INBRE-2 MAMMALIAN COPPER METABOLISM

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 本项目采用多学科方法研究铜代谢的细胞生物学和生物化学。铜是一种基本的微量营养素，在许多细胞过程中发挥作用，通常利用这种过渡金属不稳定的氧化还原状态。然而，当铜过量时，使铜在细胞新陈代谢中有用的反应性是有毒的。该初步项目旨在通过对犬铜中毒中缺失的COMMD1蛋白的细胞生物学和生化研究来了解铜的动态平衡机制。与人类肝豆状核变性一样，犬铜中毒的特征是肝脏铜的严重蓄积。这些研究旨在深入了解一种新的小的、可溶的磷脂酰肌醇结合蛋白COMMD1如何调节跨膜铜转运的机制。第二个项目旨在剖析铜转运蛋白ATP7B失活导致肝细胞铜中毒的机制。在威尔逊病小鼠模型中，肝细胞核是铜中毒的早期靶点，对该模型中肝细胞核蛋白质组的分析发现，由于铜积累，mRNA处理机制发生了特定的变化。该项目的进一步工作是研究这一新发现的铜在原子核中的作用的目标和机制。这两个项目都可能对理解遗传疾病或环境暴露造成的基本和重金属毒性的机制产生更广泛的影响。

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.