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

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 顾问:John Alcorn博士 匹兹堡大学微生物学和免疫学专业 摘要 肺部广泛的上皮损伤是流感感染的标志。我们的实验室和其他实验室 显示流感感染的小鼠具有持续的肺损伤、炎症和上皮化生, 感染后60天。在人类中,肺泡炎可以在流感感染后持续数年。我假设 用代谢靶向药物治疗小鼠将改善流感感染后的肺修复, 减少炎症和促进肺泡再生。流感感染后上皮化生 降低肺功能,并且由未分化的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点的激活, 雷帕霉素复合物1(mTORC 1)。其他干细胞群体的研究 显示mTORC 1活化可抑制分化成成熟细胞类型,但其在LNEP分化中作用 不明我建议在流感后两周用mTORC 1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,氧化应激发生在流感后21天的肺部 感染免疫途径分析显示,小鼠肺中巨噬细胞ROS产生增加, 此时,高分辨率呼吸测定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, 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, 在严重流感感染后的恢复阶段,肺中的细胞修复机制。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 在他们的病毒性呼吸道感染被清除后继续遭受痛苦。

项目成果

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Brydie Ryan Huckestein其他文献

Brydie Ryan Huckestein的其他文献

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{{ truncateString('Brydie Ryan Huckestein', 18)}}的其他基金

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
  • 批准号:
    10544138
  • 财政年份:
    2021
  • 资助金额:
    $ 1.82万
  • 项目类别:
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
  • 批准号:
    10229101
  • 财政年份:
    2021
  • 资助金额:
    $ 1.82万
  • 项目类别:

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