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

HIF1a 在新生儿缺氧缺血性脑损伤和白质脆弱性中的作用

• 批准号: 8905538
• 负责人: Chia-Yi Kuan
• 金额: $ 23.4万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8905538
• 关键词: Adult; Adverse effects; Asphyxia; Asphyxia Neonatorum; Attenuated; Behavioral; Biochemical; Birth; Brain; Brain Hypoxia; Brain Injuries; Cells; Cerebral Ischemia; Cessation of life; Data; Development; Dose; Doxycycline; Ectopic Expression; Ensure; Erythropoietin; Genes; Genetic; Glucose; Hypoxia; Hypoxia Inducible Factor; In Vitro; Infant; Injury; Investigational Therapies; Iron; Ischemic Brain Injury; Ischemic-Hypoxic Encephalopathy; Kidney; Lead; Mediating; Mediator of activation protein; Methods; Microglia; Myocardial Infarction; Neonatal; Neurodevelopmental Deficit; Neurologic; Neurons; Newborn Infant; Oligodendroglia; Outcome; Oxidative Stress; Oxygen; Perinatal; Pharmaceutical Preparations; Plasma; Premature Birth; Premature Infant; Procollagen-Proline Dioxygenase; Resistance; Rodent; Role; Safety; Siblings; Side; Small Interfering RNA; Stress; Survival Rate; System; Testing; Therapeutic Index; Transfection; Transgenic Mice; Transgenic Organisms; Up-Regulation; base; cell type; clinical application; deprivation; disability; gain of function; hypoxia inducible factor 1; improved; inhibitor/antagonist; insight; intraperitoneal; loss of function; mutant; neonatal care; neonatal hypoxic-ischemic brain injury; neonate; novel strategies; novel therapeutics; oligodendrocyte lineage; oligodendrocyte precursor; preconditioning; prevent; progenitor; public health relevance; research study; response; white matter; white matter injury

 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.

 描述（由申请人提供）：新生儿护理的最新进展极大地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% 的宫内或新生儿损伤婴儿仍出现长期神经发育缺陷（Lancet 2012；379：445-52，参考文献 #74）。因此，改善新生儿脑损伤的脑保护策略仍然是一项重要任务。缺氧诱导因子-1a (HIF1a) 是细胞适应缺氧和氧化应激的关键调节因子，可改善成人脑缺血和心肌梗死损伤，但其在出生窒息和围产期 HI 中的作用仍不清楚。在这个 R21 提案中，我们将测试这样的假设：鼻内递送 GSK360A（一种有效的 PHD 抑制剂）可以产生 CNS 特异性的 HIF1a 稳定作用，从而对抗新生儿 HI 脑损伤。此外，少突胶质细胞祖细胞 (OPC) 和早期少突胶质细胞 (pre-OL) 的 HIF1a 表达缺陷是围产期 HI 脑损伤中选择性白质脆弱性的一个重要因素。我们将在三个具体目标中检验我们的假设： 目标 1：检查 HIF1a 及其可能在体外保护 OL 的关键效应器的功能 目标 2：测试稳定 HIF1a 的 OPC/pre-OL 表达在新生儿 HI 脑损伤中的作用 目标 3：确定鼻内递送 PHD 抑制剂对新生儿 HI 损伤的影响 总之，这个探索性 R21 项目使用遗传和药理学策略来研究 HIF1a 在新生儿 HI 脑损伤和优先 WM 易感性中的作用。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，并提出一种新生儿大脑保护的新策略。