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:10328820
- 负责人:
- 金额:$ 27.74万
- 依托单位:
- 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:
- 关键词:
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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Joseph Scafidi其他文献
Joseph Scafidi的其他文献
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{{ truncateString('Joseph Scafidi', 18)}}的其他基金
Coordination of fatty acid metabolism following neonatal brain injury from preterm birth
早产新生儿脑损伤后脂肪酸代谢的协调
- 批准号:
10641924 - 财政年份:2022
- 资助金额:
$ 27.74万 - 项目类别:
Coordination of fatty acid metabolism following neonatal brain injury from preterm birth
早产新生儿脑损伤后脂肪酸代谢的协调
- 批准号:
10539030 - 财政年份:2022
- 资助金额:
$ 27.74万 - 项目类别:
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
- 批准号:
10240636 - 财政年份:2017
- 资助金额:
$ 27.74万 - 项目类别:
Mechanisms regulating KCC2 hypofunction during refractory seizures in a mouse model of ischemic neonatal seizures
缺血性新生儿癫痫发作小鼠难治性癫痫发作期间 KCC2 功能低下的调节机制
- 批准号:
10205121 - 财政年份:2017
- 资助金额:
$ 27.74万 - 项目类别:
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
- 批准号:
9382739 - 财政年份:2017
- 资助金额:
$ 27.74万 - 项目类别:
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
- 批准号:
9752675 - 财政年份:2017
- 资助金额:
$ 27.74万 - 项目类别:
Enhanced EGF Receptor Signaling Prevents White Matter Injury in Perinatal Hypoxia
增强的 EGF 受体信号传导可预防围产期缺氧时的白质损伤
- 批准号:
9098869 - 财政年份:2015
- 资助金额:
$ 27.74万 - 项目类别:
Enhanced EGF Receptor Signaling Prevents White Matter Injury in Perinatal Hypoxia
增强的 EGF 受体信号传导可预防围产期缺氧时的白质损伤
- 批准号:
8091982 - 财政年份:2011
- 资助金额:
$ 27.74万 - 项目类别:
Enhanced EGF Receptor Signaling Prevents White Matter Injury in Perinatal Hypoxia
增强的 EGF 受体信号传导可预防围产期缺氧时的白质损伤
- 批准号:
8436277 - 财政年份:2011
- 资助金额:
$ 27.74万 - 项目类别:
Enhanced EGF Receptor Signaling Prevents White Matter Injury in Perinatal Hypoxia
增强的 EGF 受体信号传导可预防围产期缺氧时的白质损伤
- 批准号:
8233981 - 财政年份:2011
- 资助金额:
$ 27.74万 - 项目类别:
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