Glutamine Metabolism in Alveolar Macrophages following Influenza A Infection

项目摘要/摘要 该提案概述了Obada Shamaa医学博士进行博士后工作的研究和培训计划 在马里兰州Gokhan Mutlu的实验室里呆了两年。这项研究项目的最终目标是提供 谷氨酰胺代谢在甲型流感所致急性呼吸窘迫中的作用 综合征(IAV诱导的ARDS)，这是一种与显著死亡率和有限的治疗选择相关的疾病。 这项工作将是成为K-Level补助金的基础。在这段指导期间，Shamaa博士将获得 擅长代谢和研究生物能量学、氧化还原状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。除了穆特鲁博士和一位 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 谷氨酰胺代谢参与甲型流感病毒复制和肺泡巨噬细胞效应功能。新陈代谢 适应以支持免疫细胞功能，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增加有氧糖酵解代谢以支持促炎作用 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- AM)仅依靠线粒体呼吸来支持其效应器功能。Shamaa医生现在有确凿的证据 Tr-am增加谷氨酰胺分解酶的表达以响应IAV感染的数据。此外，他还 研究表明，在缺乏IAV的情况下，tr-am的IAV复制和促炎细胞因子释放减少 外源性谷氨酰胺。这些数据表明，谷氨酰胺的主动调节对IAV的复制和 Tr-am的效应器功能。目的1评价谷氨酰胺代谢在IAV病毒复制和转录调节中的作用。 调幅效应器反应。目标2将重点放在靶向后感染IAV的tr-am的代谢变化 谷氨酰胺新陈代谢。拟议的工作将需要生物能量学和液相色谱学方面的培训- 在此期间，质谱学(LC-MS)和Shamaa博士将接受这两种技术方面的培训。这 工作试图了解谷氨酰胺是如何在IAV感染后的肺泡巨噬细胞中利用的 迫切需要为IAV诱导的ARDS的治疗干预确定新的靶点。

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.