Kratimenos Panagiotis, Goldstein Evan Z, Koutroulis Ioannis, Knoblach Susan, Jablonska Beata, Banerjee Payal, Malaeb Shadi N, Bhattacharya Surajit, Almira-Suarez M Isabel, Gallo Vittorio, Delivoria-Papadopoulos Maria
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.
iScience. 2020 Nov 4;23(12):101766. doi: 10.1016/j.isci.2020.101766. eCollection 2020 Dec 18.
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 Ca/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.
急性缺氧（HX）会对发育中的人类大脑皮层造成广泛的细胞损伤。我们发现HX新生儿受影响的皮质区域中活化型表皮生长因子受体（EGFR）的表达增加，并在仔猪中研究了其功能作用。仔猪具有高度进化的脑回脑，其成熟模式与人类相似。在仔猪中，HX诱导的EGFR和钙/钙调蛋白激酶IV（CaMKIV）激活导致神经元和神经胶质细胞死亡及病理改变。EGFR阻断可抑制CaMKIV激活，减轻神经元损失，增加少突胶质细胞增殖，并逆转HX诱导的星形胶质细胞增生。我们首次对仔猪皮层进行了高通量转录组分析，以确定对HX的分子反应，并揭示仔猪和人类脑损伤中EGFR信号通路特有的相关基因。我们的结果表明，由EGFR调节的特定分子反应可能作为新生儿脑HX损伤的治疗策略靶点。
