This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Asthma is a disease that affects over 20 million people and its prevalence in the US increased by 74% from 1980 to 1995. Inhibition of leukotriene production is a proven approach for the management of asthma and allergic rhinitis. We believe that leukotriene inhibition can be optimized to achieve similar results as pharmacologic agents if the mechanism of action of fatty acids in the most efficacious oils can be determined and then fatty acids altered accordingly. This proposal takes a systematic approach to answer these questions in humans. The protocol focuses on the biochemical basis by which fatty acids inhibit leukotriene biosynthesis. Experiments are directed at measuring the in vitro and in vivo effects of these fatty acids on the production of critical intermediates in the leukotriene generation pathway and the expression of enzymes and cytokines that participate in inflammation and arachidonic acid metabolism. Two specific hypotheses are tested: 1) GLA inhibition of leukotriene generation centers around the metabolic intermediate, dihommogammalinolenic acid (DGLA) and 2) and fatty acid supplementation impacts gene expression to reduce message and protein levels of enzymes that participate in leukotriene generation. We believe these studies will increase the likelihood that botanical oils such as borage can be effectively utilized to block leukotriene generation in inflammatory diseases.
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