CEREBRAL OXIDATIVE METABOLISM IN HYPOXIC NEWBORNS

缺氧新生儿的脑氧化代谢

• 批准号: 2197999
• 负责人: Maria d Delivoria-Papadopoulos
• 金额: $ 26.97万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-01 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2197999
• 关键词: NMDA receptors; brain metabolism; calcium flux; cellular pathology; cerebral ischemia /hypoxia; chronic brain damage; free radical oxygen; high performance liquid chromatography; hypoxia neonatorum; light microscopy; membrane activity; membrane channels; membrane lipids; microcirculation; microdialysis; nuclear magnetic resonance spectroscopy; oxidative phosphorylation; peroxidation; phosphorus compounds; respiratory gas analyzer; sodium potassium exchanging ATPase; swine

DESCRIPTION:This is the second revision of a competitive renewal application to study basic mechanisms of hypoxic brain damage in newborn pigs. Experiments were designed to investigate specific cellular mechanisms of brain cell injury in the piglet by correlating the degree of hypoxia with alterations in the activity and structure of the N-methyl-D-aspartate (NMDA) receptor-ion channel complex and tissue histopathologic changes. The investigators hypothesize that the severity of hypoxia will have a specific impact on the function and possibly the structure of the NMDA receptor, which is a unique aspect of the grant application. The determination of the degree of hypoxia in vivo will be achieved by the continuous monitoring of brain high energy phosphate reserves using 31-P nuclear magnetic resonance spectroscopy as well as the determination of cerebral cortical oxygen pressure by oxygen- dependent quenching of phosphorescence. Measurements of cell membrane lipid peroxidation, sodium/potassium- ATPase activity and the presence of oxygen free radicals will be used as indices of brain cell injury. Light microscopy will be performed to assess histopathologic changes at 48 hours of recovery from hypoxia. All experiments will be conducted in newborn pigs to investigate: 1) the relationship between quantitative tissue hypoxia and the structure of the recognition and modulatory sites and the activation of the receptor/ion channel complex; 2) the effect of hypoxia on NMDA-mediated influx of calcium into synaptoneurosomes; 3) the relationship between the occurrence of lipid peroxidation and alterations in the recognition and modulatory sites of the NMDA receptor; 4) the relationship between quantitative tissue hypoxia and the release of specific monoamines and amino acid neurotransmitters; and 5) the effect of increased release of amino acid and monoamine neurotransmitters during hypoxia on the activity of brain cell sodium/potassium-ATPase and alterations in NMDA activity.Additional experiments will investigate the potentiating effect of hypoglycemia during hypoxia on both NMDA receptor activity and cell membrane function. The proposed experiments will be performed using well- established techniques for the determination of ligand binding and enzyme kinetics, microdialysis, HPLC, histopathologic methods and others. It is proposed that the findings of the experiments will provide new insights into brain cell membrane function and will lead to a better understanding of basic mechanisms contributing to hypoxic neuronal injury in the newborn human infant.

描述：这是竞争性更新的第二次修订 应用研究缺氧性脑损伤的基本机制 新生猪。实验旨在研究特定 仔猪脑细胞损伤的细胞机制 缺氧程度以及活性和结构的改变 N-甲基-D-天冬氨酸 (NMDA) 受体-离子通道复合物和 组织病理学变化。 研究人员假设 缺氧的严重程度会对功能产生特定的影响 以及可能的 NMDA 受体的结构，这是一种独特的 补助金申请的一个方面。 程度的确定 通过脑部的持续监测来实现体内缺氧 使用 31-P 核磁共振测定高能磷酸盐储量 光谱学以及大脑皮质氧的测定 压力通过氧依赖性磷光猝灭。 细胞膜脂质过氧化、钠/钾的测量 将利用 ATP 酶活性和氧自由基的存在 作为脑细胞损伤的指标。将进行光学显微镜检查 评估恢复 48 小时后的组织病理学变化 缺氧。 所有实验都将在新生猪身上进行 研究：1）定量组织缺氧之间的关系 以及识别和调节位点的结构以及 受体/离子通道复合物的激活； 2）效果 缺氧对 NMDA 介导的钙流入突触神经体的影响； 3） 脂质过氧化的发生与 NMDA 识别和调节位点的改变 受体； 4）组织缺氧定量与 特定单胺和氨基酸神经递质的释放； 5)增加氨基酸和单胺释放的效果 缺氧时神经递质对脑细胞活动的影响 钠/钾-ATP 酶和 NMDA 活性的变化。其他 实验将研究低血糖的增强作用 缺氧期间 NMDA 受体活性和细胞膜的变化 功能。 所提出的实验将使用良好的进行 已建立的配体结合测定技术和 酶动力学、微透析、HPLC、组织病理学方法和 其他的。 建议将实验结果 提供对脑细胞膜功能的新见解，并将导致 更好地理解导致缺氧的基本机制 新生儿的神经元损伤。