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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