Individuals aged 65 years or older account for 80-90% of deaths from influenza A virus each year. In our preliminary data, we show that infection with the influenza virus is associated with a marked decline in the function of the proteostatic networks in the lung epithelium and that aged mice suffer increased mortality following infection with the influenza A virus. The overarching goal of this project is to systematically test the hypothesis that lung epithelial mitochondrial metabolic changes, proteostasis, aging and the susceptibility to influenza A infection are causally linked. Mitochondrial metabolism has been noted to decrease during the natural aging process. Our preliminary data shows young mice harboring decrease in mitochondrial respiratory capacity are less susceptible to and recover faster from influenza A virus-induced lung injury. Based on these data, we suggest that the reduced mitochondrial capacity during aging is an adaptive response to a decline in the function of the proteostasis network in the aging lung. We hypothesize that this decline in mitochondrial capacity triggers the mitochondrial unfolded response and increase in mitochondrial ROS production to diminish influenza A virus induced lung injury. A consequence of influenza A virus is hypoxemia, an important cause of morbidity and mortality in mice and humans. We have previously shown that mitochondrial ROS trigger hypoxic adaptation through the activation of HIFs. In our preliminary data using C. elegans, we found that mitochondrial ROS to activate mtUPR even in the absence of HIFs, suggesting a new and exciting molecular pathway for hypoxic adaptation. These led us to propose the following three aims: (1) To determine whether diminishing mitochondrial DNA encoded proteins (respiratory capacity) in the lung epithelium promotes proteostasis to attenuate lung injury during aging; (2) To determine whether low levels of mitochondrial dependent ROS promotes proteostasis to attenuate lung injury during aging; (3) To determine the molecular pathways by which hypoxia induces the mitochondrial unfolded protein response in C. elegans and mice.
It is not required per instructions stated on the Funding Opportunity Announcement PAR-13-258, Section IV. Application and Submission Information, Project, Research & Related Other Project Information (Project), ?Project Narrative: Do not complete?.
| Sala, Marc A; Balderas-Martínez, Yalbi Itzel; Buendía-Roldan, Ivette et al. (2018) Inflammatory pathways are upregulated in the nasal epithelium in patients with idiopathic pulmonary fibrosis. Respir Res 19:233 |
| Dela Cruz, Charles S; Wunderink, Richard G; Christiani, David C et al. (2018) Future Research Directions in Pneumonia. NHLBI Working Group Report. Am J Respir Crit Care Med 198:256-263 |
| Galluzzi, Lorenzo; Vitale, Ilio; Aaronson, Stuart A et al. (2018) Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ 25:486-541 |
| Soberanes, Saul; Misharin, Alexander V; Jairaman, Amit et al. (2018) Metformin Targets Mitochondrial Electron Transport to Reduce Air-Pollution-Induced Thrombosis. Cell Metab : |
| Wang, Chao; Balch, William E (2018) Bridging Genomics to Phenomics at Atomic Resolution through Variation Spatial Profiling. Cell Rep 24:2013-2028.e6 |
| Kong, Hyewon; Chandel, Navdeep S (2018) Regulation of redox balance in cancer and T cells. J Biol Chem 293:7499-7507 |
| Hutt, Darren M; Mishra, Sanjay Kumar; Roth, Daniela Martino et al. (2018) Silencing of the Hsp70-specific nucleotide-exchange factor BAG3 corrects the F508del-CFTR variant by restoring autophagy. J Biol Chem 293:13682-13695 |
| Hsiao, Hsi-Min; Fernandez, Ramiro; Tanaka, Satona et al. (2018) Spleen-derived classical monocytes mediate lung ischemia-reperfusion injury through IL-1?. J Clin Invest 128:2833-2847 |
| McQuattie-Pimentel, Alexandra C; Budinger, G R Scott; Ballinger, Megan N (2018) Monocyte-derived Alveolar Macrophages: The Dark Side of Lung Repair? Am J Respir Cell Mol Biol 58:5-6 |
| Hutt, Darren M; Loguercio, Salvatore; Campos, Alexandre Rosa et al. (2018) A Proteomic Variant Approach (ProVarA) for Personalized Medicine of Inherited and Somatic Disease. J Mol Biol 430:2951-2973 |
Showing the most recent 10 out of 58 publications
