Novel Lipid Mediators in Neutrophil Signal Transduction

本研究中心的研究表明，人体细胞将花生四烯酸酯和omega-3脂肪酸转化为高效的抗炎剂，促进炎症的消退。二碳三烯（DT），脂毒素]。这些脂质介质（LM）的生物合成需要细胞间相互作用，并受到细胞因子和阿司匹林存在的高度影响。这些介质在体外抑制中性粒细胞（PMN）的某些功能反应，并在几种急性炎症模型（包括周周破坏）中阻止白细胞的流入。虽然已经确定了其中一些LM的受体，但这些受体所使用的信号传导途径在很大程度上仍然未知。本文介绍的实验

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.