Project 1 : Novel Specialized Pro-Resolving Lipid Mediators

局部急性炎症是保护性的，理想情况下应该自我限制。我们最近的证据表明，无菌急性炎症的解决是一个积极的过程，与新的专门生产脂质衍生介质（SPM）的鉴定，我们创造了解决和保护。这些局部介质具有有效的抗炎和促溶作用。现在很明显，在模型体内系统中，由凋亡细胞或细菌入侵引起的炎症的解决在很大程度上仍然是未知的，并且是迫切需要的。本项目项目1的重点是使用无偏倚介质-脂质组学方法对渗出液中自限性和非消解性炎症的溶解成分进行系统阐明。利用这种方法，我们最近发现了一个新的脂质介质家族，称为maresin（巨噬细胞调解炎症的介质；MaR），它积极调节中性粒细胞（PMN）和巨噬细胞。项目1将测试以下新假设：

Local acute inflammation is protective and ideally should be self-limited. Our recent evidence indicates that resolution of sterile acute inflammation is an active process with the identification of novel specialized proresolving lipid-derived mediators (SPM) we coined resolvins and protectins. These local mediators possess potent anti-inflammatory and pro-resolving actions. It is now evident that the resolution of inflammation caused by apoptotic cells or bacterial invasion in model in vivo systems remains largely uncharted and is critically needed. The focus of Project 1 in this program project is the systematic elucidation of resolution components during self-limited verses un-resolved inflammation using an unbiased mediator-lipidomics approach with exudates. Using this approach, we recently uncovered a new family of lipid mediators coined maresins (macrophage mediators in resolving inflammation; MaR) that actively regulate both neutrophils (PMN) and macrophages. Project 1 will test the following novel hypothesis : During self-limited inflammation local production of novel anti-inflammatory and pro-resolving mediators in exudates enhances the clearance of apoptotic cells and microbes for timely resolution. Resolvins, protectins and maresins are a newly identified genus of SPM that temporally govern PMN and macrophage responses required for tissue resolution and return to homeostasis. To address this, 3 specific aims are proposed: 1) Determine temporal relationship between resolvin and protectin (SPM) biosynthesis during resolution. We will determine the key events involved in self-limited resolution with SPM and with Projects 2 and 3; 2) Activation of novel maresins and resolvins during resolution. MaR display potent anti-inflammatory and proresolving actions. This aim will focus on MaR biosynthesis and stereochemistry with Projects 4 and will establish pro-resolving and protective actions in models of human disease with Core C and 3) Impact of maresins and resolvins in phagocyte responses in resolution. Here, we will identify SPM that accelerate resolution, clearance phagocyte anti-microbial activities in mice and human phagocytes. Together results from these will establish the role of novel SPM in resolution of inflammation.