Copper in trace amounts is essential to life. It is also toxic, when the excess over physiologic requirements that is present in almost every diet, accumulates. The mammalian liver is the central organ for the maintenance of copper homeostasis and is also the primary target for its toxic effects. Copper balance is achieved by the interplay of uptake by hepatocytes, incorporation of the metal into cellular and secretory proteins, storage in lysosomes and the excretion of the excess via the bile. Defective biliary copper excretion, either intracellular or extracellular, results in copper retention. To obtain a better understanding of the mechanisms by which copper is retained and thus capable of exerting its toxic effects, this project will investigate the hypothesis that failure of an intracellular agent capable of controlling the biliary excretion of copper or sequestering it in an innocuous form, results in hepatocellular injury. A novel, low molecular (~10 kDa) copper-binding protein, Cuprophylin (CPP), was isolated in reactivity with a specific antibody and its variable metal content distinguish it from metallothionein. The goal of this project is to elucidate the nature; the regulation; the role in cellular copper trafficking, excretion and sequestration; and the pathologic significance of CPP. The identity of CPP will be established by amino acid and DNA sequencing studies and the role of metals in its regulation will be investigated in cell models of human hepatoblastoma cell lines. A possible role as a biliary copper transporter will be defined by studying the excretion of radiocopper labeled CPP in cannulated rat bile. The topography of the distribution of CPP in normal and disease livers will be studied immunocytochemically and the role of lysosomes in causing defective biliary excretion will be explored. Results of these studies will provide a better understanding of the abnormality responsible for the phenotypic expression of the genetic defect which results in Wilson's disease and possibly elucidate the pathogenesis of Indian childhood cirrhosis and idiopathic copper toxicosis (""""""""Western"""""""" or """"""""non-Indian"""""""" Indian childhood cirrhosis).

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
7R01DK034668-07
Application #
2139357
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1986-08-01
Project End
1995-06-30
Budget Start
1993-07-01
Budget End
1995-06-30
Support Year
7
Fiscal Year
1993
Total Cost
Indirect Cost
Name
St. Luke's-Roosevelt Institute for Health Sciences
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10019
Scheinberg, I H; Sternlieb, I (1996) Wilson disease and idiopathic copper toxicosis. Am J Clin Nutr 63:842S-5S
Iancu, T C; Perl, D P; Sternlieb, I et al. (1996) The application of laser microprobe mass analysis to the study of biological material. Biometals 9:57-65
Sternlieb, I; Quintana, N; Volenberg, I et al. (1995) An array of mitochondrial alterations in the hepatocytes of Long-Evans Cinnamon rats. Hepatology 22:1782-7
Schilsky, M L; Stockert, R J; Sternlieb, I (1994) Pleiotropic effect of LEC mutation: a rodent model of Wilson's disease. Am J Physiol 266:G907-13
Schilsky, M L; Scheinberg, I H; Sternlieb, I (1994) Liver transplantation for Wilson's disease: indications and outcome. Hepatology 19:583-7
Tanzi, R E; Petrukhin, K; Chernov, I et al. (1993) The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet 5:344-50
Sternlieb, I (1992) Fraternal concordance of types of abnormal hepatocellular mitochondria in Wilson's disease. Hepatology 16:728-32
Hunziker, P E; Sternlieb, I (1991) Copper metallothionein in patients with hepatic copper overload. Eur J Clin Invest 21:466-71
Schilsky, M L; Scheinberg, I H; Sternlieb, I (1991) Prognosis of Wilsonian chronic active hepatitis. Gastroenterology 100:762-7
Farrer, L A; Bowcock, A M; Hebert, J M et al. (1991) Predictive testing for Wilson's disease using tightly linked and flanking DNA markers. Neurology 41:992-9

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