INBRE-2 MAMMALIAN COPPER METABOLISM

INBRE-2 哺乳动物铜代谢

• 批准号: 8359583
• 负责人: JASON L BURKHEAD
• 金额: $ 13.06万
• 依托单位: UNIVERSITY OF ALASKA FAIRBANKS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8359583
• 关键词: Alaska; Binding Proteins; Biochemical; Biochemistry; Biological; Canis familiaris; Cell Nucleus; Cell physiology; Cells; Cellular biology; Copper; Disease; Environmental Exposure; Funding; Grant; Heavy Metals; Hepatic; Hepatocyte; Hepatolenticular Degeneration; Hereditary Disease; Homeostasis; Human; Messenger RNA; Metabolism; Metals; Micronutrients; Modeling; National Center for Research Resources; Nuclear; Oxidation-Reduction; Phosphatidylinositols; Principal Investigator; Process; Proteins; Proteome; Research; Research Infrastructure; Resources; Role; Source; Toxic effect; Transition Elements; United States National Institutes of Health; Wilson disease protein; Work; cost; environmental agent; insight; interdisciplinary approach; metal poisoning; mouse model; novel

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This project takes a multidisciplinary approach to study the cell biology and biochemistry of copper metabolism. Copper is an essential micronutrient that functions in a number of cellular processes, typically employing the labile redox state of this transition metal. The reactivity that makes copper useful in cellular metabolism is, however, toxic when the metal is in excess. The primary project aims to understand mechanisms of copper homeostasis through cell biological and biochemical study of the COMMD1 protein, which is absent in Canine Copper Toxicosis. Like human Wilson Disease, Canine Copper Toxicosis is characterized by severe hepatic copper accumulation. These studies aim provide insight into the mechanism of how a novel small, soluble, phosphatidylinositol-binding protein, COMMD1, can function to regulate transmembrane copper transport. A second project aims to dissect the mechanism of copper toxicity in hepatic cells resulting from inactivation of the copper transporter ATP7B. Hepatic nuclei are an early target of copper toxicity in a mouse model of Wilson Disease and analysis of the hepatic nuclear proteome in this model found specific alteration of the mRNA processing machinery as a result of copper accumulation. Further work on this project investigates targets and mechanisms of this newly discovered role for copper in nuclei. Both projects may have broader implications in understanding mechanisms of essential and heavy metal toxicity, either from genetic disease or environmental exposure.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 该项目采用多学科的方法来研究铜代谢的细胞生物学和生物化学。铜是在许多细胞过程中起作用的必不可少的微量营养素，通常使用该过渡金属的不稳定氧化还原状态。然而，当金属过量时，使铜在细胞代谢中有用的反应性是有毒的。主要项目旨在通过对COMMD1蛋白的细胞生物学和生化研究来了解铜稳态的机制，COMMD1蛋白不存在于犬铜毒理中。像人类威尔逊病一样，犬铜毒性症的特征是严重的肝铜积累。这些研究的目的是深入了解新型的小型，可溶性，磷脂酰肌醇结合蛋白Commd1如何起作用以调节跨膜铜转运的机制。第二个项目旨在剖析因铜转运蛋白ATP7B失活而导致的肝细胞中铜毒性的机制。在威尔逊疾病的小鼠模型中，肝核是铜毒性的早期靶标，并且在该模型中对肝核蛋白质组的分析发现，由于铜的积累，mRNA加工机械的特定改变。该项目的进一步研究研究了铜在核中这种新发现的作用的目标和机制。这两个项目都可能从遗传疾病或环境暴露中理解必需和重金属毒性的机制具有更广泛的意义。