Metabolic Reprogramming of Recruited Alveolar Macrophages by Arginine In Acute Lung Injury

项目总结 项目摘要：本提案描述了一个五年的培训计划，该计划最终将培养Kara博士 塑造成为独立的学术基础科学研究者。她的长期职业目标是推进 巨噬细胞生物学领域通过阐明肺修复的靶点和患者的治疗 急性呼吸窘迫综合征或炎症性肺部疾病。在本次K08大奖期间，莫尔德博士将 获得与创新研究计划密切相关的特定职业发展培训和指导。她 建议研究精氨酸代谢对急性肺损伤模型肺泡巨噬细胞编程的影响。 肺损伤。鉴于其对多发性肺疾病的适用性和对损伤修复的潜在适用性 其他器官，这项工作与NHLBI直接相关。 候选人：莫尔德博士是加州大学肺部和重症监护医学委员会认证的内科医生 科罗拉多医学院。她在团契培训的最后一年，选择完成一项 可选的一年专职研究。她以前的学术成就，基础科学研究，以及 科学出版物表明了作为一名学术临床科学家的坚定承诺。 培训：拟议的职业发展计划加强了莫尔德博士在 本科生、医学、住院医师和研究员培训。她建议实现她的短期目标 通过由国际知名巨噬细胞专家进行的密集指导的集成组合 生物学和(I)免疫学，(Ii)免疫细胞代谢编程的教学和实践经验 (3)生物信息学；(4)科学写作和演示；(5)实验室领导。 导师/环境：莫尔德博士与经验丰富的人建立了密切的工作关系 在巨噬细胞和肺部生物学方面贡献专业知识的导师和合作者(Henson博士和 代谢组学(D‘Alessandro博士)、生物信息学(Fingerlin博士)、人类肺和上皮生物学 (Mason博士)、内皮生物学(Petrache博士)和临床医生-科学家的职业发展(Douglas博士， Eickelberg和Voelker。)拟议的活动将设在国家犹太人健康中心，并得到 科罗拉多大学，既有著名的呼吸医学中心，也有世界级的研究机构。 研究项目：这项建议的主要目标是确定肺泡形成的机制 巨噬细胞被编程来化解炎症并促进受损肺的修复。具体地说，我们的 研究将验证代谢酶精氨酸酶1是两者的关键检查点的假设 肺泡巨噬细胞的炎症和修复性程序。这将用一口井进行测试- 小鼠肺损伤模型的建立及人肺原代细胞的分离 控制。在此过程中，精氨酸代谢对巨噬细胞编程和 调控炎症性肺部疾病恢复的途径将被阐明。

PROJECT SUMMARY Project Summary: This proposal describes a five-year training program that will ultimately develop Dr. Kara Mould into an independent academic basic science investigator. Her long-term career goal is to advance the field of macrophage biology through the elucidation of targets for lung repair and the treatment of patients with the acute respiratory distress syndrome or inflammatory lung diseases. During this K08 Award, Dr. Mould will gain specific career development training and mentorship closely aligned with an innovative research plan. She proposes to study the affect of arginine metabolism on alveolar macrophage programming in models of acute lung injury. Given its applicability to multiple pulmonary disorders and potential applicability to repair of injury in other organs, this work is directly relevant to the NHLBI. Candidate: Dr. Mould is a board-certified Pulmonary and Critical Care Medicine physician at the University of Colorado School of Medicine. She is in the final year of fellowship training, having elected to complete an optional year of dedicated research. Her previous record of academic excellence, basic science research, and scientific publications demonstrates a firm commitment to a career as an academic clinician-scientist. Training: The proposed career development plan augments Dr. Mould's prior mentored research during her undergraduate, medical, residency, and fellowship training. She proposes to meet her short-term objectives through an integrated combination of intensive mentoring by internationally renowned experts in macrophage biology and didactic and hands-on experiences in (i) Immunology, (ii) metabolic programming of immune cells (iii) bioinformatics, (iv) scientific writing and presentation, and (v) laboratory leadership. Mentors/Environment: Dr. Mould has established close working relationships with highly experienced mentors and collaborators who contribute expertise in macrophage and lung biology (Drs. Henson and Janssen), metabolomics (Dr. D'Alessandro), bioinformatics (Dr. Fingerlin), human lung and epithelial biology (Dr. Mason), endothelial biology (Dr. Petrache), and career development of clinician-scientists (Drs. Douglas, Eickelberg, and Voelker.) The proposed activities will be based at National Jewish Health with support from the University of Colorado, both renowned respiratory medical centers and world-class research institutions. Research Project: The primary objective of this proposal is to identify the mechanism by which alveolar macrophages are programmed to resolve inflammation and promote repair of the injured lung. Specifically, our study will test the hypothesis that the metabolic enzyme, arginase 1, is a critical checkpoint for both inflammatory and reparative programming of alveolar macrophages. This will be tested using a well- established murine model of lung injury and primary cells isolated from diseased human lungs or non-diseased controls. In doing so, the specific contribution of arginine metabolism to macrophage programming and pathways that regulate recovery from inflammatory lung diseases will be elucidated.