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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：
10544138
负责人：
Brydie Ryan Huckestein
金额：
$ 4.68万
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/10544138
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 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 Pulmonary Inflammation Pulmonary alveolar structure 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 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.

靶向代谢改善严重流感感染后的预后