Nutritional Copper Status and the Nervous System

描述(申请人提供)：啮齿动物围产期发育过程中铜的不足会对中枢神经系统造成重大影响，导致神经化学和行为的改变，即使在长期补充铜之后也是如此。人类在怀孕和哺乳期间的铜摄入量可能不是最理想的，但目前的RDA建议并不鼓励对补充剂的需求。这项研究的长期目标是确定铜在围产期铜缺乏引起的严重的长期神经化学和行为后果中所起的生化作用。四个具体的目标将检验铜酶改变是所观察到的表型的总体假设。研究将利用Holtzman大鼠和转基因小鼠的营养和遗传模型。 目的：通过给予L-3，4-二羟基苯丝氨酸(L-DOPS)绕过铜依赖酶步骤，恢复脑内低水平去甲肾上腺素，验证铜依赖酶-多巴胺-β-单加氧酶活性受限的假说。 目的：通过比较铜缺乏的小鼠和野生型对照小鼠的铜缺乏特征，验证铜锌超氧化物歧化酶(SOD)活性受限的假说。其次，我们将这些小鼠与由于铜转运能力降低而导致SOD活性改变的小鼠Ctrl+/-小鼠进行比较。第三，我们将用一种膜透性的超氧化物歧化酶模拟物坦普尔来修复这些处理后的超氧化物歧化酶活性的不足。 目的：采用氰化物慢性抑制细胞色素C氧化酶(CCO)的大鼠模型，通过对铜缺乏大鼠脑能量代谢的研究，验证线粒体细胞色素C氧化酶(CCO)活性受限与脑能量代谢的关系。 目的4：我们将通过比较以铁强化饮食喂养的大鼠恢复脑铁的情况，来检验限制铜依赖的铁氧合酶导致脑铁降低的假设。

DESCRIPTION (provided by applicant): Insufficient copper (Cu) during perinatal development of rodents has a major impact on the central nervous system leading to altered neurochemistry and behavior even after long-term Cu repletion. Human intakes of Cu during pregnancy and lactation may be suboptimal but current RDA recommendations do not encourage the need for supplements. The long-range goal of this research is to identify the biochemical roles of Cu responsible for severe long-term neurochemical and behavioral consequences of perinatal Cu deficiency. Four specific aims will test the overall hypothesis that altered cuproenzymes are responsible for the phenotype observed. Research will utilize nutritional and genetic models with Holtzman rats and transgenic mice. AIM 1: We will test the hypothesis that limitation in the Cu-dependent enzyme dopamine beta- monooxygenase (DBM) is responsible by treating rats with L-3.4-dihydroxyphenvlserine (L-DOPS) to bypass the DBM step and restore low brain norepinephrine. AIM 2: We will test the hypothesis that limitation in Cu.Zn-superoxide dismutase (SOD) is responsible by comparing features of Cu deficiency in SOD -/- mice to wild-type controls Secondly, we will compare these mice to mice with altered SOD activity, Ctrl +/- mice, due to lower copper transport capacity. Thirdly, we will restore the deficit in SOD activity following these treatments with TEMPOL a membrane permeable SOD mimetic. AIM 3: We will test the hypothesis that limitation in mitochondrial cytochrome C oxidase (CCO) is responsible by characterizing brain energy metabolism in Cu deficient rats with a rat model of chronic CCO inhibition that uses cyanide. AIM 4: We will test the hypothesis that limitation in Cu-dependent ferroxidases lead to lower brain iron and are responsible by comparing rats reared on an iron-fortified diet to restore brain iron.