Compared with younger individuals, older people exposed to the same environmental or genetic stressors are more likely to develop lung disease that reduces lifespan and healthspan. Understanding the cause of this frailty of the aging lung is one of the most important challenges for clinical medicine. Preliminary proteomic data from Dr. Balch (Core B) confirm work from C.elegans suggesting the function of the proteostasis network in the lung declines with age. Tissue-resident alveolar macrophages are a self-renewing population of cells that develop outside the bone marrow and are present in nearly every alveolus of the healthy lung where they reciprocally interact with cells in the alveolar epithelium via a network of cell surface receptors and chemokine/cytokines to finely tune the immune response to environmental pathogens and particulates in the lung. In response to injury or proteostatic stress, monocytes are recruited from the bone marrow to the lung where they assist in an orchestrated pro-inflammatory response. We have found that these bone marrow- derived alveolar macrophages persist in the lung after the resolution of injury where they appear similar to the tissue-resident alveolar macrophages but exhibit a much more exuberant inflammatory response in response to influenza A infection. These data support our hypothesis that the loss of tissue-resident alveolar macrophages and their replacement by bone marrow-derived alveolar macrophages in response to proteostatic stress over the lifespan contributes to the age related loss of proteostatic reserve in the alveolar epithelium and the associated enhanced susceptibility to influenza A pneumonia.
Aim 1. To determine whether replacement of tissue-resident alveolar macrophages by bone marrow- derived alveolar macrophages during aging contributes to the enhanced susceptibility to influenza A pneumonia in aged mice.
Aim 2. To determine whether tissue-resident alveolar macrophages or bone marrow-derived alveolar macrophages differentially respond to or modulate epithelial proteostasis in response to influenza A infection.
Aim 3. To determine whether the preventing differentiation of bone marrow-derived alveolar macrophages attenuates influenza A-induced changes in proteostasis and lung injury during aging. In concert with Dr. Balch (Core B) and the other project investigators, our experiments will provide an unprecedented window into the role played by the alveolar macrophage in responding to and preventing the age related decline in the function of the proteostasis networks in the lung epithelium. We will generate unbiased gene expression and proteomic data to identify therapeutically targetable regulatory hubs activated by tissue-resident macrophages to maintain proteostasis in the epithelium.
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?.
| 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 |
| Mandelin 2nd, Arthur M; Homan, Philip J; Shaffer, Alexander M et al. (2018) Transcriptional Profiling of Synovial Macrophages Using Minimally Invasive Ultrasound-Guided Synovial Biopsies in Rheumatoid Arthritis. Arthritis Rheumatol 70:841-854 |
| Chandel, Navdeep S (2018) Mitochondria: back to the future. Nat Rev Mol Cell Biol 19:76 |
Showing the most recent 10 out of 58 publications
