INDUCTION AND EXPRESSION OF BRAIN METALLOTHIONEIN

描述(调查人员摘要)：这是一个长期目标 该项目是为了描绘出不平衡的分子机制 锌的分布、锌金属硫蛋白的合成以及锌金属硫蛋白 锌介导的事件与不同区域的突触事件相关 大脑的部分是受调控的。这项建议的直接目标是 评价锌金属硫蛋白在预防黄斑狼疮发生中的作用 氧自由基和大脑中的氧化损伤。因为很多锌 含有神经元的也是谷氨酸能神经元，由于 哺乳动物的海马区富含锌、谷氨酸和NMDA 受体，这些研究将在海马神经元中进行 原生文化。据推测，在炎症性疾病期间 反应，细胞因子诱导的金属硫蛋白的诱导提供 一种持久的保护，以最大限度地减少氧化应激造成的损害，如 作为自由基。该提案的具体目的是：1)评估 丁硫氨酸-SR降低谷胱甘肽水平的后果 亚磺胺，耗尽金属硫蛋白的水平 寡核苷酸和诱导金属硫蛋白的合成 白介素1对有机氢过氧化氢细胞毒性的影响 海马神经元；2)学习是否诱导 IL-1介导的金属硫蛋白对细胞凋亡的保护作用 由超氧化物歧化酶抑制所带来的；以及3)确定 ··· 金属硫蛋白的性质与酶活性的改变有关 一氧化氮合酶。锌的浓度降低了 帕金森病和肌萎缩侧索硬化症患者的脑 这两种情况都与氧化损伤有关。 从这些研究中获得的结果将提供另一个 锌金属硫蛋白在氧化应激中的作用 与这些和其他神经性疾病有关。

DESCRIPTION (Investigator's Abstract): The long term goal of this project is to delineate the molecular mechanisms whereby the uneven distribution of zinc, the synthesis of zinc metallothionein, and the zinc-mediated events associated with synaptic events in various areas of brain are regulated. The immediate objective of this proposal is to assess the role of zinc metallothionein in preventing the generation of oxygen radicals and oxidative damage in the brain. Since many zinc containing neurons are also glutamatergic neurons, and since the mammalian hippocampus is enriched with zinc, glutamate and NMDA receptors, these studies will be carried out in hippocampal neurons in primary culture. It is hypothesized that during the inflammatory responses, the cytokine-induced induction of metallothionein provides a long lasting protection to minimize damage by oxidative stress, such as free radicals. The specific aims of this proposal are: 1) to assess the consequence of depleting the level of glutathione by buthionine-SR- sulfoximine, of depleting the level of metallothionein by oligodeoxynucleotide, and of inducing the synthesis of metallothionein by interleukin-1 on the cytotoxicity of an organic hydroperoxide in hippocampal neurons; 2) to learn whether the induction of metallothionein by interleukin-1 can prevent the apoptotic cell death brought about by inhibition of superoxide dismutase; and 3) to ascertain whether or not the induction of and the hydroxyl radical scavenging properties of metallothionein are associated with altered activity of nitric oxide synthase. The concentrations of zinc are reduced in the brains of patients with Parkinson's disease and amyotrophic lateral sclerosis; and oxidative damage has been implicated in both conditions. The results to be gained from these studies will provide an additional insight on the role of zinc metallothionein in oxidative stress associated with these and other neurological disorders.