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.

项目概要/摘要 该提案概述了 Obada Shamaa 博士从事博士后工作的研究和培训计划 在医学博士 Gokhan Mutlu 的实验室工作了两年。该研究项目的最终目标是提供 关于谷氨酰胺代谢如何在甲型流感引起的急性呼吸窘迫中发挥作用的新见解 综合征（IAV 诱发的 ARDS），一种与高死亡率和有限的治疗选择相关的疾病。 这项工作将成为成为 K 级资助的基础。在这段指导期间，Shamaa 博士将获得 代谢方面的专业知识和研究生物能量学、氧化还原态和代谢组学的技术以及 增强他以前的细胞和分子生物学技能。除了 Mutlu 博士和 多学科研究监督委员会 (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 谷氨酰胺代谢参与甲型流感复制和肺泡巨噬细胞效应功能。代谢 适应支持免疫细胞功能，以及甲型流感病毒（IAV）支持病毒复制。 虽然人们认为巨噬细胞会增加有氧糖酵解代谢以支持促炎 巨噬细胞反应，Mutlu 实验室最近的工作表明，组织驻留的肺泡巨噬细胞（TR- AMs）仅依靠线粒体呼吸来支持其效应器功能。 Shamaa 博士现已确认 数据表明，TR-AM 会增加谷氨酰胺分解酶的表达以应对 IAV 感染。此外，他 has shown that IAV replication and pro-inflammatory cytokine release is reduced in TR-AMs in the absence of 外源性谷氨酰胺。这些数据表明，谷氨酰胺的主动调节对于 IAV 复制和 TR-AM 的效应器功能。目标 1 将评估谷氨酰胺代谢在 IAV 病毒复制和 TR- AM 效应器响应。目标 2 将重点关注感染 IAV 的 TR-AM 在靶向后的代谢变化 谷氨酰胺代谢。拟议的工作将需要生物能量学和液相色谱方面的培训- 质谱 (LC-MS) 和 Shamaa 博士将在该奖学金期间获得这两种技术的培训。这 这项工作旨在了解 IAV 感染后肺泡巨噬细胞如何利用谷氨酰胺，因为 迫切需要确定 IAV 诱发的 ARDS 治疗干预的新靶点。