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Endothelial Metabolic Reprogramming by Interferon-gamma in Coronary Artery Disease

干扰素γ在冠状动脉疾病中的内皮代谢重编程

基本信息

批准号：
10662850
负责人：
Laurel Yong-Hwa Lee
金额：
$ 16.89万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662850
关键词：
5&apos -AMP-activated protein kinase Acceleration Adhesions Advisory Committees Affect Anti-Inflammatory Agents Antiatherogenic Aorta Apolipoprotein E Arterial Fatty Streak Atherosclerosis Biochemistry Biological Assay Biological Availability Biology Blood Vessels Carbon Cardiology Cardiovascular system Carnitine Palmitoyltransferase I Catabolism Cell Adhesion Molecules Cell Communication Cell Line Cellular Metabolic Process Circulation Citric Acid Cycle Clinical Coronary Arteriosclerosis Coronary artery Data Development Diet Disease Doctor of Medicine Endothelial Cells Endothelium Environment Enzymes Equilibrium Fellowship Free Radical Scavengers Functional disorder Funding Genetic Transcription Glucose Glycolysis Glycolysis Inhibition Goals Guanosine Homeostasis Hospitals Human Immune Immunofluorescence Immunologic Immunological Models Immunologics Immunology Impairment In Vitro Inflammation Mediators Inflammatory Response Interferon Type II Kinetics Label Lead Leukocytes Link Lipid Peroxidation Lipids Lipoxins Mediating Medicine Mentors Metabolic Metabolism Modeling Modification Morbidity - disease rate Mus Myocardial Infarction Oxidation-Reduction Oxidative Stress Pathologic Pathology Periodicity Phenotype Physicians Physiological Predisposition Principal Investigator Production Proliferating Prostaglandins I Radioisotopes Reactive Oxygen Species Research Research Personnel Risk Factors Role Scientist Signaling Molecule Source Stroke Surface Systems Biology T-Cell Activation T-Lymphocyte Testing Time Training Training Programs Trimetazidine Tube Up-Regulation Vasodilation Woman Work angiogenesis atherogenesis cell type cytokine disorder prevention endothelial dysfunction extracellular fatty acid oxidation glucose metabolism immune activation immunoregulation improved in vivo inhibitor instructor limb loss liquid chromatography mass spectrometry medical schools metabolic profile metabolomics migration mortality mouse model novel novel therapeutic intervention overexpression pharmacologic prevent shear stress single cell technology single-cell RNA sequencing skills stable isotope thrombotic transcriptomics

项目摘要

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.

项目SUMARY /文摘