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：
10615912
负责人：
Brydie Ryan Huckestein
金额：
$ 1.82万
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 2023-12-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10615912
关键词：
Acute Adenosine Monophosphate Affect Alveolar Alveolitis Antioxidants Biological Assay Cell Differentiation process Cells Complex Contracts Data Disease Epithelial Cells Epithelium 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 Macrophage 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 Predisposition Process Production Protein Kinase Proteins Pulmonary Inflammation Pulmonary alveolar structure Reactive Oxygen Species Recovery Resolution Risk Role Sampling Secondary to Signal Transduction Sirolimus Spirometry 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 lung injury lung repair mitochondrial metabolism mortality notch protein programs pulmonary function repaired restoration stem cell population stem cells synthetic polymer Bioplex

Acute Adenosine Monophosphate Affect Alveolar Alveolitis Antioxidants Biological Assay Cell Differentiation process Cells Complex Contracts Data Disease Epithelial Cells Epithelium 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 Macrophage 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 Predisposition Process Production Protein Kinase Proteins Pulmonary Inflammation Pulmonary alveolar structure Reactive Oxygen Species Recovery Resolution Risk Role Sampling Secondary to Signal Transduction Sirolimus Spirometry 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 lung injury lung repair mitochondrial metabolism mortality notch protein programs pulmonary function repaired restoration stem cell population stem cells synthetic polymer Bioplex

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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结局布莱迪·哈克斯坦（Brydie Huckestein）顾问：John Alcorn博士匹兹堡大学微生物学和免疫学计划抽象的肺部广泛的上皮损害是流感感染的标志。我们的实验室和其他实验室有表明感染流感的小鼠具有持续性的肺部损伤，炎症和上皮变质至感染后60天。在人类中，流感感染后可以持续多年。我假设通过靶向代谢药物治疗小鼠的小鼠在通过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，并由未分化的谱系阴性上皮祖细胞（LNEP）引起。初步数据表明，LNEP的能量感测激酶哺乳动物靶标的激活增加流感感染后21天，雷帕霉素复合物1（MTORC1）。其他干细胞群体的研究表明MTORC1激活可以抑制分化为成熟的细胞类型，但其在LNEP分化中的作用是未知的。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，初步数据表明流感后21天发生在肺中发生氧化应激感染。 Ingenuity途径分析表明，小鼠肺中巨噬细胞ROS的产生增加目前，高分辨率呼吸测定数据表明氧化磷酸化增加。我建议用AMPK激活剂二甲双胍治疗小鼠将减少肺部修复期间的氧化应激流感感染。以下研究将决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的肺部细胞修复机制。目标这个项目的是确定靶向药物的代谢是否可以重新使用以治疗患者清除了病毒呼吸道感染后继续遭受痛苦。