Novel Lipid Mediators in Human Neutrophil Signal Transduction in Resolution

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Studies in this Research Center have shown that human cells convert arachidonate and omega-3 fatty acids into highly potent, anti-inflammatory agents that promote the resolution of inflammation[e.g., resolvins, docosatrienes (DT), lipoxins]. Biosynthesis of these lipid mediators (LM) requires cell-cell interactions and is highly influenced by the presence of cytokines and aspirin. These mediators inhibit certain functional responses of neutrophils (PMN) in vitro and prevent influx of leukocytes in several models of acute inflammation including peridontal destruction. While receptors for some of these LM have been identified, the signaling pathways employed by these receptors remain largely unknown. Experiments presented in this proposal are aimed at filling this gap. Specifically, this sub-Project focuses on four unexplored areas of the signal transduction pathways in PMN. These are: (1) identifying receptors for the resolvins and DT in PMN and elucidating the signal transduction pathways that become activated when these receptors are occupied; (2) determining how resolvins and DT each impact the p38-MAPK cascade in PMN and the exact function(s) of leukocyte specific protein 1 (LSP1) in this pathway; (3) determine the biochemical basis for the reduced phosphorylation of LSP 1 in PMN from patients with localized aggressive periodontitis (LAP) and establish if this is responsible for the PMN functional defects in LAP, and (4) establish the functional responses of PMN that are altered by resolvins and DT, and evaluate the therapeutic potential of these compounds in tissue bioengineering implant studies for use in reconstructive craniofacial surgery. Techniques of biochemistry (enzymology), molecular biology (knockout experiments, protein expression), cell biology (IF microscopy) and animal pathophysiology (tissue bioengineering) will be employed in these investigations. These studies should provide new mechanistic insights into the beneficial effects of aspirin and omega-3 fatty acids on a variety of inflammatory diseases, and may result in new therapies to treat these conditions.