Endothelial Metabolic Reprogramming by Interferon-gamma in Coronary Artery Disease

项目摘要/摘要 这项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。作为一种 独立的，R01资助的学术心脏病学医生兼科学家，在免疫调节方面的专业知识 动脉粥样硬化中的内皮代谢。这一独特的科学关注点结合了李博士在T- 细胞免疫学与她后来在布里格姆大学心血管内科的临床和研究奖学金 以及妇女医院(BWH)和哈佛医学院(HMS)。她目前是一名副医生， BWH/HMS心血管内科和一名内科讲师。 冠状动脉疾病仍然是世界范围内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先兆，内皮新陈代谢的改变如何影响动脉粥样硬化 动脉粥样硬化的形成机制尚不完全清楚。首席调查员的长期目标是定义当地 免疫激活改变内皮细胞代谢，促进动脉粥样硬化的形成。作为迈向 为了实现这一目标，她最近发现，干扰素-γ是一种在人类体内丰富的T细胞细胞因子 动脉粥样硬化损害人冠状动脉内皮细胞葡萄糖代谢并激活脂肪酸氧化 动脉内皮细胞(Lee等人，《循环》，2021)。这些代谢紊乱与 致动脉粥样硬化的内皮细胞表型改变，提高了干扰素-γ诱导内皮细胞的中心假设 代谢重编程形成了加速动脉粥样硬化的新的机制基础。这一假说将 通过以下目的进行测试：(1)确定干扰素-γ对内皮细胞燃料利用的影响，(2)建立 内皮代谢重新编程和内皮表型改变之间的机制联系，以及(3) 明确免疫加重动脉粥样硬化小鼠体内内皮细胞代谢的变化。 使用包括代谢组学、血管表型鉴定、单细胞技术和 小鼠动脉粥样硬化模型，首席研究人员将获得新的技能和专业知识 实验性免疫-血管内皮细胞相互作用的代谢、脂质生物学及体内分析 动脉硬化。如果这些研究成功，将建立免疫介导的内皮代谢紊乱 作为将病理性T细胞激活与动脉粥样硬化联系起来的新的机制基础，并可能打开新的 治疗策略。约瑟夫·洛斯卡尔佐博士，著名的血管生物学家，在血管方面有专长 新陈代谢、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 门托。由细胞代谢和动脉粥样硬化研究方面的内科专家和科学家组成的咨询委员会 将为她的进步提供进一步的科学和专业的发展指导和评估。在……里面 总结，李博士创造了一流的环境和指导团队，以发展她在免疫领域的独特利基 内皮细胞代谢的调节。建议的研究、培训计划和卓越的环境 BWH、HMS和MIT将推动她向独立研究员和血管研究领先者的转变。

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.