This Program Project consists of three research projects and an Administrative Core. Our working hypothesis proposes that (a) aging tissues exhibit an increase in mitochondrially generated ROS causing (b) a locked-in cycle of ROS production that amplifies oxidative stress and (c) stabilizes the homeostatic changes in regulators of the stress caused by the ROS (d) that result in a state of chronic stress and progressive decline in tissue function. Our PP is focused on the consequences of these ROS-mediated changes. P1 (JP) investigates the function of p38 MAPK, its targeted transcription factors and mitochondriai factors in the aged liver and in response to signals due to ROS generation by 3-NPA, rotenone, and antimycin A, inhibitors of mitochondrial complexes I, II and III. P1. A subcontractor, WRW will identify the site of ROS generated by 3-NPA and interact mechanistically with all 3 projects. P2 (SM) investigates how aging affects the role of APE1 in nuclear and mtDNA repair; the role of the negative Ca++ response element (nCaRE) in regulation of expression of Ca++ - responsive genes, how changing the nuclear and APE levels in transgenic mice affects the cellular response to ROS; whether the age-dependent modulation of stressinduced APE1 modification affects the shear and oxidative stress responses in aged cells. P3 (IB) investigates the regulation of mtDNA repair by 8 oxo-guanine DNA glycosylase (OGG1), and whether the age-associated decline in mitochondrial function is caused by impaired/inefficient DNA repair due to changes in expression/activity, posttranslational modification and/or compartmentalization of OGGI. All three projects contribute to our shared PP aims, to understand the effects of ROS generated by mitochondrial dysfunction and how protein modifications may affect changes in stress responses and the activity of their genes investigated in each project. The Administrative Core A will assist the PI in administrative tasks and coordinate animal use. Programmatic interactions include: active collaborations, sharing tissues to reduce animal costs; an 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 response in the same and different experimental systems, we will more clearly discern common regulatory themes that affect the decline in proper tissue functions with age.
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