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.

项目总结/文摘