Bob Clark, MD & Hülya Bayır, MD receive Grant to Find Druggable Mitochondrial Targets after Pediatric Brain Injury

Principal investigators Bob Clark, MD and Hülya Bayır, MD have received funding for a five-year, $2.9 million, R01 award from the National Institute of Neurological Disorders and Stroke entitled “Druggable Mitochondrial Targets for Treatment of Cerebral Ischemia.” Their goal is to synthesize, test and develop novel mitochondria-targeting therapeutics, toward meaningfully improving neurological outcome and quality of life in infants and children suffering from cerebral hypoxia-ischemia.

“Quality survival after brain injury is the greatest challenge for critically ill or injured infants and children due to the devastating impact of hypoxic-ischemia,” said Bob Clark, who is a professor of Critical Care Medicine and Pediatrics and the vice chair for Pediatric Critical Care in the Department of Critical Care Medicine. “This research is a paradigm-shifting approach to improving neurological outcome for these youngsters.”

Specifically, first-in-class, proprietary mitochondria-targeting poly(ADP-ribose) polymerase (PARP) inhibitors--conceptualized by Drs. Clark and Bayır and synthesized by Peter Wipf, PhD in Pitt’s Department of Chemistry—will be tested in experimental models of pediatric cardiac arrest in the Safar Center for Resuscitation Research.

The graphic (below) shows proposed therapeutic advantages of using mitochondria-targeting vs. non-targeting PARP inhibitors and is modified from Krainz et al., Synthesis and Evaluation of a Mitochondria-Targeting Poly(ADP-ribose) Polymerase-1 Inhibitor, published in ACS Chemical Biology 2018;13:2868-2879.

Hülya Bayır is professor of Critical Care Medicine, and Environmental and Occupational Health, and is director of the Children's Neuroscience Institute. The research project is a multi-school, multi-departmental effort that also includes Pat Kochanek, MD (director, Safar Center; professor, Critical Care Medicine, Anesthesiology, and Pediatrics), Ivet Bahar, PhD (chair, Department of Computational and Systems Biology), Claudette St. Croix, PhD (associate professor, Department of Cell Biology), Mio Manole, MD (associate professor, Department of Pediatrics) and Valerian Kagan, PhD (professor, Environmental and Occupational Health, Graduate School of Public Health).