Fatty acid binding proteins (FABPs) act as intracellular receptors for a variety of hydrophobic ligands and are believed to play a role in lipid transport, enabling delivery of hydrophobic compounds to enzyme systems responsible for metabolism and intracellular signaling. The importance of FABPs has been underscored by recent studies in which genetically engineered mice deficient in expression of adipocyte fatty acid binding protein (aP2) were found to display profound protection from both obesity-induced diabetes and atherosclerosis. Macrophages express high levels of aP2 and keratinocyte fatty acid binding protein (mal-1). AP2 and mal-1 are FABPs which have been demonstrated to bind several identified ligands for the peroxisome proliferator-activated receptors (PPARs) which include metabolites of cyclooxygenase and lipoxygenase. PPAR family members have been demonstrated to play an important role in the regulation of gene expression in macrophages. This proposal tests the hypothesis that FABPs control the availability of PPAR ligands, thus impacting macrophage gene expression and function. Experiments have been designed which distinguish between a role of FABPs in sequestration of PPAR ligands versus the synthesis of PPAR ligands. PPAR activity will be assessed, and the activity of transcription factors known to be regulated by PPARs will be analyzed in wild-type and FABP-deficient macrophages. Data collected thus far indicate that FABPs act as positive regulators of pro-inflammatory activity, suggesting that absence of FABPs may be protective in autoimmune inflammatory disease. This concept is supported by preliminary data using the experimental autoimmune encephalomyelitis (EAE) murine model of multiple sclerosis. This model will be employed to provide a means to analyze FABP function, in vivo, in an autoimmune inflammatory response in which macrophage pro-inflammatory activity has been shown to be key to the progression of disease. These studies may reveal a unique means of modulating macrophage function for therapeutic purposes. ? ?
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