The working hypothesis of this continuing Program Project states that (a) biological characteristics of aging reflect altered homeostatic levels of such stress mediators as cytokines and reactive oxygen species (ROS), rendering aged tissues vulnerable to adverse effects of environmental factors and disease; (b) these intrinsic changes are causative factors for the gradual age-associated decline intissue function and for eventual organ failure; and (c) the structure and function of key trans-acting actors (C/EBPs, NfkappaB/Rel, AP-1) that regulate stress response genes are targets of these mediators and their signal pathways. Our long-range goal if to focuse on how aging affects the activity of trans-acting factors that control expression of stress response genes, and determine whether their regulatory signalling pathways are targets of ROS. The four scientific components of the PP address these aims using various approaches to examine the effects of aging on intrinsic responses to stress, in normal, mutant, and calorically restricted rodent models, and senescing cultured cells. Project 1 (JP) focuses on age-related changes in regulation of the alternative translational initiation of C/EBP mRNAs during the acute phase response to LPS, and under conditions of oxidative stress. Project (BVH) focuses on two major hypotheses: (a) that the catastrophic demise of mitochondrial function is a primary mechanism in aging, and (b) that mitochondrially generated ROS cause mtDNA damage, leading tothe release of more ROS and further mitochondrial decline and age-related pathologies. Project (SM) tests the hypothesis that aged tissues have reduced AP-endonuclease (APE/Ref-1) activity, which plays a central role in repair of oxidative damage to nuclear DNA. Administrative and Molecular Biology Cores will provide administrative, statistical, and molecular biological services and expertise to the four projects. These complement one another both mechanistically and conceptually. Programmatic interactions include: active collaborations, sharing tissues among the various projects to reduce animal costs; and active seminar series; and frequent consultations as to experimental design, methodology, and data analysis. By bringing a range of different approaches to bear on various age-related changes in stress responses in the same and different experimental systems, we will more clearly discern common regulatory themes that effect the decline improper tissue functions with age.
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