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/摘要该提案提出了一项为期五年的研究和培训计划，以建立Laurel Y. Lee，M.D.，D.Phil。作为独立的R01资助的物理科学家在学术心脏病学领域具有专业知识动脉粥样硬化中的内皮代谢。这个独特的科学焦点结合了李博士在T-中的博士培训细胞免疫学及其随后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的心血管医学和医学教练的分裂。冠状动脉疾病仍然是全球死亡率和发病率的主要原因。而内皮功能障碍被称为动脉粥样硬化的前体，内皮代谢改变如何有助于动脉粥样硬化仍然不完全理解。主要研究者的长期目标是定义如何本地免疫激活改变了内皮代谢，并有助于动脉粥样硬化。作为迈向的第一步实现这一目标，她最近发现干扰素伽玛（IFN-γ）是人类丰富的T细胞细胞因子动脉瘤，会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，循环，2021）。这些代谢进化与促进性内皮表型变化，提出了IFN-γ诱导的内皮的中心假设代谢重编程构成了加速动脉粥样硬化的新机械基础。这个假设将会通过以下目的进行测试：（1）定义IFN-γ对内皮燃料利用的影响，（2）确定内皮代谢重编程和内皮表型变化之间的机械联系，（3）在体内的免疫验证动脉粥样硬化的小鼠模型中定义内皮代谢的变化。使用包括代谢组学，血管表型，单细胞技术和A的尖端方法首席研究员的动脉粥样硬化的小鼠模型将获得新技能和定量专家实验中的代谢，脂质生物学和体内分析的分析动脉粥样硬化。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T细胞激活和动脉粥样硬化的新机械基础，并可能打开新的机械基础治疗策略。 Joseph Loscalzo博士，杰出的血管生物学家，具有血管专家代谢，氧化还原生物化学和系统生物学将作为主要研究者的主要研究 Menor。细胞代谢和动脉粥样硬化研究专家的身体科学家咨询委员会将为她的进步提供进一步的科学和专业发展指导和评估。总结，李博士创建了一个出色的环境和心理团队，以开发她在免疫中独特的利基市场内皮代谢的调节。拟议的研究，培训计划和杰出的环境 BWH，HMS和MIT将推动她向独立研究者和血管研究领导者的过渡。