The basic principle underlying this proposal for renewal of support for years 11-15 of this grant is the assumption that the pathogenesis of alcoholic liver injury may be intimately related to membrane alterations. We propose to study the effects of ethanol and acetaldehyde in vitro, and of chronic ethanol ingestion on hepatocyte membranes at three levels: (1) combined biophysical and biochemical analysis of the structures of intact and reconsituted membranes, (2) correlation of changes in membrane-associated functions with the physciochemical state of the membranes, and (3) effects of perturbation of membrane structure and function. In addition to biochemical methods previously used, techniques will include temperature dependence, fluorescence anisotropy with several dyes, EPR, NMR, light scattering, reconstitution of extracted lipids into liposomes, and phospholipid transfer. Preparations will include the intact rat, isolated hepatocytes in suspension and in primary culture, and various cell fractions containing membranes of mitochondria, endoplasmic reticulum and the plasma membrane. We hope that these studies will contribute to our understanding of the molecular basis of cellular alterations in the liver caused by alcohol abuse.
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