The overall goal of the proposed research is to understand how the essential trace element copper is transported, stored, and delivered to its target proteins in mammalian cells and tissues. We shall examine the mechanisms by which copper is taken up, relayed to the secretory pathway, and transported across a membrane for incorporation into other proteins or for export by the Menkes (MNK) and Wilson (WND) disease gene products. These studies will further elucidate the roles for copper in the pathogenesis of disease phenotypes.
The specific aims are the following: l) To test our hypothesis that CTR1 is an essential high-affinity copper uptake protein in mammals. 2) To understand how the copper chaperone protein HAH1 relays copper to the MNK ATPase. 3) To delineate the features of the MNK ATPase that are required for copper transport by site-directed mutagenesis. 4) To test our hypothesis that the MNK and WND ATPases mediate different and reciprocal functions.
| Kuo, Y M; Su, T; Chen, H et al. (2004) Mislocalisation of hephaestin, a multicopper ferroxidase involved in basolateral intestinal iron transport, in the sex linked anaemia mouse. Gut 53:201-6 |
| Fu, X; Rinaldo, P; Hahn, S H et al. (2003) Mutation analysis of copper transporter genes in patients with ethylmalonic encephalopathy, mitochondriopathies and copper deficiency phenotypes. J Inherit Metab Dis 26:55-66 |
| Murata, Y; Kodama, H; Abe, T et al. (1997) Mutation analysis and expression of the mottled gene in the macular mouse model of Menkes disease. Pediatr Res 42:436-42 |
| Ferenci, P; Gilliam, T C; Gitlin, J D et al. (1996) An international symposium on Wilson's and Menkes' diseases. Hepatology 24:952-8 |
| Vulpe, C D; Packman, S (1995) Cellular copper transport. Annu Rev Nutr 15:293-322 |
| Das, S; Levinson, B; Vulpe, C et al. (1995) Similar splicing mutations of the Menkes/mottled copper-transporting ATPase gene in occipital horn syndrome and the blotchy mouse. Am J Hum Genet 56:570-6 |
