Mitochondrial Mechanisms of Hypoxic Ischemic Neonatal Brain injury

新生儿缺氧缺血性脑损伤的线粒体机制

• 批准号: 7013469
• 负责人: GARY M FISKUM
• 金额: $ 18.87万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-17 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7013469
• 关键词: apoptosis; astrocytes; bioenergetics; biological signal transduction; brain injury; calcium ion; carnitine; cell death; cerebral ischemia /hypoxia; hypoxia neonatorum; juvenile animal; laboratory rat; mitochondrial disease /disorder; neuroprotectants; oxidative stress

Mitochondrial dysfunction plays a critical role in etiology of neural cell death associated with ischemia, hypoxia and traumatic brain injury (TBI). Despite the large number of neonates who suffer permanent neurologic impairment due to hypoxia, and the high incidence of childhood traumatic brain injury, no information about the effects of stress on the activities of mitochondria from the brains of immature animals is available. We have recently discovered that compared to brain mitochondria from adult rats, mitochondria from immature rats exhibit resistance to bioenergetic failure caused by exposure to high levels of Ca 2+, and exhibit greatly enhanced sensitivity to release of pro-apoptotic cytochrome c by a peptide containing the BH3 "cell death" domain. We hypothesize that the molecular and physiological characteristics of immature brain mitochondria are important determinants in the sensitivity of the immature brain to cell death caused by metabolic and pro-apoptotic insults. We further hypothesize that acetyI-L-carnitine, an agent that we have shown to be neuroprotective in adult ischemic brain injury, will protect the immature brain from acute neurodegeneration due to its beneficial effects on neuronal and astrocyte mitochondria and on neuronal/astrocyte metabolic interactions. The following specific aims will test these hypotheses and provide novel information important in designing strategies for treating infants and children at risk for mental retardation. 1. Establish relationships between developmental changes in mitochondrial metabolic and apoptotic protein levels and activities and sensitivity of brain mltochondria to metabolic stress, oxidative stress, Ca2+induced dysfunction, and pro-apoptotic molecular signals. 2. Determine the pattern of molecular, metabolic, and apoptotic alterations to brain mitochondria caused by acute brain injury caused by neonatal hypoxia/ischemia. 3. Test the ability of acetyI-L-carnitine to ameliorate the mitochondrial alterations, metabolic derangements, and cell death in an animal model of neonatal hypoxia/ischemia and cell models of metabolic stress. This project will lay the foundation for the molecular etiology of neural cell death in immature animals following acute ischemic, hypoxic, and traumatic brain injury. These and future studies will aid in the development of targeted neuroprotective interventions that will minimize the neurologic impairment caused by acute brain injury in neonates and children.

线粒体功能障碍在与缺血，缺氧和创伤性脑损伤（TBI）有关的神经细胞死亡的病因中起关键作用。尽管由于缺氧引起的永久性神经系统损害以及儿童创伤性脑损伤的高发病，但尚无关于压力对未成熟动物大脑的线粒体活性的影响的信息。我们最近发现，与成年大鼠的脑线粒体相比，未成熟大鼠的线粒体表现出对暴露于高水平Ca 2+的生物能衰竭的抵抗力，并且表现出对含有BH3的肽C释放的促凋亡细胞色素C的敏感性，并且表现出极大的敏感性。 “细胞死亡”领域。我们假设未成熟脑线粒体的分子和生理特征是未成熟脑对由代谢和促凋亡损伤引起的细胞死亡敏感性的重要决定因素。我们进一步假设，由于其对神经元和星形细胞线粒体和神经胶质/星形胶质细胞代谢的神经胶质细胞的有益作用，由于其在成人缺血性脑损伤中具有神经保护作用的乙酸乙醇氨基氨酸将保护未成熟的脑免受急性神经退行性的影响。以下具体目的将检验这些假设，并为设计有智力降低风险的婴儿和儿童设计策略提供重要的新信息。 1。建立线粒体代谢和凋亡蛋白水平的发育变化以及脑mltoondria对代谢应激的敏感性的活性，氧化的敏感性 应力，Ca2+诱导的功能障碍和促凋亡分子信号。 2。确定由新生儿缺氧/缺血引起的急性脑损伤引起的分子，代谢和凋亡改变的脑线粒体的模式。 3。在新生儿缺氧/缺血性的动物模型和代谢应激的细胞模型中，测试乙酸-L-肉碱改善线粒体改变，代谢紊乱和细胞死亡的能力。该项目将在急性缺血，低氧和脑外伤后未成熟动物中神经细胞死亡的分子病因奠定基础。这些和未来的研究将有助于开发有针对性的神经保护干预措施，这将最大程度地减少由新生儿和儿童急性脑损伤引起的神经系统损害。