Nutritional Copper Status and the Nervous System

铜的营养状况和神经系统

• 批准号: 7075651
• 负责人: JOSEPH Robert PROHASKA
• 金额: $ 4.32万
• 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 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7075651
• 关键词: 3,4 dihydroxyphenylacetate; apoptosis; auditory reflex; behavior disorders; behavior test; brain disorders; copper; developmental neurobiology; developmental nutrition; dietary mineral; laboratory rat; mitochondrial disease /disorder; mother /embryo /fetus nutrition; necrosis; nervous system disorder; neurochemistry; neurogenesis; norepinephrine; northern blottings; nutrition disorders; nutrition related tag; perinatal; western blottings

DESCRIPTION (provided by applicant): Insufficient copper (Cu) during perinatal development has a major impact on the central nervous system leading to severe long-term neurochemical and behavioral consequences. The long-range goal of this research is to identify the neurochemical roles of Cu to better understand the elusive mechanisms of Cu-deficient neuropathology. Research in rodents demonstrates that there are selected regional neurochemical alterations induced by Cu deficiency and that restoration of brain Cu following perinatal deficiency may be difficult, if not impossible. Furthermore sensory-motor function is altered in Cu-repleted rats even after months of nutritional supplementation. Human Cu RDAs for pregnancy and lactation may be set too low. Three specific aims are the focus of this research and will utilize nutritional and genetic models with Holzman rats and mice. AIM 1: We will establish the critical dietary Cu level necessary to block expression of permanent behavior alterations and neuropathology. We will determine the biochemical and behavioral outcomes following the imposition of variable dietary copper intakes to rats. Marginal Cu status will also be studied using diet and mice heterozygous for the Cu transporter gene Ctrl +/-. AIM 2: We will test two specific hypotheses. Using L-3,4-dihydroxyphenylserine (L-DOPS) to bypass the Cu-dependent enzyme dopamine t3-monooxvqenase we will test if low brain norepinephrine is responsible for altered brain development and motor function. We will determine the role of brain Cu, Zn-superoxide dismutase by comparing the challenge of Cu deficiency in SOD -/- mice to wild-type controls using biochemical and behavioral outcomes. AIM 3: We will characterize the genomic, proteomic, and metabolomic profile of Cu-deficient and Cu-repleted brain. Rat brain transcripts will be compared using DNA microarrays. Cerebellar protein profiles will be compared using 2-D gel electrophoresis and mass spectrometry. Brain metabolite profiles will be compared using MS and HPLC technology.

描述（由申请人提供）：围产期发育期间铜（Cu）不足对中枢神经系统有重大影响，导致严重的长期神经化学和行为后果。这项研究的长期目标是确定铜的神经化学作用，以更好地了解铜缺乏神经病理学的难以捉摸的机制。啮齿动物的研究表明，有选择的区域神经化学变化引起的铜缺乏症和脑铜恢复围产期缺乏症可能是困难的，如果不是不可能的。此外，感觉运动功能的改变，在铜充满大鼠，即使经过几个月的营养补充。妊娠期和哺乳期的人体铜RDA可能设置得过低。三个具体的目标是这项研究的重点，并将利用营养和遗传模型与霍尔茨曼大鼠和小鼠。目的1：我们将建立关键的饮食铜水平，阻断永久性行为改变和神经病理学的表达。我们将确定的生化和行为的结果后，施加可变的饮食铜摄入量的大鼠。还将使用饮食和铜转运蛋白基因Ctrl +/-杂合子小鼠研究边缘铜状态。目的2：我们将测试两个特定的假设。使用L-3，4-二羟基苯丝氨酸（L-DOPS）绕过Cu依赖性酶多巴胺t3-单氧化酶，我们将测试低脑去甲肾上腺素是否是改变脑发育和运动功能的原因。我们将确定脑铜，锌-超氧化物歧化酶的作用，通过比较铜缺乏的挑战SOD -/-小鼠野生型控制使用生化和行为的结果。目的3：我们将描述铜缺乏和铜补充脑的基因组，蛋白质组和代谢组学特征。将使用DNA微阵列比较大鼠大脑转录物。小脑蛋白质谱将使用2-D凝胶电泳和质谱进行比较。将使用MS和HPLC技术比较脑代谢产物谱。