Role of Lipid Peroxidation in ALD: The long-term goal is to determine the pathogenesis of alcoholic liver disease (ALD).
Specific Aims are: 1) To determine the role played by 26s proteasome peptidase inhibition in the protein retention in hepatocytes in experimental ALD in the rat and mouse. 2) To determine the role played by the 20s proteasome peptidase inhibition in the removal of oxidized proteins in hepatocytes in experimental ALD. 3) To determine at the individual liver cell level, using in situ assessment of the phosphorylation-ubiquitin- proteasome pathway, whether the proteasome function is damages in ALD. The studies will focus on correlations made between histopathology, immunohistochemistry and biochemical measurements made on the livers of rats and mouse fed ethanol intragastrically for 2-4 months when significant alterations of liver histology has developed. The basic concept to be tested is that oxidative stress and free radical induced injury initiates a change in protein turnover in the liver cell which shifts the balance between protein synthesis and protein elimination in the liver cell where the net result is protein retention and cell enlargement. Mice deficient in or over expressing CYP2E1 will be studies using the intragastric ethanol feeding model in order to better access the role of CYP2E1 in the pathogenesis of liver cell protein retention in experimental ALD. The mechanism which accounts for the up regulation of CYP2E1 and other proteins retained in the liver cytosol will be identified. In this way the pathogenesis o liver cell enlargement will be determined and the role that this phenomenon plays in ALD will be defined.
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