Novel Mechanisms of Neonatal Hypoxic-Ischemic Brain Injury and Repair

缺氧缺血性脑病（hypoxia-ischemia encephalopathy，HIE）是导致重症颅脑损伤的主要原因 0.1 - 0.2%的足月或近足月婴儿发生的损伤，其中 大约20%的人死亡，多达40%的幸存者经常遭受毁灭性的痛苦， 残疾。迄今为止，没有有效的临床治疗可用于减轻脑损伤。 损害和促进这些孩子的大脑功能发育。胰岛素样 生长因子I（IGF-I）是一种对发育至关重要的多营养因子， 哺乳动物的神经系统IGF-I减少了脑损伤， 缺氧缺血大鼠和胎羊的存活率。最近，我们发现， 外源性IGF-I能更有效地减轻缺氧缺血性脑损伤 在改善功能性行为发育方面，如果在24小时后给予， 复苏我们推测，在缺氧缺血的延迟阶段， 恢复，IGF-I治疗将促进脑修复（1）减少延迟 神经元凋亡;和（2）刺激神经元和少突神经元发生， 血运重建我们将使用互补的方法来检验这个新的假设。 缺氧缺血的体外和体内模型。目标1将描述 IGF-I预防或减少迟发性神经元凋亡的机制 缺氧缺血后。目标2将研究IGF-I是否以及如何刺激 新生儿缺氧缺血后的血管重建和神经/少突神经发生。 调查结果将提供重要信息， 为新生儿缺氧缺血性疾病建立有效的治疗方法 脑病

Hypoxia-ischemia encephalopathy (HIE) remains a leading cause of severe brain damage that occurs in 0.1-0.2% of term or near-term infants, among whom approximately 20% die and up to 40% of the survivors often suffer devastating disabilities. To date, no effective clinical treatment is available to mitigate brain damage and improve the brain functional development of these children. Insulinlike growth factor I (IGF-I) is a pleiotrophic factor essential for the development of the mammalian nervous system. IGF-I reduced brain damage and improved the survival of hypoxic-ischemic rats and fetal sheep. Recently, we found that exogenous IGF-I was more effective in reducing hypoxic-ischemic brain injury and in improving functional behavior development,13 if given after 24 hours of recovery. We hypothesize that, in the delayed phase of hypoxia-ischemia recovery, IGF-I treatment will promote brain repair by (1) reducing delayed neuronal apoptosis; and (2) stimulating neuro- and oligodendrogenesis and revascularization. We will examine this novel hypothesis using complementary in vitro and in vivo models of hypoxia-ischemia. Aim 1 will characterize the mechanisms by which IGF-I prevents or reduces delayed neuronal apoptosis following hypoxia-ischemia. Aim 2 will investigate if and how IGF-I stimulates revascularization and neuro-/oligodendrogenesis following neonatal hypoxiaischemia. Results of this investigation will provide crucial information towards establishing an effective therapy for newborn patients suffering from hypoxicischemic encepholapathy.