INDUCTION AND EXPRESSION OF BRAIN METALLOTHIONEIN

描述：HIS项目的长期目标是勾勒出 锌分布不均匀的分子机制 锌金属硫蛋白及其受体的合成，锌-金属硫蛋白的合成 与丘脑不同区域的突触事件相关的中介事件 大脑是受调控的。这项建议的直接目标是评估 锌金属硫蛋白在防止氧生成中的作用 产生自由基的实验模型中的自由基与氧化损伤 激进分子。据推测，帕金森氏症是由 持续接触一种或多种内源性或外源性的 产生的毒素，可能类似于1-甲基-4-苯基-1，2，3，6- 四氢吡啶，随之而来的自由基生成调节 一种受损的清除机制，从而导致复合体I受损 呼吸链和随后的脂质过氧化和细胞死亡。 电子自旋共振研究表明，6-羟基多巴胺 产生羟基自由基(OH)，这是通过形成 司来吉兰一旦形成，就被金属硫蛋白亚型I和 二、本建议的具体目的是了解A) 金属硫蛋白在细胞因子-谷胱甘肽介导的诱导中的作用 对一氧化氮合酶和一氧化氮产生的影响；B) 司来吉兰促进金属硫蛋白和/或超氧化物合成的研究 从而使超氧化物的神经毒性特性失效 能杀死纹状体神经元的阴离子(OS)和/或过氧亚硝酸盐(ONOO) C)金属硫蛋白在潜在的营养效应中的作用 脑源性神经营养因子在抢救神经元中的作用 甲基沙林醇等多巴介导的四氢异喹啉 衍生品。从完成这些研究中获得的信息 将有助于进一步了解生物化学缺陷。 帕金森病的多巴胺能传递及其神经保护作用 金属硫蛋白亚型的作用。此外，它还将探索 司来吉兰除了抑制单胺氧化物B， 可能通过减少产生而避免纹状体神经元的神经变性 一氧化氮、超氧阴离子和过氧亚硝酸根；和/或司来吉兰 可能通过增强超氧化物的作用来促进神经保护 歧化酶、金属硫蛋白或神经营养因子。

DESCRIPTION: The long-term goal of the his project is to delineate the molecular mechanisms whereby the uneven distribution of zinc, the synthesis of zinc metallothioneins and their receptors, and the zinc- mediated events associated with synaptic events in various areas of the 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 experimental models generating free radicals. It has been hypothesized that Parkinson's disease results from the ongoing exposure to one or more of endogenously or exogenously generated toxins, perhaps similar to 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine, with consequent free radical generation regulating in a compromised scavenging mechanism, thus causing impairment of complex I of the respiratory chain and subsequent lipid peroxidation and cell death. Electron spin resonance studies have shown that 6-hydroxydopamine generates hydroxyl radicals (OH) which is prevented by forming by selegiline and once formed is scavenged by metallothionein isoforms I and II. The specific aims of this proposal are to learn A) the effects of metallothionein in modulating the cytokine-glutathione-mediated induction of nitric oxide synthase and nitric oxide production; B) the influence of selegiline in enhancing the synthesis of metallothionein and/or superoxide dismutase and hence nullifying the neurotoxic properties of superoxide anion (OS) and/or peroxynitrite (ONOO) capable of killing striatal neurons c) the actions of metallothionein in potential the trophic effects of brain-derived neurotrophic factor in rescuing neurons against methylsalsolinol and other dopa-mediated tetrahydroisoquinoline derivatives. The information to be gained from completing these studies will contribute to understanding further the biochemical defects in dopaminergic transmission in Parkinson's disease and the neuroprotective action of metallothionein isoforms. In addition, it will explore the possibility that selegiline in addition to inhibiting monoamine oxides B, may avert neurodegeneration of striatal neurons by reducing the production of nitric oxide, superoxide anions, and peroxynitrite; and/or selegiline may foster neuroprotection by augmenting the actions of superoxide dismutase, metallothionein, or neurotrophins.