Brain damage of the ischemia/reperfusion type resulting from cardiac arrest and stroke is a major cause of mortality and disability in the United States, attacking one person every minute, and creating more than 500,000 victims every year. Cerebral ischemia causes oxidative damage to lipids, proteins and nucleic acids, reduces energy source with consequent functional deterioration leading to cell death. Restoration processes normally repair genes with few errors. However, ischemia causes elevated oxidative DNA lesions (ODLs) despite these repair mechanisms. These episodes occur concurrently with Fos expression and critical activation of other late genes in the signal transduction pathway. To date, the effect of ODLs on gene function of the brain is not totally understood. We will investigate whether gene damage could affect the function of the c-fos gene using a forebrain ischemia (30-90 min)/reperfusion (FblR) model in male C57black/6 mice. This model induces neuronal death in the hippocampus, similar to that observed after cardiac arrest and in some neurological disorders. Our hypothesis is that repair of genes in the signal transduction benefits neuronal recovery after oxidative stress.
The specific aims are to: 1. Establish whether Fos activity induces gene repair function after FblR, we will determine (a) Fos protein, repair activity and neuronal death in the hippocampus using 3-bromo-7nitroindazole that inhibits brain nitric oxide but enhances the expression of c-fos mRNA after FblR. (b) Correlation in Fos activity, repair activity and neuronal death in the hippocampus using antisense technology that specifically abolishes the expression of Fos after FblR. 2. Establish whether repair of gene damage protects the hippocampus, we will determine (c) ODLs and ORLs (base modifications) in the c-fos transcript after FblR. (d) Correlation between repair activity, Fos activity and the expression of late effector genes after FblR. We have shown the feasibility of the studies by developing an array of technology to detect Fos expression and DNA repair processes in the brain. We have developed effective means to deliver antisense cDNA that abolishes Fos activity to the brain. Several end-points (FblR-induced Fos/AP-1 activity, nerve growth factor mRNA, gene repair activity and neuronal death) will be measured. Future directions include detections of additional gene activators in animals treated with FblR, and application of additional antisense cDNA to these gene activators to elucidate their roles in repair process of the brain.
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