CEREBRAL OXIDATIVE METABOLISM IN HYPOXIC NEWBORNS

拟议的研究将研究特定的细胞和分子。 新生儿缺氧性神经元损伤机制的探讨 低氧程度对神经细胞核膜和超微结构的影响 核内Ca/++以及细胞凋亡和抗凋亡基因的表达 凋亡基因。我们认为，缺氧的严重程度将会有一个 对神经元核膜钙功能的特异性影响 流入机制和关键的核功能。监督和监督 在体脑组织缺氧程度将通过持续的 31P核磁测量脑高能化合物 共振光谱和生化确认的ATP和 磷酸肌酸。将进行组织化学方法来评估 组织病理学改变。实验方案将在以下项目上进行 初生仔猪调查：(1)数量组织间的关系 低氧对神经元钙内流机制的改变：高亲和力 Ca/++-ATPase、肌醇1、3、4、5四氢磷酸(IP/4)受体和 三磷酸肌醇(IP/3)受体；(2)低氧的影响 核内钙离子浓度升高；(3)核内钙离子浓度的关系 神经元核内Ca/+增加对Bax转录的影响(细胞凋亡) 和bcl-2(抗凋亡)基因、核酸内切酶活性和模式 DNA碎片对组织分级缺氧的响应；(4) 神经细胞死亡的形态变化，特别是 缺氧后细胞程序性死亡；(5)抑制作用 NMDA受体或自由基产生或缺氧的途径- 引起神经元核团改变和细胞程序性死亡。建议数 实验将利用成熟的技术进行。 这些研究将为神经元核功能提供新的见解。 这将有助于更好地理解缺氧性脑损伤的机制 受伤。细胞反应的基本机制的阐明 缺氧性脑损伤。人类免疫缺陷病毒基本细胞机制的阐明 对低氧的反应将使开发新的策略成为可能 预防或减轻低氧的有害影响 刚出生的。

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.