This collaborative project combines efforts of three laboratories with complementary expertise to elucidate the fundamental mechanisms underlying tissue response to a genetically-induced copper misbalance. The overarching, long-term goal of this study is to generate information necessary for the development of novel approaches to treatment of Wilson disease (WD) and other disorders associated with copper misbalance in the liver. WD is a potentially lethal hepato-neurologic disease caused by inactivating mutations in the copper transporter ATP7B. The disease is associated with copper overload in the liver and significant metabolic and transcriptional changes. A large variability in symptoms, as well as slow and often suboptimal response to copper chelation complicate both diagnosis and treatment. To develop strategies overcoming these persistent challenges, three specific aims are proposed. Studies under Aim 1 will identify the molecular basis for reduced liver pathology in Atp7b?Hep mice (hepatocyte-specific deletion of Atp7b) compared to! Atp7b-/-mice (global knockout of Atp7b). This will be done by comparing the redox environment of liver cells, investigating whether the inflammatory response in Atp7b?Hep mice can be induced by a Cu-enriched diet, or be diminished in Atp7b-/- mice by the replacement of non-parenchymal liver cells.
In Aim 2, we will investigate the mechanism of Cu- dependent dis-lipidemic. This will be done by characterizing the intracellular distribution of elevated Cu in Atp7b?Hep hepatocytes, identifying the signaling and metabolic pathways affected by Cu overload in Atp7b?Hep mice and comparing these parameters to those in Atp7b-/- livers. Experiments under Aim 3 will define the molecular basis for the beneficial effects of the nuclear receptor agonist T0901317 in Atp7b-/- mice. The experiments will determine the metabolic and signaling pathways that are altered by the treatment with the drug and determine whether beneficial effect can be achieved if treatment is initiated at the late disease stage. The results of the proposed experiments are expected to significantly update the current model of Wilson disease pathogenesis, and provide a fundamental basis for new therapeutic approaches to diseases of Cu overload.

Public Health Relevance

This project aims to understand how copper misbalance in the liver, caused by genetic inactivation of the copper transporter ATP7B, induces changes in lipid metabolism and triggers liver pathology. The results will facilitate better understanding of known and emerging disorders of copper metabolism, modernize the current model for Wilson disease, and test new approaches to treatment.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Nutrition and Metabolic Processes Study Section (INMP)
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Burgess-Beusse, Bonnie L
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Johns Hopkins University
Schools of Medicine
United States
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