Copper is an essential micronutrient in humans and the reactions catalyzed by copper-containing enzymes play a key role in cellular respiration, antioxidant defense, iron metabolism, connective tissue biosynthesis, pigment formation and neurotransmitter production. The long-term objective of these studies is to define the cellular and molecular determinants of human hepatocyte copper metabolism.
The specific aim of this proposal is to elucidate the structure and function of the Wilson disease P-type ATPase. Previous studies in our laboratory have resulted in the cloning and characterization of the P-type ATPase encoded by the Wilson disease gene and the definition of the LEC rat as a bona fide model for this disorder. We now propose to extend these studies by defining the cellular localization, membrane structure and transport function of the Wilson ATPase. Using polyclonal antisera, available human cell lines, data on missense mutations, expression and cloning studies in yeast and in vitro hepatocyte reconstitution approaches we will dissect the mechanisms of copper transport by this protein. These studies should permit an understanding of the mechanisms of copper traffic within the hepatocyte as well as further definition of the molecular pathology of Wilson disease. Ultimately such data may provide novel approaches to the treatment of human disorders of copper metabolism and may offer new insights into the biological roles of copper in human nutrition and disease.
| Soma, Shivatheja; Latimer, Andrew J; Chun, Haarin et al. (2018) Elesclomol restores mitochondrial function in genetic models of copper deficiency. Proc Natl Acad Sci U S A 115:8161-8166 |
| Hodgkinson, Victoria L; Zhu, Sha; Wang, Yanfang et al. (2015) Autonomous requirements of the Menkes disease protein in the nervous system. Am J Physiol Cell Physiol 309:C660-8 |
| Gitlin, Jonathan D (2014) Copper homeostasis: specialized functions of the late secretory pathway. Dev Cell 29:631-2 |
| Wang, Yanfang; Zhu, Sha; Hodgkinson, Victoria et al. (2012) Maternofetal and neonatal copper requirements revealed by enterocyte-specific deletion of the Menkes disease protein. Am J Physiol Gastrointest Liver Physiol 303:G1236-44 |
| Wang, Yanfang; Zhu, Sha; Weisman, Gary A et al. (2012) Conditional knockout of the Menkes disease copper transporter demonstrates its critical role in embryogenesis. PLoS One 7:e43039 |
| van Boxtel, Antonius L; Gansner, John M; Hakvoort, Henk W J et al. (2011) Lysyl oxidase-like 3b is critical for cartilage maturation during zebrafish craniofacial development. Matrix Biol 30:178-87 |
| Mendelsohn, Bryce A; Malone, James P; Townsend, R Reid et al. (2009) Proteomic analysis of anoxia tolerance in the developing zebrafish embryo. Comp Biochem Physiol Part D Genomics Proteomics 4:21-31 |
| Gansner, John M; Madsen, Erik C; Mecham, Robert P et al. (2008) Essential role for fibrillin-2 in zebrafish notochord and vascular morphogenesis. Dev Dyn 237:2844-61 |
| Gansner, John M; Gitlin, Jonathan D (2008) Essential role for the alpha 1 chain of type VIII collagen in zebrafish notochord formation. Dev Dyn 237:3715-26 |
| Thiele, Dennis J; Gitlin, Jonathan D (2008) Assembling the pieces. Nat Chem Biol 4:145-7 |
Showing the most recent 10 out of 44 publications
