HIF1a in Neonatal Hypoxic-Ischemic Brain Injury and White-Matter Vulnerability

 描述(申请人提供)：新生儿护理的最新进展大大提高了早产儿和患有窒息或缺氧缺血(HI)脑损伤的婴儿的存活率。然而，高达37%的宫内或新生儿受到侮辱的婴儿仍会发展为长期的神经发育缺陷(《柳叶刀》2012；379：445-52，参考文献74)。因此，改善对新生儿缺氧缺血性脑损伤的脑保护策略仍然是一项重要的任务。缺氧诱导因子-1a(HIF1a)是细胞对缺氧和氧化应激适应的关键调节因子，可改善成人脑缺血和心肌梗死损伤，但其在新生儿窒息和围产期HI中的作用尚不清楚。在这项R21提案中，我们将检验这样一种假设，即鼻腔给药GSK360A，一种有效的PHD抑制剂，产生中枢神经系统特异性的HIF1a稳定，以对抗新生儿HI脑损伤。此外，少突胶质细胞前体细胞(OPC)和早期少突胶质细胞(Pre-OL)HIF1a的表达不足是围产期HI脑损伤中选择性白质易损性的重要因素。我们将在三个特定的目标中验证我们的假设：目的1：在体外检测HIF1a及其可能保护OL的关键效应分子的功能。目的2：测试稳定的HIF1a在新生儿HI脑损伤中的表达效果。目的3：确定PHD抑制剂鼻腔给药对新生儿HI损伤的影响。综上所述，本探索性R21项目使用遗传学和药理学策略来研究HIF1a在新生儿HI脑损伤和优先的WM易损性中的作用。该项目的积极成果将为HIF1a在新生儿中的作用提供新的见解，并建议一种新的新生儿脑保护策略。

 DESCRIPTION (provided by applicant): Recent advances in neonatal care have greatly increased the survival rate of preterm births and infants suffering from asphyxia or hypoxic-ischemic (HI) brain injury. However, as high as 37% infants with intrauterine or neonatal insults still developed long-term neurodevelopmental deficits (Lancet 2012; 379: 445-52, Ref #74). Hence, it remains an important task to improve brain protection strategies against neonatal HI injury. Hypoxia Inducible Factor-1a (HIF1a), a key regulator of cellular adaptation to hypoxia and oxidative stress, ameliorates adult cerebral ischemia and myocardial infarction injury, but its roles in birth asphyxia and perinatal HI remain unclear. In this R21 proposal, we will test the hypothesis that intranasal delivery of GSK360A, a potent PHD inhibitor, produces CNS-specific stabilization of HIF1a to oppose neonatal HI brain injury. Moreover, deficient HIF1a expression by oligodendrocyte progenitors (OPC) and early oligodendrocytes (pre-OL) is an important contributor to selective white-matter vulnerability in perinatal HI brain injury. We will test our hypothesis in three specific aims: Aim 1: Examine the functions of HIF1a and its key effectors that may protect OLs in vitro Aim 2: Test the effects of OPC/pre-OL expression of stable HIF1a in neonatal HI brain injury Aim 3: Determine the effects of intranasal delivery of PHD inhibitors against neonatal HI injury In summary, this exploratory R21 project uses genetic and pharmacological strategies to investigate the roles of HIF1a in neonatal HI brain injury and preferential WM vulnerability. Positive outcomes of this project will shed new insights into the roles of HIF1a in neonates and suggest a novel strategy for brain protection in newborns.