The long-term health of pulmonary tissue is inextricably linked to the sustainability of the protein fold and its function that is tightly coupled to the energetic health of the cell. This is achieved by the emerging paradigm of protein homeostasis or proteostasis, a collection of integrated ATP-dependent biological pathways that generate and maintain the proteome. Proteostasis balances protein biosynthesis, folding, translocation, protein complex assembly and/or disassembly and clearance with the challenges imposed by endogenous and exogenous folding stress in response to the local physical environment and aging. We suggest that changes in the proteostasis network (PN) in response to normal aging and environmental insults that accrue with age challenge the folding health of the aging lung. In Core B, we propose to quantitatively measure proteostasis in the lung epithelium to understand `resilience', the physiology that reflects the resistance of younger lungs to environmental challenges, `reserve', the inducible buffering capacity of the lung that protects against daily/chronic challenges, and `frailty'- the physiologic changes that underlie the enhanced susceptibility to loss of healthspan, all of which contribute to the clinical/financial burden of aging for the individual and the healthcare system.
In Specific Aim 1, Core B will establish a rigorous understanding of the response of the proteome and proteostasis environment to normal aging and in response to the influenza A infection in young and old mice. This will provide a baseline to address the normal aging and viral perturbed folding/aging health questions outlined in Projects 1-3. Core B will achieve an understanding of the changing proteostatic health program during aging by systematic application of mass spectrometry (MS) to quantitatively characterized the proteostasis environment of the lung throughout the normal and challenged lifespan of the mouse through application of label-free Multidimensional Protein Identification Technology (MudPIT), tandem mass tagging (TMT) MS and Signal Ion Reaction (SRM) technologies. The studies in Aim 1 will be integrated with the use of newly developed biosensor imaging technologies in Aim 2 that measure the global state of protein folding health in the alveolar epithelium and muscle in a systematic and quantitative fashion. Biosensors allow us to follow in real-time the state of folding health throughout a mouse lifespan using the quantum recording capabilities of the Caliper CIVIS-K. The imaging technology is based on new and emerging proteostasis principles that are expected to strongly impact our understanding of the normal healthspan of the alveolar epithelial environment and muscle and their response to stress challenges such as influenza A. Whereas Aim 1 rigorously quantifies the granular features of the proteostasis program during aging, Aim 2 images live how the proteostasis program functions as an integrated unit to protect the lung in youth, activities we proposed are compromised during aging. Core B will contribute to the efforts of each of the Projects 1-3 by performing analyses that integrate mechanistic Project Aims designed to address proteostatic frailty during aging.
It is not required per instructions stated on the Funding Opportunity Announcement PAR-13-258, Section IV. Application and Submission Information, Optional Cores, Research & Related Other Project Information (Optional Cores), ?Project Narrative: Do not complete?.
Showing the most recent 10 out of 58 publications
