The long term of this study is to provide detailed mechanistic understanding of the Wilson s disease (WD) pathology. WD is a severe human disorder of copper homeostasis, caused by mutations in the copper transporting ATPase ATP7B. The disease is associated with copper overload in tissues, particularly in the liver, and a wide spectrum of hepatic, neurological, and psychiatric abnormalities. Currently, specific molecular pathways through which copper triggers WD are poorly understood. The proposed studies will use the multidisciplinary approach and modern methodologies to identify biochemical and cellular events that lead to the onset and progression of WD. Specifically, the experiments will be carried out to determine the kinetics of copper accumulation in tissues of Atp7b-/- mice, an animal model of WD, at different stages of the disease and to characterize the role of cellular copper uptake and export machinery in this process. The oxidation state of nuclear proteins and their metal content will be examined to establish the biochemical basis of copper effects in diseased nuclei. The role of hnRNP A2/B1 in cell response to copper overload will be determined by characterizing its intracellular localization, interacting proteins, and a subset of transcripts affected by the hnRNPA2 upregulation. Lastly, the studies will be performed to identify the role of copper chelation in developing neurological manifestation in WD. The experiments will yield new information that would significantly facilitate the diagnostic and treatment of WD.
The project focuses on better understanding of Wilson?s disease, a severe genetic disorder in humans with hepatic and neurologic manifestations. The studies will determine the key molecular factors and processes that underlie the development and progression of Wilson?s disease. The results will contribute to improvement of diagnostic and treatment of this disorder of copper metabolism.
| Peng, Fangyu; Lutsenko, Svetlana; Sun, Xiankai et al. (2012) Imaging copper metabolism imbalance in Atp7b (-/-) knockout mouse model of Wilson's disease with PET-CT and orally administered 64CuCl2. Mol Imaging Biol 14:600-7 |
| Hirayama, Tasuku; Van de Bittner, Genevieve C; Gray, Lawrence W et al. (2012) Near-infrared fluorescent sensor for in vivo copper imaging in a murine Wilson disease model. Proc Natl Acad Sci U S A 109:2228-33 |
| Peng, Fangyu; Lutsenko, Svetlana; Sun, Xiankai et al. (2012) Positron emission tomography of copper metabolism in the Atp7b-/- knock-out mouse model of Wilson's disease. Mol Imaging Biol 14:70-8 |
