The current proposal represents a continuation of the candidate's research on the regulation of epidermal differentiation, with specific emphasis on the effects of polyunsaturated fatty acids. The proposal sets forth the hypothesis that specific n3 fatty acids found in fish oil can regulate and alter normal epidermal biology. Since other fatty acids of the n6 polyunsaturated family and their eicosanoid derivatives are known regulators of epidermal biology, it is reasonable to propose that the n3 fatty acid family and their unique metabolites may alter the normal progression of keratinocyte differentation by substitution for n6 fatty acids in membrane lipids, metabolic reactions, and structural components of the keratinocyte. This hypothesis will be tested by enriching cultured human neonatal keratinocytes with either eicosapentaenoic (20:5n3) or docosahexaenoic (22:6n3) acids and monitoring their proliferation and differentiation patterns, using known morphologic and biochemical markers of keratinocyte maturation. The pattern of incorporation of these fatty acids into cellular lipids as well as their leukotriene and prostaglandin metabolic products will be examined. Additionally, the preferential sequestration of n3 fatty acids to specific keratinocyte organelles will be determined. These studies should not only clarify what effect fish oil derived n3 fatty acids, now gaining popularity as dietary supplements, have on skin structure and function, but should also help to elucidate the mechanism by which these fatty acids alter epidermal biology. An RCDA would free the candidate from clinical, teaching, and administrative responsibilities within the department, enhancing the candidate's research in two ways. First, more uninterrupted time would become available for reading, writing and long-term experiments. Second, and more important, with large blocks of time available, the candidate will be able to develop new techniques necessary to establish herself as an independent investigator.
