# DNA repair promotes stroke recovery

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $343,488

## Abstract

Project Summary
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 PKCζ 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 PKCζ 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 PKCζ. 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 PCKζ inhibitor.

## Key facts

- **NIH application ID:** 9896860
- **Project number:** 5R01NS100803-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Ruth ANNE Stetler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $343,488
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896860

## Citation

> US National Institutes of Health, RePORTER application 9896860, DNA repair promotes stroke recovery (5R01NS100803-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9896860. Licensed CC0.

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