaques. However the value of such annotations in vivo will only be as powerful as our ability to interpret theircorresponding functional states and underlying mechanisms. Therefore the proposed research will complementin vivo analysis of human plaques by testing the ability of putative pro-atherogenic in vitro EC models torecapitulate in vivo EC molecular signatures. Moreover a role for the endothelial-restricted transcription factorERG has recently been clarified in the regulation of endothelial homeostasis cell activation angiogenesis andinflammation. ERG phosphorylation is required for quiescent (non-activated) physiologic angiogenesis. Yet ERGis diminished in the most vulnerable regions of human advanced atherosclerotic lesions where angiogenesis stilloccurs. This indicates that inflammation-induced angiogenesis occurs independent of ERG phosphorylationthough a separate mechanism downstream of IL-1b. The overarching hypothesis is that IL-1b-inducedangiogenesis is a hallmark of EC pathophysiology in human atherosclerotic lesions and that this angiogenesisis mediated by NF-kb rather than physiological ERG phosphorylation. The goal of this proposal is to movetoward development of diagnostic strategies identifying vulnerable atherosclerotic lesions and therapies thatmay act in synergy with existing lipid approaches to promote vascular health. The integrated research and clinicaltraining plan will enhance the applicants knowledge and technical clinical and professional skills and facilitateher transition to the next career stage as a productive physician-scientist dedicated to academic medicine. Theinterdisciplinary focus and collaborative nature of the University of Arizona provides a rich training environmentto complete the proposed aims and nurture the applicants scientific career.