The mammalian liver is the central organ for the maintenance of copper homeostasis. This balance is achieved through the interplay of uptake of copper by the hepatocytes, incorporation of the metal into constitutive and export proteins, storage in certain organelles and excretion of the excess copper via the bile. In order to better identify and characterize these functions, we plan to use a human hepatoblastoma derived cell line, HepG2. This in vitro system should help identify the intracellular storage proteins as well as the site where copper is incorporated into the export glycoprotein, ceruloplasmin. The effects of copper toxicity on cellular structure and function caused by increasing copper concentrations will be studied. The isolation and characterization of mutants tolerant to excessive amounts of copper will be attempted in order to elucidate the nature of alterations of copper homeostasis. These studies should contribute to a better understanding of the mechanisms that regulate or disturb copper balance in human subjects who suffer from one or another form of hepatic copper toxicosis, namely Wilson's disease, Indian childhood cirrhosis, idiopathic copper toxicosis and primary biliary cirrhosis. Detailed knowledge of the effects of chelating agents on copper uptake, storage and efflux at the cellular level should lead to the design of improved therapeutic regimens for patients and animals suffering from hepatic copper overload.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK034668-03
Application #
3232949
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1986-08-01
Project End
1989-07-31
Budget Start
1988-08-01
Budget End
1989-07-31
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461
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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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