INBRE-2 MAMMALIAN COPPER METABOLISM

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 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。铜是一种必需的微量营养素，在许多细胞过程中发挥作用，通常采用这种过渡金属的不稳定氧化还原状态。然而，当铜过量时，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COMMD 1蛋白的细胞生物学和生物化学研究来了解铜稳态的机制，该蛋白在犬铜中毒中缺失。与人类威尔逊病一样，犬铜中毒的特征是严重的肝脏铜蓄积。这些研究旨在深入了解一种新的小的可溶性磷脂酰肌醇结合蛋白COMMD 1如何发挥作用来调节跨膜铜转运。第二个项目旨在剖析铜转运蛋白ATP 7 B失活导致肝细胞铜毒性的机制。肝细胞核是肝豆状核变性小鼠模型中铜毒性的早期靶点，在该模型中对肝细胞核蛋白质组的分析发现，由于铜积累，mRNA加工机制发生了特异性改变。该项目的进一步工作研究了铜在核中的这种新发现的作用的目标和机制。这两个项目可能对了解遗传疾病或环境暴露引起的必需金属和重金属毒性机制具有更广泛的影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.