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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的首席研究员可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 该项目采用多学科方法来研究铜代谢的细胞生物学和生物化学。铜是一种重要的微量营养素，在许多细胞过程中发挥作用，通常利用这种过渡金属的不稳定氧化还原态。然而，当金属过量时，使铜在细胞代谢中发挥作用的反应性就会产生毒性。主要项目旨在通过对 COMMD1 蛋白（犬铜中毒中不存在）的细胞生物学和生化研究来了解铜稳态机制。与人类威尔逊病一样，犬铜中毒的特点是严重的肝脏铜积累。这些研究旨在深入了解一种新型的小型可溶性磷脂酰肌醇结合蛋白 COMMD1 如何发挥调节跨膜铜转运的作用。第二个项目旨在剖析铜转运蛋白 ATP7B 失活导致的肝细胞铜毒性机制。肝细胞核是威尔逊病小鼠模型中铜毒性的早期目标，对该模型中肝核蛋白质组的分析发现，由于铜积累，mRNA 加工机制发生了特定改变。该项目的进一步工作研究了铜在原子核中新发现的作用的目标和机制。这两个项目可能对理解遗传病或环境暴露引起的必需金属和重金属毒性机制产生更广泛的影响。