Targeting metabolism to improve outcomes following severe influenza infection

以代谢为靶点改善严重流感感染后的预后 布莱迪·哈克斯坦 顾问：约翰·奥尔科恩博士 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一个标志。我们的实验室和其他实验室有 显示感染流感的小鼠有持续性的肺损伤、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 用新陈代谢靶向药物治疗小鼠将通过以下方式改善流感感染后的肺修复 消炎、促进肺泡再生。流感感染后上皮化生 降低肺功能，由未分化的阴性上皮祖细胞(LNEP)引起。 初步数据表明，LNEP增加了哺乳动物靶标能量感应激酶的激活 雷帕霉素复合体1(MTORC1)在流感感染后21天。对其他干细胞群体的研究 表明mTORC1的激活可以抑制向成熟细胞类型的分化，但它在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 感染会促进LNN分化为AT II细胞，并减少上皮化生的出现。 此外，初步数据显示，流感后21天，肺部出现氧化应激。 感染。独创性通路分析表明，小鼠肺内巨噬细胞ROS产生增加 此时，高分辨率的呼吸测量数据表明氧化磷酸化增强。我提议 用AMPK激活剂二甲双胍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期肺部的细胞修复机制。目标是 该项目的目的是确定新陈代谢靶向药物是否可以被重新用于治疗 在他们的呼吸道病毒感染被清除后，他们继续遭受痛苦。

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.