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Targeting metabolism to improve outcomes following severe influenza infection

靶向代谢以改善严重流感感染后的预后

基本信息

批准号：
10229101
负责人：
Brydie Ryan Huckestein
金额：
$ 4.6万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10229101
关键词：
Acute Adenosine Monophosphate Affect Alveolar Alveolitis Antioxidants Biological Assay Cell Differentiation process Cells Complex Contracts Data Disease Epithelial Epithelial Cells FRAP1 gene Failure Flow Cytometry Formalin Free Radicals Gene Expression Glucose Goals Hematoxylin and Eosin Staining Method Hepatic Human Immune Immunoassay Immunology Impairment Infection Inflammation Inflammatory Influenza Influenza Therapeutic Injury Laboratories Literature Lung Lung Inflammation Metabolic Metabolism Metaplasia Metformin Methods Microbiology Mitochondria Molecular Mus Natural regeneration Oxidative Phosphorylation Oxidative Stress Pathway Analysis Pathway interactions Patients Pharmaceutical Preparations Phase Phosphotransferases Physiology Plasma Population Process Production Protein Kinase Proteins Raptors Reactive Oxygen Species Recovery Resolution Risk Role Sampling Secondary to Signal Transduction Sirolimus Stains Structure of parenchyma of lung Symptoms Tamoxifen Therapeutic Time Tissues Undifferentiated Universities Up-Regulation Viral Viral Respiratory Tract Infection Virus alveolar type II cell cell type cellular targeting cytokine epithelial repair epithelial stem cell glucophage glucose production improved improved outcome influenza infection inhibitor/antagonist lung injury lung repair macrophage mitochondrial metabolism mortality notch protein programs pulmonary function repaired restoration stem cell population stem cells synthetic polymer Bioplex

项目摘要

Targeting Metabolism to Improve Outcomes following Severe Influenza Infection Brydie Huckestein Advisor: Dr. John Alcorn Program in Microbiology and Immunology, University of Pittsburgh ABSTRACT Widespread epithelial damage in the lungs is a hallmark of influenza infection. Our laboratory and others have shown that influenza infected mice have persistent lung damage, inflammation, and epithelial metaplasia up to 60 days post-infection. In humans, alveolitis can persist for years following an influenza infection. I hypothesize that treating mice with metabolism-targeting medications will improve lung repair following influenza infection by reducing inflammation and promoting alveolar regeneration. Epithelial metaplasia following influenza infection reduces lung function and is caused by undifferentiated lineage negative epithelial progenitor cells (LNEPs). Preliminary data indicates LNEPs have increased activation of the energy sensing kinase mammalian target of rapamycin complex 1 (mTORC1) 21 days following influenza infection. Studies in other stem cell populations show that mTORC1 activation can inhibit differentiation into mature cell types, but its role in LNEP differentiation is unknown. I propose that treating mice with the mTORC1 inhibitor rapamycin two weeks following influenza infection will promote differentiation of LNEPs into AT II cells and reduce the presence of epithelial metaplasia. Additionally, preliminary data suggests oxidative stress is occurring in the lungs 21 days following influenza infection. Ingenuity Pathway Analysis shows that macrophage ROS production is increased in the mouse lung at this time, and high resolution respirometry data indicates increased oxidative phosphorylation. I propose that treating mice with metformin, an AMPK activator, will reduce oxidative stress during lung repair following influenza infection. The following studies will determine how rapamycin and metformin impact inflammation and cellular repair mechanisms in the lung during the recovery phase following severe influenza infection. The goal of this project is to determine if metabolism targeting medications can be repurposed to treat patients who continue to suffer after their viral respiratory infection has been cleared.

靶向代谢以改善严重流感感染后的预后布赖迪·哈克斯坦顾问：约翰·奥尔康博士匹兹堡大学微生物学和免疫学项目抽象的肺部广泛的上皮损伤是流感感染的标志。我们实验室和其他实验室有研究表明，感染流感的小鼠有持续的肺损伤、炎症和上皮化生感染后 60 天。在人类中，流感感染后肺泡炎可能持续数年。我假设用代谢靶向药物治疗小鼠将改善流感感染后的肺部修复减少炎症并促进肺泡再生。流感感染后上皮化生降低肺功能，由未分化谱系阴性上皮祖细胞 (LNEP) 引起。初步数据表明 LNEP 增加了能量感应激酶哺乳动物靶标的激活流感感染后 21 天的雷帕霉素复合物 1 (mTORC1)。其他干细胞群的研究表明 mTORC1 激活可以抑制分化为成熟细胞类型，但其在 LNEP 分化中的作用未知。我建议在流感后两周用 mTORC1 抑制剂雷帕霉素治疗小鼠感染将促进 LNEP 分化为 AT II 细胞并减少上皮化生的存在。此外，初步数据表明，流感发生后 21 天肺部出现氧化应激感染。 Ingenuity Pathway Analysis 显示小鼠肺中巨噬细胞 ROS 产量增加此时，高分辨率呼吸测量数据表明氧化磷酸化增加。我建议用二甲双胍（一种 AMPK 激活剂）治疗小鼠将减少肺修复过程中的氧化应激流感感染。以下研究将确定雷帕霉素和二甲双胍如何影响炎症和严重流感感染后恢复阶段肺部的细胞修复机制。目标该项目的目的是确定代谢靶向药物是否可以重新用于治疗以下患者：在病毒性呼吸道感染被清除后，他们仍继续遭受痛苦。