The human lung is charged with the dynamic maintenance of oxidative phosphorylation in all of the tissues of the body through the transport of oxygen and carbon dioxide between the blood and the ambient air. Therefore, the “normal” decline in lung function with age imposes a systemic metabolic limit, reflected in the increased contribution of age-related lung diseases to the loss of resiliency and frailty in the aging population that impair the healthspan--reducing independence and shortening the duration of freedom from disability and pain. Interventional strategies to improve the healthspan will require novel approaches targeting malleable systems that improve the resiliency and reduce the frailty of the aging lung in the face of environmental challenges. Dr. Balch and Dr. Morimoto have shown the function of the proteostasis networks decline with age and demonstrated the feasibility of proteostasis based therapies for the treatment of age-related diseases in humans. These findings drive the central hypothesis of this PPG that a loss in the reserve of the lung epithelial proteostasis network is the cause of age-related lung frailty. To address this fundamental question in lung aging, the project investigators have generated three inter-related projects/aims all focused on infection with the influenza A virus, which disproportionately affects older individuals and can be rigorously applied across the entire lifespan to report on the resiliency of the proteostasis networks in the lung in the face of stress. Aim 1. To test the hypothesis that replacement of the developmental alveolar macrophage pool with bone marrow derived alveolar macrophages over the lifespan impairs proteostasis to increase the susceptibility to influenza A infection in aged mice. Aim 2. To test the hypothesis that reducing mitochondrial respiratory chain capacity promotes epithelial proteostasis to attenuate influenza A virus induced lung injury during aging. Aim 3. To test the hypothesis that the enhanced susceptibility of aged mice to influenza A-induced skeletal muscle dysfunction results from an altered balance between proteostasis-disruptive and proteostasis protective signaling from the lung. This PPG is a highly integrated effort that brings together scientists with a broad spectrum of expertise sharply focused on the hypothesis that a declining proteostasis program plays a causal role in the development of lung disease during aging. The investigators will generate a quantitative “proteostasis map” of the aging lung based on novel imaging and proteomic analysis in normal animals and animals with influenza A-induced lung injury. They will use this map to determine the effect of mutations in genes encoding conserved proteostasis/aging pathways implicated from discovery-based approaches using C. elegans to determine the whether the manipulation of these pathways can improve proteostatic function relative to chronologic age to increase lung reserve and reduce lung frailty during aging.
|Effective start/end date||7/1/15 → 5/31/20|
- National Institute on Aging (3P01AG049665-04S2)
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