Bioenergetic Failure Underlies Cerebral Dysmaturity After Perinatal Brain Injury

生物能衰竭是围产期脑损伤后脑功能障碍的基础

基本信息

批准号：
9382739
负责人：
Joseph Scafidi
金额：
$ 39.4万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9382739
关键词：
Ablation Acute Address Affect Aftercare Animal Model Behavior Behavioral Biochemical Biochemical Markers Bioenergetics Brain Brain Injuries Cell Differentiation process Cell Maturation Cell Respiration Cells Cerebrum Child Chronic Cognition Data Dependence Development Energy Metabolism Energy-Generating Resources Epidermal Growth Factor Epidermal Growth Factor Receptor Excision Failure Glial Fibrillary Acidic Protein Glucose Growth Growth Factor HIF1A gene Heparin Binding Hippocampus (Brain)Hypoxia Impaired cognition Impairment Infant Injury Knowledge Learning Learning Disabilities Life Measures Mediator of activation protein Memory impairment Metabolic Mitochondria Mitochondrial Proteins Mus N-acetylaspartate Neonatal Brain Injury Neuroglia Nuclear Magnetic Resonance Outcome Oxidative Stress PDH kinase Perinatal Brain Injury Perinatal Hypoxia Predisposition Premature Birth Premature Infant Preterm brain injury Process Production Proteins Public Health Publishing Radial Recovery Recovery of Function Research Rodent Model Stem cells Stress Structure Testing Time Treatment Factor Undifferentiated Work base cell type critical period gray matter improved inhibitor/antagonist lung injury mitochondrial dysfunction mitochondrial metabolism nerve stem cell neurobehavioral neuromechanism novel premature prevent pyruvate dehydrogenase relating to nervous system restoration stem white matter

项目摘要

PROJECT SUMMARY ABSTRACT Long-term cognitive impairment and learning disabilities are a major public health concern that affects more than half of infants born very preterm with immature lung injury. Such infants have a global delay in cerebral maturation of gray and white matter structures, likely caused by high susceptibility to hypoxia-induced oxidative stress during this critical period. This stress can result in mitochondrial dysfunction. If mitochondrial-dependent oxidative metabolism is required for immature progenitor cells to mature, then mitochondrial dysfunction can result in failure of timely progenitor cell maturation. Little is known about the metabolic alterations or the dependence of neural progenitor cell maturation on mitochondrial metabolism in the developing brain. Our work will fill this gap in knowledge. We use a rodent model of chronic hypoxia to recapitulate the immature lung injury commonly found in very preterm infants, which causes global gray and white matter cellular dysmaturity and associated ultrastructural and behavioral deficits. In this study, we will investigate the metabolic effects of hypoxia on hippocampal dysmaturation and determine the developmental outcome of mitochondrial disruption. Our preliminary data on the hippocampus indicate that: i) hypoxia causes long-term decreases in biochemical markers of mitochondrial function; ii) hypoxia impairs expression of pyruvate dehydrogenase E1α independent of its inhibitors; and iii) conditional removal of pyruvate dehydrogenase E1α from GFAP-expressing radial glia stem cells prevents their maturation. A potential target for promoting recovery after perinatal brain injury is timely restoration of mitochondrial function and oxidative metabolism. Our published and preliminary data strongly suggest the novel findings that intranasal heparin-binding epidermal growth factor [HB-EGF] treatment after hypoxia may reverse hypoxia-induced cellular dysmaturation, restore mitochondrially produced N-acetyl aspartate, and ameliorate neurobehavioral deficits by targeting the mitochondria. We hypothesize that mitochondrial dysfunction results in delayed development of hippocampal neural progenitor cell capacity to perform oxidative energy metabolism, thus preventing their maturation. We will test the hypothesis that restoring mitochondrial function will enable these cells to meet their bioenergetic demands, permitting timely cellular maturation and recovery of function in the hippocampus. These hypotheses will be tested in three specific aims. In Aim 1, we will determine whether hypoxia impairs mitochondrial function in the hippocampus. In Aim 2, we will determine whether hypoxia or cell-specific removal of pyruvate dehydrogenase E1α in hippocampal neural progenitor cells delays differentiation and hippocampal behavioral deficits. In Aim 3, we will determine whether intranasal HB-EGF treatment after hypoxia enhances mitochondrial function. Successful completion of these aims will elucidate a fundamental biochemical mechanism that determines differentiation failure of neural progenitor cells after hypoxia-induced injury and define a novel metabolic mechanism by which HB-EGF facilitates cellular and functional recovery after neonatal brain injury.

项目摘要摘要长期的认知障碍和学习障碍是一个主要的公共卫生问题，会影响更多一半的婴儿出生于未成熟的肺部受伤。这些婴儿的脑延迟灰色和白质结构的成熟，可能是由于对缺氧诱导的氧化性高敏感性引起的在这个关键时期的压力。这种应力会导致线粒体功能障碍。如果线粒体依赖性未成熟的祖细胞成熟需要氧化代谢，然后线粒体功能障碍可以导致及时的祖细胞成熟失败。关于代谢改变或神经祖细胞成熟对发育中大脑中线粒体代谢的依赖性。我们的工作将在知识中填补这一空白。我们使用慢性缺氧的啮齿动物模型来概括未成熟的肺在非常早产的婴儿中常见的损伤，这会导致全球灰色和白质细胞不正常以及相关的超微结构和行为缺陷。在这项研究中，我们将研究海马肿瘤急性缺氧，并确定线粒体破坏的发育结果。我们关于海马的初步数据表明：i）缺氧导致生化长期下降线粒体功能的标记； ii）缺氧会损害丙酮酸脱氢酶E1α独立的表达其抑制剂； iii）从表达GFAP的radial胶质的条件去除丙酮酸脱氢酶E1α 干细胞阻止其成熟。围产期脑损伤后促进恢复的潜在目标是及时恢复线粒体功能和氧化代谢。我们已发布和初步数据强烈建议新发现，即鼻内肝素结合表皮生长因子[HB-EGF]治疗缺氧后可能逆转低氧诱导的细胞不饱和度，恢复线粒体产生的N-乙酰基天冬氨酸和改善神经行为通过靶向线粒体来定义。我们假设这一点线粒体功能障碍导致海马神经祖细胞细胞的发展延迟执行氧化能代谢，从而防止其成熟。我们将检验以下假设恢复线粒体功能将使这些细胞能够满足其生物能量需求，从而及时海马中的细胞成熟和功能的恢复。这些假设将在三个具体目标。在AIM 1中，我们将确定缺氧是否会损害海马中的线粒体功能。在AIM 2中，我们将确定缺氧或细胞特异性去除丙酮酸脱氢酶E1α 海马神经祖细胞延迟分化和海马行为缺陷。在AIM 3中，我们将确定缺氧后鼻内HB-EGF治疗是否增强线粒体功能。这些目标的成功完成将阐明一种基本的生化机制缺氧引起的损伤后神经祖细胞的分化失败并定义了一种新陈代谢新生儿脑损伤后HB-EGF促进细胞和功能恢复的机制。