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

项目摘要 项目概要：该提案描述了一个五年的培训计划，最终将培养卡拉博士 塑造成一个独立的学术基础科学研究者。她的长期职业目标是推动 巨噬细胞生物学领域通过阐明肺修复的靶点和治疗 急性呼吸窘迫综合征或炎性肺病。在本次K 08奖期间，Mould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 目的：研究急性肺损伤模型中精氨酸代谢对肺泡巨噬细胞编程的影响， 肺损伤鉴于其适用于多种肺部疾病和潜在的适用性， 在其他机构中，这项工作与《国家法律文书》直接相关。 候选人：Mould博士是芝加哥大学获得委员会认证的肺和重症监护医学医师。 科罗拉多医学院。她已进入奖学金培训的最后一年，并选择完成一项 选择一年的专门研究。她以前的学术成就，基础科学研究， 科学出版物表明了坚定的承诺，作为一个学术临床科学家的职业生涯。 培训：拟议的职业发展计划增强了Mould博士在她任职期间的先前指导研究。 本科、医学、住院医师和研究员培训。她建议实现她的短期目标 通过国际知名的巨噬细胞专家的密集指导， 生物学和教学和动手经验（i）免疫学，（ii）免疫细胞的代谢编程 (iii)生物信息学，（iv）科学写作和演示，以及（v）实验室领导。 导师/环境：Mould博士与经验丰富的 在巨噬细胞和肺生物学方面贡献专业知识的导师和合作者（Henson博士和 Janssen）、代谢组学（D 'Alessandro博士）、生物信息学（Fingerlin博士）、人肺和上皮生物学 (Dr. Mason博士）、内皮生物学（Petrache博士）和临床科学家的职业发展（道格拉斯博士， Eickelberg和Voelker）。拟议的活动将以国家犹太人健康中心为基础， 科罗拉多大学，既是著名的呼吸医学中心和世界一流的研究机构。 研究项目：该提案的主要目标是确定肺泡 巨噬细胞被编程以解决炎症并促进受损肺的修复。具体来说，我们 一项研究将检验这样一种假设，即代谢酶--β-淀粉酶1是这两种酶的关键检查点。 肺泡巨噬细胞的炎症和修复编程。这将使用一个良好的测试- 建立的肺损伤鼠模型和从患病人肺或非患病人肺分离的原代细胞 对照在此过程中，精氨酸代谢对巨噬细胞编程和 将阐明调节炎症性肺病恢复的途径。

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.