DNA damage and repair are critical components to ischemic injury and recovery. DNA base excision repair (BER) is the primary pathway activated in the brain to repair oxidative lesions that predominate following cerebral ischemic injury. BER proceeds via the sequential coordination of repair enzymes, but most notably centers on the activity of AP endonuclease-1 (APE1). APE1 not only functions to remove the prominent AP sites that occur in oxidatively damaged DNA but also coordinates and stimulates the activity of other BER proteins. Ongoing studies are implicating a role of BER DNA repair in ischemic recovery, but these have focused primarily on neurons. White matter injury is a major cause of long-term sensorimotor and cognitive deficits following stroke. The recovery of white matter following ischemic injury necessitates either the survival of existing oligodendrocytes or repair of demyelinated axons via axonal regrowth and oligodendrogenesis to fully rebuild neuronal connectivity and functional axonal signal conduction. Therapeutic strategies to promote white matter recovery following ischemic injury may lead to improved long-term recovery in stroke patients. We have exciting preliminary data to demonstrate that DNA damage readily occurs in ischemic white matter, and that APE1 is critical to functional recovery of white matter following stroke. Furthermore, we have discovered that PKC? negatively regulates the repair activity of APE1, giving us a powerful new target for therapeutic intervention aimed at bolstering BER following ischemic injury. These data support the novel hypothesis that bolstering DNA repair, and APE1 in particular, by PKC? inhibition is critical for white matter survival and functional recovery following focal cerebral ischemic injury. Using our novel conditional APE1 knockout mouse, transgenic rats overexpressing APE1 and APE1 point mutations, and neuronal/oligodendrocytic co-cultures, this project will 1) examine the role of APE1 and DNA repair in oligodendrocytic death and white matter integrity following ischemic injury, and 2) determine the extent of ischemic protection afforded by inhibiting the phosphorylation of APE1 by PKC?. This project will significantly advance the understanding of the pathogenesis of white matter damage following cerebral ischemic injury, and explore a translatable approach to improving DNA repair activity via administration of a cell-permeable PCK? inhibitor.
Recent research has found that base excision repair (BER) is critical to the recovery of neural tissue following cerebral ischemic injury, and that APE1 is a pivotal enzyme in this process. This proposal will test the hypothesis that manipulation of APE1 activity improves long-term neurological outcomes after cerebral ischemia by promoting the white matter recovery. The successful completion of this project will contribute a novel framework for restorative therapeutics focused on DNA repair in ischemic white matter injury.
| Li, Peiying; Stetler, R Anne; Leak, Rehana K et al. (2018) Oxidative stress and DNA damage after cerebral ischemia: Potential therapeutic targets to repair the genome and improve stroke recovery. Neuropharmacology 134:208-217 |
