Nutritional Copper Status and the Nervous System

描述（由申请人提供）：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，即使长期铜补充。人类在孕期和哺乳期的铜摄入量可能不是最理想的，但目前的RDA建议不鼓励补充。本研究的长期目标是确定铜在围产期铜缺乏的严重长期神经化学和行为后果中的生化作用。四个特定的目标将测试改变的铜原酶对观察到的表型负责的总体假设。研究将利用Holtzman大鼠和转基因小鼠的营养和遗传模型。

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.