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?.
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