PROJECT SUMARY/ABSTRACT
This proposal presents a five-year research and training program to establish Laurel Y. Lee, M.D., D.Phil. as an
independent, R01-funded physician-scientist in academic cardiology with expertise in immune modulation of
endothelial metabolism in atherosclerosis. This unique scientific focus combines Dr. Lee’s doctoral training in T-
cell immunology with her subsequent clinical and research fellowships in cardiovascular medicine at the Brigham
and Women’s Hospital (BWH) and Harvard Medical School (HMS). She is currently an Associate Physician in
the Division of Cardiovascular Medicine and an Instructor in Medicine at BWH/HMS.
Coronary artery disease remains a leading cause of mortality and morbidity worldwide. While endothelial
dysfunction is known as a precursor to atherosclerosis, how altered endothelial metabolism contributes to
atherogenesis remains incompletely understood. The principal investigator’s long-term goal is to define how local
immune activation alters endothelial metabolism and contributes to atherogenesis. As a first step toward
achieving this goal, she recently discovered that interferon gamma (IFN-¿), a T-cell cytokine abundant in human
atheroma, impairs endothelial glucose metabolism and activates fatty acid oxidation in primary human coronary
artery endothelial cells (Lee et al., Circulation, 2021). These metabolic derangements were associated with
proatherogenic endothelial phenotypic changes, raising the central hypothesis that IFN-¿-induced endothelial
metabolic reprogramming forms a novel mechanistic basis for accelerated atherosclerosis. This hypothesis will
be tested through the following aims: (1) Define the effect of IFN-¿ on endothelial fuel utilization, (2) Establish
the mechanistic link between endothelial metabolic reprogramming and endothelial phenotypic changes, and (3)
Define the changes in endothelial metabolism in a mouse model of immune exacerbated atherosclerosis in vivo.
Using the cutting-edge approaches including metabolomics, vascular phenotyping, single-cell technology, and a
mouse model of atherosclerosis, the principal investigator will acquire new skills and expertise in quantitative
analyses of metabolism, lipid biology, and in vivo analysis of immune-endothelial interaction in experimental
atherosclerosis. These studies, if successful, will establish immune mediated endothelial metabolic perturbations
as a novel mechanistic basis for linking pathologic T-cell activation and atherosclerosis and may open new
therapeutic strategies. Dr. Joseph Loscalzo, a distinguished vascular biologist with expertise in vascular
metabolism, redox biochemistry, and systems biology will serve as the principal investigator’s primary research
mentor. An advisory committee of physician-scientist experts in cellular metabolism and atherosclerosis research
will provide further scientific and professional development guidance and assessment of her progress. In
summary, Dr. Lee has created a superb environment and mentoring team to develop her unique niche in immune
modulation of endothelial metabolism. The proposed research, training plans, and outstanding environment at
BWH, HMS, and MIT will propel her transition to an independent investigator and a leader in vascular research.