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.
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