Epidermal Growth Factor Receptor Inhibition Reverses Cellular and Transcriptomic Alterations Induced by Hypoxia in the Neonatal Piglet Brain
Panagiotis Kratimenos,
Evan Z. Goldstein,
Ioannis Koutroulis,
Susan Knoblach,
Beata Jablonska,
Payal Banerjee,
Shadi N. Malaeb,
Surajit Bhattacharya,
M. Isabel Almira-Suarez,
Vittorio Gallo,
Maria Delivoria-Papadopoulos
Affiliations
Panagiotis Kratimenos
Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, George Washington University School of Medicine and Health Sciences, 111 Michigan Avenue, NW, Washington, DC 20010 P 202-476-5922, USA; Department of Pediatrics, Division of Neonatology, Children's National Hospital and George Washington University School of Medicine and Health Sciences, 111 Michigan Avenue, NW, Washington, DC 20010 P 202-602-4889, USA; Corresponding author
Evan Z. Goldstein
Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, George Washington University School of Medicine and Health Sciences, 111 Michigan Avenue, NW, Washington, DC 20010 P 202-476-5922, USA
Ioannis Koutroulis
Department of Pediatrics, Division of Emergency Medicine, Children's National Hospital and George Washington University School of Medicine and Health Sciences, Washington, DC, USA; Research Center for Genetic Medicine, Children's National Research Institute, Washington, DC, USA; Department of Genomics and Precision Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
Susan Knoblach
Research Center for Genetic Medicine, Children's National Research Institute, Washington, DC, USA; Department of Genomics and Precision Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
Beata Jablonska
Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, George Washington University School of Medicine and Health Sciences, 111 Michigan Avenue, NW, Washington, DC 20010 P 202-476-5922, USA
Payal Banerjee
Research Center for Genetic Medicine, Children's National Research Institute, Washington, DC, USA
Shadi N. Malaeb
Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA, USA
Surajit Bhattacharya
Research Center for Genetic Medicine, Children's National Research Institute, Washington, DC, USA
M. Isabel Almira-Suarez
Department of Pathology, Children's National Hospital and George Washington University School of Medicine and Health Sciences, Washington, DC, USA
Vittorio Gallo
Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, George Washington University School of Medicine and Health Sciences, 111 Michigan Avenue, NW, Washington, DC 20010 P 202-476-5922, USA; Corresponding author
Maria Delivoria-Papadopoulos
Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA, USA
Summary: Acute hypoxia (HX) causes extensive cellular damage in the developing human cerebral cortex. We found increased expression of activated-EGFR in affected cortical areas of neonates with HX and investigated its functional role in the piglet, which displays a highly evolved, gyrencephalic brain, with a human-like maturation pattern. In the piglet, HX-induced activation of EGFR and Ca2+/calmodulin kinase IV (CaMKIV) caused cell death and pathological alterations in neurons and glia. EGFR blockade inhibited CaMKIV activation, attenuated neuronal loss, increased oligodendrocyte proliferation, and reversed HX-induced astrogliosis. We performed for the first time high-throughput transcriptomic analysis of the piglet cortex to define molecular responses to HX and to uncover genes specifically involved in EGFR signaling in piglet and human brain injury. Our results indicate that specific molecular responses modulated by EGFR may be targeted as a therapeutic strategy for HX injury in the neonatal brain.
