This is a request for an ADAMHA SDA, Level II award. The long-term career goal is to integrate immunology and alcohol research to study the effect of ethanol as an immune modulator of carcinogenesis, cancer growth, and metastasis. Specifically, the applicant will broaden his technological expertise in cell-mediated immunity and conduct experiments to define the mechanisms of ethanol's immunomodulation of natural killer (NK) cell activity at the biochemical and molecular levels. This award will facilitate the implementation of human research involving the role of alcohol as an immune modulator, and determine the biological relevance of alcohol-related immunosuppression to cancer. Currently, the applicant's research efforts are hampered by a high teaching load and substantial service responsibilities. If the SDA is funded, teaching responsibilities will be decreased from 25% to 0%, service responsibilities from 15% to 1%, and administrative responsibilities from 15% to 9%. Concurrent with these reductions will be an increase in research effort from 40% to 85%. The additional time for research will enable the applicant to visit other immunology laboratories and to import new biochemical and molecular techniques into his own research program. The hypothesis of the research proposal is that the suppressive effects of alcohol on NK cells are due to a combination of changes in the proportion of NK cells to other lymphocytes and decreased responsiveness of the NK cell. To examine this hypothesis, NK cell activity and distribution within the body will be determined after short-term and long-term ethanol consumption. Splenic NK cell activity will be compared with activity from other body compartments. The proportion and total number of NK cells relative to B lymphocytes, T lymphocytes, and macrophages will be assessed by flow cytometry. If distribution is affected, then the hypothesis that stress induced by ethanol consumption and/or decreased interferon (IFN) production contributes to these effects will be tested. Both factors modulate lymphocyte recruitment and distribution. The award will enhance the applicant's ability to examine the mechanisms underlying the suppressive effects of ethanol on NK cell activity. Possible defects in production of NK cytotoxic factors, alteration of target specificity, and altered binding or internalization of IL2 will be examined. If initial studies suggest that NK cell activity is modulated by the presence of other lymphocytes and macrophages, then controlled mixing experiments will be conducted using spleen cell suspensions purified for macrophages, B lymphocytes, T lymphocytes, and highly enriched NK cells. Enhanced production of suppressive factors such as PGE2 or reduced production of stimulatory factors, such as ILl, IL2, and/or TFN, will be examined if mixing experiments indicate a role for one or more of these cells in modulation of NK cell activity. The additional expertise obtained in molecular biology will enable the applicant ultimately to evaluate ethanol's effect on immunomodulators at the molecular level.
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