|SOM Address||203 Hunterian|
Uncovering the mechanisms of human disorders is a fascinating and challenging process due to complexity of human physiology and marked variations that may exist between individuals. To successfully treat human disorders it is necessary to integrate genetic and metabolic findings and have the ability to follow the disease progression from a single cell to the entire organism. Our research uses such integrative approach to identify the mechanisms responsible for variable manifestations in monogenic human diseases. Specifically, we are studying Wilson’s disease, a potentially fatal disorder, which manifests as a liver disease and/or neurologic and psychiatric pathologies. The disease affects primarily children and young adults and is associated with genetic mutations in the copper transporter ATP7B. In our laboratory, we investigate how various disease-causing mutations affect the structure, function, and intracellular targeting of ATP7B. To link our biochemical and cell-biological findings to the organism physiology, we are characterizing the Atp7b-/- mice, an animal model for Wilson’s disease. We have recently discovered a link between copper homeostasis, lipid metabolism, and RNA biogenesis. We are currently investigating how interplay between these important processes determine the time of onset and manifestations of the disease in the liver and central nervous system.
- Gupta A, Bhattacharjee A, Dmitriev OY, Nokhrin S, Braiterman L, Hubbard AL, Lutsenko S. (2011) Cellular copper levels determine the phenotype of the Arg875 variant of ATP7B/Wilson disease protein. Proc Natl Acad Sci U S A.108(13):5390-5
- Burkhead JL, Gray LW, Lutsenko S. (2011) Systems biology approach to Wilson’s disease. Biometals. 24(3):455-66
- Burkhead JL, Ralle M, Wilmarth P, David L, Lutsenko S. (2011) Elevated copper remodels hepatic RNA processing machinery in the mouse model of Wilson’s disease. J Mol Biol. 406(1):44-5
- Ralle M, Huster D, Vogt S, Schirrmeister W, Burkhead JL, Capps TR, Gray L, Lai B, Maryon E, Lutsenko S (2010). Wilson disease at a single cell level: intracellular copper trafficking activates compartment-specific responses in hepatocytes. J Biol Chem. 285(40):30875-83
- Huster D, Lutsenko S. (2007) Wilson disease: not just a copper disorder. Analysis of a Wilson disease model demonstrates the link between copper and lipid metabolism. Mol Biosyst. 3(12):816-24