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This proposal is a request for an ADAMHA RSDA Level II award to continue the many new investigations that were instigated following the awarding of a K01 award in 1984. By carefully following and expanding upon the Supervised Research Experience and Development Plans outlined in the K01 program and taking full advantage of he personnel and equipment resources of the Alcohol Research Center, new approaches and methodologies have been developed and fruitfully applied to long-standing problems posed to alcohol researchers. This award has provided an opportunity to apply a strong background in membrane biochemistry and biophysics toward helping to better understand the mechanisms governing cellular adaptation to long-term alcohol exposure. We seek to elucidate the relationship between the physicochemical changes induced in biological membranes by short- and long- term ethanol treatment and the functional alterations in a variety of cells and tissues, ultimately leading to irreversible cell injury. Cells and sub-cellular organelles from the major body organs and tissues have been shown to undergo many cellular adaptations during chronic ethanol consumption, a common one being the development of so-called membrane tolerance. Membrane tolerance, or the inability of the membrane to be disordered by ethanol or anesthetics, has been shown in liver microsomes and mitochondria to be caused by alterations in particular anionic phospholipids. The major goals of this proposal are twofold. 1) To develop and utilize new methodologies (i.e. ESR and NMR (1H,2H,13C,31P and 19F) to investigate the molecular nature of the perturbations caused by ethanol, other alcohols and anesthetics with well-defined model membranes and biological membranes. These studies will provide unique information regarding the localized site of perturbation of the lipid molecules in the membrane by these agents, effects of alcohols and anesthetics on lipid polymorphic properties and the measurement of membrane partition coefficients. 2) To elucidate the molecular basis of membrane tolerance identical studies will be performed on lipids and membranes from animals chronically-fed ethanol. In addition, alterations in lipid fatty acyl chains and molecular species composition will be measured by capillary GC, reverse-phase HPLC and 1H and 13CNMR. Chemical alterations of the lipid headgroups (i.e. salt forms) will be measured by atomic absorption spectroscopy. The importance of the chemistry of the lipids, i.e the salt for (e.g Na+,Mg2+,Ca+2) or molecular species composition of the lipid, in determining the extent of the perturbation caused by ethanol will be systematically determined by substitution of lipids of different salt forms or molecular species into liposomes composed of lipids from untreated animals or a synthetic model system and measuring by ESR whether they are tolerant to disordering by ethanol in vitro.
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