Human endothelial cell heterogeneity and activation in atherosclerosis - ABSTRACT
Atherosclerosis is the primary pathobiology underlying ischemic heart disease (IHD) which is the leading cause
of morbidity and mortality worldwide. Atherosclerosis occurs in-part through inflammation-induced abnormalities
of endothelial cells (EC), including decreased barrier function, endothelial-to-mesenchymal transition, and
aberrant angiogenesis. EC state transitions in atherosclerosis are thus novel therapeutic targets, however the
cell state transitions remain largely uncharacterized. Existing single cell (sc) RNA datasets of human
atherosclerosis provide unprecedented opportunity to identify novel EC activation states that populate human
plaques. However, the value of such annotations in vivo will only be as powerful as our ability to interpret their
corresponding functional states and underlying mechanisms. Therefore, the proposed research will complement
in vivo analysis of human plaques by testing the ability of putative pro-atherogenic in vitro EC models to
recapitulate in vivo EC molecular signatures. Moreover, a role for the endothelial-restricted transcription factor
ERG has recently been clarified in the regulation of endothelial homeostasis, cell activation, angiogenesis, and
inflammation. ERG phosphorylation is required for quiescent (non-activated) physiologic angiogenesis. Yet, ERG
is diminished in the most vulnerable regions of human advanced atherosclerotic lesions where angiogenesis still
occurs. This indicates that inflammation-induced angiogenesis occurs independent of ERG phosphorylation
though a separate mechanism downstream of IL-1b. The overarching hypothesis is that IL-1b-induced
angiogenesis is a hallmark of EC pathophysiology in human atherosclerotic lesions and that this angiogenesis
is mediated by NF-kb, rather than physiological ERG phosphorylation. The goal of this proposal is to move
toward development of diagnostic strategies identifying vulnerable atherosclerotic lesions, and therapies that
may act in synergy with existing lipid approaches to promote vascular health. The integrated research and clinical
training plan will enhance the applicant’s knowledge and technical, clinical, and professional skills, and facilitate
her transition to the next career stage as a productive physician-scientist dedicated to academic medicine. The
interdisciplinary focus and collaborative nature of the University of Arizona provides a rich training environment
to complete the proposed aims and nurture the applicant’s scientific career.