Nutritional Copper Status and the Nervous System

铜的营养状况和神经系统

• 批准号: 7035900
• 负责人: JOSEPH Robert PROHASKA
• 金额: $ 20.21万
• 依托单位: UNIVERSITY OF MINNESOTA DULUTH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7035900
• 关键词: behavior disorders; brain disorders; copper; cyanides; cytochrome c; developmental neurobiology; developmental nutrition; dietary mineral; dopamine beta monooxygenase; ferroxidase; laboratory mouse; laboratory rat; mother /embryo /fetus nutrition; nervous system disorder; neurochemistry; norepinephrine; nutrition disorders; nutrition related tag; perinatal; superoxide dismutase

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.

描述（由申请方提供）：啮齿动物围产期发育期间铜（Cu）不足对中枢神经系统有重大影响，导致神经化学和行为改变，即使在长期铜补充后也是如此。人类在怀孕和哺乳期间摄入的铜可能是次优的，但目前的RDA建议不鼓励需要补充剂。本研究的长期目标是确定铜的生化作用，负责严重的长期神经化学和行为后果围产期铜缺乏症。四个具体的目标将测试的总体假设，改变铜酶负责观察到的表型。研究将利用Holtzman大鼠和转基因小鼠的营养和遗传模型。 目标1：我们将通过用L-3，4-二羟基苯丝氨酸（L-DOPS）处理大鼠以绕过DBM步骤并恢复低脑去甲肾上腺素来检验Cu依赖性酶多巴胺β-单加氧酶（DBM）的限制是负责的假设。 目标2：我们将通过比较SOD -/-小鼠与野生型对照组中Cu缺乏的特征来检验Cu. Zn-超氧化物歧化酶（SOD）的限制是负责的假设。其次，我们将比较这些小鼠与SOD活性改变的小鼠（Ctrl +/-小鼠），由于铜转运能力降低。第三，我们将用TEMPOL（一种膜渗透性SOD模拟物）恢复这些处理后SOD活性的不足。 目标3：我们将测试的假设，限制线粒体细胞色素C氧化酶（CCO）是负责表征铜缺乏大鼠的脑能量代谢与慢性CCO抑制，使用氰化物的大鼠模型。 目标4：我们将测试的假设，限制铜依赖性铁氧化酶导致较低的脑铁，并负责比较大鼠饲养的铁强化饮食，以恢复脑铁。