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. Over the past decade, my laboratory, in collaboration with the General Clinical Research Center at Wake Forest University School of Medicine and the Phase I Clinical Trials Center at Quintiles Transnational, have conducted six early stage (discovery and phase I-like) clinical trials in over 240 subjects examining the effects of fatty acids found in dietary supplements on leukotriene biosynthesis in both healthy and asthmatic subjects. These studies reveal that fatty acids such as gammalinolenic acid (GLA) and eicosapentaenoic acid (EPA) can induce modest inhibition of leukotriene generation. However it is our hypothesis 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 (i.e.borage oil emulsions) can be determined, if other botanical oils can safely substitute for oils that contain EPA to enhance leukotriene inhibition and if we can determine why fatty acid emulsions block leukotriene production in some healthy subjects and some asthmatic patients and have little effect in others. This proposal takes a systematic approach to answer these questions in humans.
Aim 1 a of the proposal focuses on the biochemical basis by which fatty acids, and GLA in particular, 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.
Aim 1 b will clarify the association between leukotriene inhibition and leukotriene generation and determine whether the potency in some individuals is associated with the presence of genetic variants in the enzymes that participate leukotriene biosynthesis.
The second aim of this application will examine the potential of a fatty acid, stearidonic acid, in a relatively new seed oil from Echium Plantagineum to block the delta-5 desaturase activity and leukotriene production in healthy humans. We believe these studies will increase the likelihood that botanical oils such as borage and echium can be utilized to block leukotriene generation in inflammatory diseases.
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