CEREBRAL OXIDATIVE METABOLISM IN HYPOXIC NEWBORNS

拟议的研究将调查特定的细胞和分子 新生儿缺氧性神经元损伤的机制 缺氧程度对神经元核膜的改变， 核内Ca/++，以及凋亡和抗- 凋亡基因我们认为，缺氧的严重程度将有一个 对神经细胞核膜钙离子功能的特异性影响 流入机制和关键的核功能。的监测 在体内的脑组织缺氧程度将通过连续的 脑高能化合物的~（31）P核磁共振测量 共振光谱，并通过ATP和 磷酸肌酸将采用组织化学方法评估 组织病理学改变。实验方案将在 新生仔猪的研究：（1）数量组织关系 缺氧改变神经元钙内流机制：高亲和力 Ca/++-ATP酶、肌醇1，3，4，5-四磷酸（IP/4）受体和 1，4，5-三磷酸肌醇（IP/3）受体：（2）缺氧的影响 核内钙离子浓度增加;（3） 增加神经元核内Ca/++对bax转录的影响（凋亡） 和bcl-2（抗凋亡）基因，核酸内切酶活性，和模式 组织缺氧时DNA片段化程度的变化;（4） 形态学变化表明神经元死亡，特别是 缺氧后的程序性细胞死亡;和（5）抑制的效果 NMDA受体或自由基生成途径或缺氧- 诱导神经细胞核的变化和程序性细胞死亡。拟议 实验将通过利用完善的技术进行。 这些研究将为神经元核功能提供新的见解 并将导致更好地了解缺氧脑的机制 损伤阐明了细胞的基本机制 缺氧性脑损伤基本细胞机制的阐明， 对缺氧的反应将使开发新的策略， 预防或减轻缺氧对机体的有害影响， 新生儿

The proposed studies will investigate specific cellular and molecular mechanisms of hypoxic neuronal injury in the newborn by relating the degree of hypoxia to alterations in neuronal nuclear membrane and intranuclear Ca/++, as well as the expression of apoptotic and anti- apoptotic genes. We propose that the severity of hypoxia will have a specific impact on the function of the neuronal nuclear membrane calcium influx mechanisms and critical nuclear functions. The monitoring of the degree of brain tissue hypoxia in vivo will be achieved by the continuous measurement of brain high energy compounds with 31P nuclear magnetic resonance spectroscopy and confirmed biochemically by ATP and phosphocreatine. Histochemical methods will be performed to assess histopathologic changes. Experimental protocols will be carried out on newborn piglets investigating: (1) The relationship of quantitative tissue hypoxia to changes in neuronal calcium influx mechanisms: high affinity Ca/++-ATPase, inositol 1, 3, 4, 5 tetrakisphosphate (IP/4) receptor and inositol 1, 4, 5 triphosphate (IP/3) receptor; (2) The effect of hypoxia on increased intranuclear calcium concentration; (3) The relationship of increased neuronal intranuclear Ca/++ to transcription of bax (apoptotic) and bcl-2 (anti-apoptotic) genes, endonuclease activity, and the pattern of DNA fragmentation in response to graded tissue hypoxia; (4) Morphological changes indicative of neuronal death, particularly programmed cell death following hypoxia; and (5) The effect of inhibition of the NMDA receptor or pathways of free radical generation or hypoxia- induced changes in neuronal nuclei and programmed cell death. The proposed experiments will be performed by utilizing well established techniques. These studies will provide new insights into neuronal nuclear functions and will lead to a better understanding of the mechanisms of hypoxic brain injury. The elucidation of basic cellular mechanisms in response to hypoxic brain injury. The elucidation of basic cellular mechanisms in response to hypoxia will enable the development of novel strategies of preventing or attenuating the deleterious effects of hypoxia in the newborn.