Glutamine Metabolism in Alveolar Macrophages following Influenza A Infection

甲型流感感染后肺泡巨噬细胞的谷氨酰胺代谢

• 批准号: 10607319
• 负责人: Obada Shamaa
• 金额: $ 8.09万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-16 至 2024-06-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10607319
• 关键词: Acute Lung Injury; Acute Respiratory Distress Syndrome; Affect; Alveolar Macrophages; Attenuated; Bioenergetics; Bone Marrow; Carbon; Cell physiology; Cells; Cellular Metabolic Process; Cellular biology; Cessation of life; Chicago; Citric Acid Cycle; Consumption; Data; Disease; Doctor of Philosophy; Education; Energy-Generating Resources; Enzyme Inhibitor Drugs; Enzymes; Excision; Fellowship; Foundations; Future; Generations; Genetic Transcription; Genus Hippocampus; Glutamate Dehydrogenase; Glutaminase; Glutamine; Glycolysis; Goals; Grant; Hour; Immune; Immunology; Infection; Inflammatory; Inflammatory Response; Influenza; Influenza A virus; Interdisciplinary Study; Knowledge; Label; Laboratories; Lower respiratory tract structure; Lung; Lung diseases; Macrophage; Mass Fragmentography; Measures; Mentors; Messenger RNA; Metabolic; Metabolism; Mitochondria; Molecular Biology; Monitor; Morbidity - disease rate; Mus; Non-Essential Amino Acid; Oxidation-Reduction; Pathogenesis; Pathway interactions; Physicians; Play; Population; Postdoctoral Fellow; Production; Proteins; Proteomics; Regulation; Research; Research Personnel; Research Project Grants; Respiration; Respiratory Tract Infections; Role; Scientist; Sepsis; Site; Small Interfering RNA; Structure of parenchyma of lung; Techniques; Testing; Therapeutic; Therapeutic Intervention; Tissues; Training; Universities; Viral Proteins; Virus Diseases; Virus Replication; Work; aerobic glycolysis; alveolar bone; career; cytokine; experimental study; immune function; improved; in vivo; influenza infection; influenzavirus; insight; knock-down; liquid chromatography mass spectrometry; macromolecule; metabolomics; monocyte; mortality; mouse model; new therapeutic target; novel; protein expression; recruit; respiratory pathogen; response; skills; targeted treatment

Project Summary/Abstract The proposal outlines a research and training plan for Obada Shamaa, MD, PhD, to perform postdoctoral work in the laboratory of Gokhan Mutlu, MD, for two years. The ultimate goal of this research project is to provide novel insights into the how glutamine metabolism plays a role in Influenza A-induced Acute Respiratory Distress Syndrome (IAV-induced ARDS), a disease associated with significant mortality and limited therapeutic options. This work will be the foundation for becoming a K-level grant. During this mentored period, Dr. Shamaa will gain expertise in metabolism and techniques to study bioenergetics, redox states, and metabolomics as well as enhance his previous cellular and molecular biology skills. In addition to mentoring by Dr. Mutlu and a multidisciplinary Research Monitoring Committee (RMC), Dr. Shamaa will supplement his training with educational opportunities provided at the University of Chicago. The overall research goal is to identify how glutamine metabolism is involved in influenza A replication and alveolar macrophage effector function. Metabolic adaptations to support immune cell function, as well as by influenza A virus (IAV) to support viral replication. While it is thought that macrophages increase aerobic glycolysis metabolism to support a pro-inflammatory macrophage response, recent work by the Mutlu lab showed that tissue-resident alveolar macrophages (TR- AMs) rely solely on mitochondrial respiration to support their effector function. Dr. Shamaa now has confirmatory data that TR-AMs increase expression of glutaminolysis enzymes in response to IAV infection. Additionally, he has shown that IAV replication and pro-inflammatory cytokine release is reduced in TR-AMs in the absence of exogenous glutamine. These data indicate that active regulation of glutamine is critical for IAV replication and TR-AMs’ effector function. Aim 1 will evaluate the role of glutamine metabolism in IAV viral replication and TR- AM effector response. Aim 2 will focus on the metabolic changes in TR-AMs infected with IAV following targeting of glutamine metabolism. The proposed work will require training in bioenergetics and liquid chromatography- mass spectrometry (LC-MS) and Dr. Shamaa will obtain training in both techniques during this fellowship. This work seeks to understand how glutamine is utilized in alveolar macrophages following IAV infection as there is a significant need to identify novel targets for therapeutic interventions for IAV-induced ARDS.

项目摘要/摘要 该提案概述了医学博士Obada Shamaa博士的研究和培训计划，以执行博士后工作 在医学博士Gokhan Mutlu实验室中，已有两年。该研究项目的最终目标是提供 对谷氨酰胺代谢如何在流感A诱导的急性呼吸窘迫中起作用的新颖见解 综合征（IAV诱导的ARDS），这是一种疾病，与显着死亡率和有限的治疗选择有关。 这项工作将成为成为K级赠款的基础。在此修订期间，Shamaa博士将获得 用于研究生物能学，氧化还原国家和代谢组学以及代谢和技术方面的专业知识以及 提高他以前的细胞和分子生物学技能。除了Mutlu博士和A的心理 多学科研究监测委员会（RMC），Shamaa博士将补充他的培训 芝加哥大学提供的教育机会。总体研究目标是确定如何 谷氨酰胺代谢参与了影响的复制和肺泡巨噬细胞效应子功能。代谢 适应以支持免疫细胞功能，以及通过影响力的病毒（IAV）支持病毒复制。 虽然认为巨噬细胞会增加有氧糖酵解代谢以支持促炎性 巨噬细胞反应，Mutlu实验室最近的工作表明，组织居民肺泡巨噬细胞（Tr- AMS）仅依靠线粒体呼吸来支持其效应子功能。 Shamaa博士现在有确认 Tr-AMS响应IAV感染而增加谷氨酰胺溶解酶的表达。另外，他 已经表明，在不存在的情况下，IAV复制和促炎性细胞因子释放减少了 外源谷氨酰胺。这些数据表明，谷氨酰胺的主动调节对于IAV复制至关重要 TR-AMS的效应函数。 AIM 1将评估谷氨酰胺代谢在IAV病毒复制和Tr-的作用 AM效应子响应。 AIM 2将重点放在靶向后感染IAV的TR-AM的代谢变化上 谷氨酰胺代谢。拟议的工作将需要在生物能和液相色谱法进行培训 - 在此研究金期间，质谱法（LC-MS）和Shamaa博士将获得两种技术的培训。 工作试图了解IAV感染后如何在肺泡巨噬细胞中使用谷氨酰胺 确定IAV诱导的ARDS治疗干预措施的新目标的重要需求。