Novel Mechanisms of Neonatal Hypoxic-Ischemic Brain Injury and Repair

缺氧缺血性脑病(HIE)仍然是重型脑病的主要原因 发生在0.1%-0.2%的足月儿或近月儿的损害，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 残疾人士。到目前为止，还没有有效的临床治疗方法来缓解脑部疾病。 损害和改善这些儿童的大脑功能发育。胰岛素样 生长因子-I(Growth Factor-I，IGF-I)是一种多种营养因子，在肿瘤的发生、发展中起重要作用。 哺乳动物的神经系统。IGF-I减少脑损伤并改善 缺氧缺血大鼠和胎羊的存活。最近，我们发现， 外源性IGF-I在减轻缺氧缺血性脑损伤中的作用 在改善功能行为发育方面，13如果在24小时后给予 恢复。我们假设，在缺氧-缺血的延迟期 康复，IGF-I治疗将通过以下方式促进脑修复：(1)减少延迟 神经元凋亡；(2)刺激神经元和少突胶质细胞的形成和 血运重建。我们将使用互补性检验这一新假设 体外和体内缺氧缺血模型的建立。目标1将描述 IGF-I预防或减少迟发性神经细胞凋亡的机制 在缺氧-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/少突胶质细胞再生。 这项调查的结果将为 建立新生儿缺氧缺血性脑病的有效治疗方法 脑麻木。

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.