Bioenergetic Failure Underlies Cerebral Dysmaturity After Perinatal Brain Injury

项目总结摘要 长期认知障碍和学习障碍是一个主要的公共卫生问题，影响到更多 超过一半的早产儿患有未成熟肺损伤。这类婴儿的大脑发育迟缓。 灰质和白质结构的成熟，可能是由于对缺氧诱导的氧化高度敏感所致 在这个关键时期的压力。这种压力会导致线粒体功能障碍。如果线粒体依赖 未成熟的祖细胞需要氧化代谢才能成熟，然后线粒体功能障碍可能 导致祖细胞不能及时成熟。对新陈代谢变化或 发育中脑内神经前体细胞的成熟依赖于线粒体代谢。我们的 工作将填补这一知识空白。我们使用了一个慢性缺氧的啮齿动物模型来概括未成熟的肺。 损伤常见于早产儿，可导致全球灰质和白质细胞发育不成熟 以及相关的超微结构和行为缺陷。在这项研究中，我们将调查代谢的影响 低氧对海马区发育不成熟的影响，并决定线粒体断裂的发育结果。 我们对海马体的初步数据表明：i)低氧会导致长期的生化下降。 线粒体功能的标志物；II)低氧损害非依赖于α的丙酮酸脱氢酶的表达 以及iii)有条件地从表达胶质纤维酸性蛋白的放射状胶质细胞中去除丙酮酸脱氢酶E1α 干细胞会阻止它们的成熟。促进围产期脑损伤后康复的潜在目标是 及时恢复线粒体功能和氧化代谢。我们已公布的和初步的数据 强烈提示鼻腔注射肝素结合的表皮生长因子治疗的新发现 缺氧后可逆转缺氧诱导的细胞发育不成熟，恢复线粒体产生的N-乙酰基 天冬氨酸，并通过靶向线粒体来改善神经行为缺陷。我们假设 线粒体功能障碍导致海马神经祖细胞能力发育延迟 进行氧化能量代谢，从而阻止它们的成熟。我们将检验这一假设 恢复线粒体功能将使这些细胞能够满足其生物能量需求，如果允许的话 海马区的细胞成熟和功能恢复。这些假说将在三个方面进行检验 明确的目标。在目标1中，我们将确定缺氧是否会损害海马区线粒体的功能。 在目标2中，我们将确定是否缺氧或细胞特异性移除丙酮酸脱氢酶E1α。 海马神经祖细胞延迟分化和海马区行为缺陷。在目标3中，我们 将确定低氧后鼻腔注射HB-EGF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，它决定了 神经前体细胞在低氧损伤后的分化障碍及新代谢的定义 HB-EGF促进新生儿脑损伤后细胞和功能恢复的机制

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.