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

• 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
• 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' -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

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 该提案提出了一个为期五年的研究和培训计划，以建立月桂Y。Lee，医学博士D.Phil.作为 独立的，R 01资助的医生，科学家在学术心脏病学与免疫调节的专业知识， 动脉粥样硬化的内皮代谢。这种独特的科学重点结合了李博士在T- 细胞免疫学与她随后的临床和研究奖学金在心血管医学在布里格姆 妇女医院（BWH）和哈佛医学院（HMS）。她目前是一名副医师， 心血管医学部和BWH/HMS医学讲师。 冠状动脉疾病仍然是全球死亡率和发病率的主要原因。虽然内皮 功能障碍被认为是动脉粥样硬化的前兆，改变内皮代谢如何有助于 动脉粥样硬化的形成仍不完全清楚。首席研究员的长期目标是确定当地 免疫激活改变内皮代谢并促进动脉粥样硬化形成。作为迈向 为了实现这一目标，她最近发现干扰素γ（IFN-γ），一种在人类中丰富的T细胞细胞因子， 动脉粥样硬化，损害内皮葡萄糖代谢和激活脂肪酸氧化在原发性人类冠状动脉 动脉内皮细胞（Lee等，Circulation，2021）.这些代谢紊乱与 促动脉粥样硬化内皮细胞表型改变，提出了IFN-γ诱导内皮细胞表型改变的中心假设， 代谢重编程形成了加速动脉粥样硬化的新机制基础。这一假设将 通过以下目的进行测试：（1）确定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，和（3） 定义免疫加重动脉粥样硬化小鼠模型体内内皮代谢的变化。 利用包括代谢组学、血管表型分析、单细胞技术和 小鼠动脉粥样硬化模型，主要研究者将获得新的技能和专业知识，定量 代谢分析，脂质生物学，和免疫-内皮细胞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紊乱 作为一种新的机制基础，连接病理性T细胞活化和动脉粥样硬化，并可能打开新的 治疗策略Joseph Loscalzo博士是一位杰出的血管生物学家，在血管生物学方面具有专长。 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 导师一个由细胞代谢和动脉粥样硬化研究方面的医生-科学家专家组成的咨询委员会 将提供进一步的科学和专业发展指导和评估她的进展。在 总而言之，李博士创造了一个极好的环境和指导团队，以发展她在免疫领域的独特优势。 调节内皮代谢。拟议的研究，培训计划，和优秀的环境在 BWH，HMS和麻省理工学院将推动她过渡到一个独立的研究者和血管研究的领导者。