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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.

项目总结/摘要该提案提出了一项为期五年的研究和培训计划，旨在建立 Laurel Y. Lee 医学博士、哲学博士。作为独立的、由 R01 资助的学术心脏病学医师科学家，拥有免疫调节方面的专业知识动脉粥样硬化中的内皮代谢。这一独特的科学重点结合了李博士在 T- 细胞免疫学以及随后在布里格姆大学心血管医学领域的临床和研究奖学金以及妇女医院 (BWH) 和哈佛医学院 (HMS)。她目前是一名副医师 BWH/HMS 心血管医学科和医学讲师。冠状动脉疾病仍然是全世界死亡和发病的主要原因。而内皮细胞功能障碍被认为是动脉粥样硬化的前兆，内皮代谢的改变如何导致动脉粥样硬化的形成仍不完全清楚。主要研究者的长期目标是确定本地如何免疫激活改变内皮代谢并导致动脉粥样硬化。作为迈向的第一步为了实现这一目标，她最近发现了干扰素γ（IFN-γ），一种人类体内丰富的T细胞细胞因子动脉粥样硬化，损害内皮葡萄糖代谢并激活原代人冠状动脉中的脂肪酸氧化动脉内皮细胞（Lee 等人，Circulation，2021）。这些代谢紊乱与促动脉粥样硬化内皮表型变化，提出了 IFN-γ 诱导内皮细胞表型变化的中心假设代谢重编程为加速动脉粥样硬化形成了新的机制基础。这个假设将通过以下目标进行测试：（1）定义 IFN-γ 对内皮燃料利用的影响，（2）建立内皮代谢重编程和内皮表型变化之间的机制联系，以及（3）定义体内免疫加剧动脉粥样硬化小鼠模型中内皮代谢的变化。使用代谢组学、血管表型分析、单细胞技术和动脉粥样硬化小鼠模型，首席研究员将获得定量方面的新技能和专业知识实验中的代谢、脂质生物学分析以及免疫-内皮相互作用的体内分析动脉粥样硬化。这些研究如果成功，将建立免疫介导的内皮代谢扰动作为连接病理性 T 细胞激活和动脉粥样硬化的新机制基础，并可能开辟新的领域治疗策略。 Joseph Loscalzo 博士，一位杰出的血管生物学家，在血管领域拥有丰富的专业知识代谢、氧化还原生物化学和系统生物学将作为首席研究员的主要研究导师。由细胞代谢和动脉粥样硬化研究领域的医师科学家专家组成的咨询委员会将为她的进步提供进一步科学和专业的发展指导和评估。在总之，李博士创造了一个极好的环境和指导团队来发展她在免疫领域的独特地位内皮代谢的调节。拟议的研究、培训计划和优越的环境 BWH、HMS 和 MIT 将推动她转型为一名独立研究者和血管研究领域的领导者。