NUTRITIONAL COPPER STATUS AND THE NERVOUS SYSTEM

铜的营养状况和神经系统

• 批准号: 6530553
• 负责人: JOSEPH Robert PROHASKA
• 金额: $ 16.71万
• 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 2004-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6530553
• 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

Our previous research demonstrates that 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 broad long-range goal of this research is to identify the neurochemical roles for Cu which will lead to a better understanding of the elusive mechanisms of Cu deficient neuropathology. Our ongoing research in rodents demonstrates that there are selected regional neurochemical alterations induced by Cu deficiency including changes in Cu levels, catecholamine pools, and altered activity of cuproenzymes. Our research also suggests that restoration of brain Cu following perinatal deficiency may be difficult, if not impossible. More importantly, we have been able to show that at least one sensory-motor function, acoustic startle, is exquisitely altered in Cu-repleted rats even after months of nutritional supplementation. The specific aims of this focused multidisciplinary project are both descriptive and mechanism based. AIM 1: Firstly, we wish to establish the critical time period and dietary Cu level necessary for expression of permanent behavior alterations and neuropathology. To accomplish these goals, experiments will be conducted using Sprague Dawley rats. Dietary Cu deficiency will be produced during perinatal development and post lactation to investigate nutrition-related responses in the developing nervous system. In all cases, the Cu-deficient or Cu-repleted rats will be compared to Cu-adequate control animals. AIM 2: Secondly, we will identify the mechanism(s) for impaired brain development. Specifically, we will test the hypothesis that low brain norepinephrine is responsible for the altered brain development (hypomyelination and delayed synaptogenesis) and altered auditory startle by including studies with L-3,4-dihydroxyphenylserine (L-DOPS) to bypass the Cu-dependent enzyme dopamine-beta-monooxygenase. Biochemical and behavioral endpoints will be employed. AIM 3: Thirdly, we will identify the mechanism(s) for neuronal pathology. These experiments are based on the hypothesis that necrosis and apoptosis are driven by alterations in brain mitochondrial function. We will study isolated mitochondria and test specific hypotheses related to mechanisms of apoptosis and necrosis. Collectively, accomplishment of these aims will lead to a better understanding of the molecular mechanisms of Cu and are relevant because failure to accumulate Cu during brain development may lead to permanent alterations in neurotransmission, abnormal behavior, and diminished cognitive capacity.

我们以前的研究表明，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。的 这项研究的一个广泛的长期目标是确定神经化学作用 这将导致更好地了解难以捉摸的机制， 铜缺乏神经病理学。我们正在进行的啮齿动物研究表明， 铜缺乏引起的局部神经化学改变 包括铜水平的变化，儿茶酚胺池，和改变的活动， 铜酶我们的研究还表明， 围产期缺乏症即使不是不可能，也可能是困难的。更重要的是我们 已经能够证明至少有一种感觉运动功能， 即使经过几个月的惊吓，在富含铜的大鼠中也发生了微妙的变化 营养补充。其具体目标集中在 多学科项目既有描述性，又有机制性。目标1： 首先，我们希望建立临界时间段和膳食铜水平 表达永久性行为改变和神经病理学所必需的。 为了实现这些目标，将使用Sprague道利进行实验 大鼠饮食性铜缺乏症会在围产期发育过程中产生， 哺乳后，研究发育中的营养相关反应， 神经系统在所有情况下，铜缺乏或铜充足的大鼠将 与Cu充足的对照动物相比。目标2：其次，我们将确定 大脑发育受损的机制。具体来说，我们将测试 假设大脑去甲肾上腺素减少是大脑改变的原因 发育（髓鞘形成不足和突触发生延迟）和听觉改变 将L-3，4-二羟基苯丝氨酸（L-DOPS）的研究纳入 绕过铜依赖酶多巴胺-β-单加氧酶。生化和 将采用行为终点。目标3：第三，我们将确定 神经病理学的机制。这些实验是基于 假设坏死和凋亡是由大脑中的改变驱动的， 线粒体功能我们将研究分离的线粒体， 与凋亡和坏死机制有关的假说。总的来说， 这些目标的实现将有助于更好地了解 分子机制的铜和相关的，因为未能积累铜 大脑发育过程中可能会导致永久性的改变， 神经传递、异常行为和认知能力下降。