Endothelial Metabolic Reprogramming by Interferon-gamma in Coronary Artery Disease

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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-γ), 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-γ-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-γ 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.