OPTIMIZING NEUROPROTECTION FOLLOWING NEONATAL HYPOXIC-ISCHEMIC BRAIN INJURY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 围产期窒息占全球新生儿死亡的23%。高达60%的幸存者患有终身神经发育障碍，包括智力低下、脑瘫、癫痫发作和学习障碍。目前有效的治疗策略有限：低温已被证明可减少脑损伤，但仅适用于轻度和中度窒息；重组促红细胞生成素(REPO)可在动物模型中改善脑损伤后的短期和长期神经学结果，但尚未在人类婴儿身上进行测试。任何一种治疗方法都不能提供完全的保护。我们的目标是开发一种安全有效的围产期窒息治疗方法，减少随后的神经损伤，从而帮助受影响的儿童充分发挥潜力，过上健康和富有成效的生活。我们假设，回购和低温都将减少围产期窒息对近期短尾猴(Macaca Nomestrina)的神经发育和结构影响，回购和低温联合治疗将提供更大的好处。我们将利用围产期窒息的非人类灵长类动物模型来测试以下特定目标：目的1)确定在减少围产期窒息的神经发育后遗症方面，哪种治疗策略最有效：单次回购、单独低温，还是回购加低温(与载体对照组相比)；目的2)确定哪种治疗策略在减少围产期窒息对近期新月形吸虫脑的结构性后果方面最有效：单用回购、单独低温或回购+低温(与载体对照组相比)；目的3)探讨大剂量回购、低温及回购加低温治疗围产期窒息新月形吸虫的安全性。这项工作将产生重要的数据，直接应用于围产期窒息，并可能对婴儿和儿童脑损伤的其他机制进行研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Perinatal asphyxia accounts for 23% of neonatal deaths globally. Up to 60% of survivors are left with life-long neurodevelopmental handicaps that include mental retardation, cerebral palsy, seizures and learning disabilities. Effective treatment strategies are currently limited: Hypothermia has been shown to decrease brain injury, but only for mild and moderate asphyxia; recombinant erythropoietin (rEpo) improves both short and long term neurologic outcome following brain injury in animal models, but has not been tested in human infants. Neither treatment provides complete protection. Our goal is to develop a safe and effective treatment for perinatal asphyxia that will decrease the subsequent neurologic injury, thereby helping affected children achieve their full potential and lead healthy and productive lives. We hypothesize that both rEpo and hypothermia will decrease the neurodevelopmental and structural consequences of perinatal asphyxia in near-term pigtailed macaques (Macaca nemestrina), and that combined therapy with rEpo and hypothermia will provide even greater benefit. We will utilize a non-human primate model of perinatal asphyxia to test the following specific aims: Aim 1) To determine which therapeutic strategy is most effective in decreasing the neurodevelopmental sequelae of perinatal asphyxia in near-term M. nemestrina: rEpo alone, hypothermia alone, or rEpo plus hypothermia (vs. vehicle controls); Aim 2) To determine which therapeutic strategy is most effective in decreasing the structural consequences of perinatal asphyxia in brains of near-term M. nemestrina: rEpo alone, hypothermia alone, or rEpo plus hypothermia (vs. vehicle controls); Aim 3) To establish the safety of high dose rEpo treatment, hypothermia, and rEpo plus hypothermia in near-term M. nemestrina exposed to perinatal asphyxia. This work will produce important data with direct clinical application to perinatal asphyxia, and possibly to other mechanisms of brain injury in infants and children.