Oxidative damage caused by the release of cytokines is thought to play a major role in this cellular response to injury. Mitochondrial DNA (mtDNA) is one of the critical targets of this damage. Therefore, this competitive renewal will remain focused on the mechanisms by which cells of the central nervous system, particularly oligodendrocytes, deal with such genotoxic insults. Our overall working hypothesis is that acceptable lesion equilibrium is maintained within the mtDNA of cells through a combination of reactions that result in a balance between mtDNA damage and mtDNA repair. If this lesion equilibrium is shifted such that the damage exceeds the repair capacity, fewer functioning mitochondrial genomes will be available for transcription and cellular bioenergetics will decrease. The cell will then either adapt to accommodate to this change in lesion equilibrium or, if the damage becomes excessive, mitochondrial function will cease and the cell will undergo death by either necrosis or apoptosis. During the previous funding period, we have shown that enhanced mtDNA repair can protect oligodendrocytes from damage generated by cytokines. Consequently, we hypothesize that enhanced mtDNA repair will ameliorate the development and progression of radiation-induced brain injury. This hypothesis will be tested through the pursuit of the following two specific aims. In aim one;we will develop a therapeutic approach for protecting glial cells from oxidative stress by targeting DNA repair enzymes to the mitochondria. These studies will use primary cultures of oligodendrocytes to optimize the delivery to mitochondria of recombinant mtDNA repair enzymes in order to enhance mtDNA repair and provide protection from genotoxic insults. In aim two, we will test the therapeutic efficacy of enhanced mtDNA repair in a clinically relevant model of radiation-induced cognitive impairment. These studies will use an animal model to help determine whether the strategies developed in the first aim can be used therapeutically for protection of the CNS from oxidative insults. When successfully completed, these studies will provide novel information which will form the groundwork for developing a new strategy for preventing the debilitating dementia that results from radiation therapy for brain tumors.