Project 1 : Novel Specialized Pro-Resolving Lipid Mediators

局部急性炎症是保护性的，理想情况下应该是自我限制的。我们最近的证据表明，无菌急性炎症的消退是一个活跃的过程，我们发明了溶血素和保护素来鉴定新的专门化的脂类衍生介质(SPM)。这些本地调解人具有强大的抗炎和亲消解作用。现在很明显，在活体模型系统中，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未知，并且是迫切需要的。本计划项目中项目1的重点是使用无偏倚的介质-脂质组学方法对渗出物的自限和未分解炎症期间的拆分成分进行系统的阐明。使用这种方法，我们最近发现了一种新的脂类介体家族，称为maresins(化解炎症的巨噬细胞介体；MAR)，它可以主动调节中性粒细胞(PMN)和巨噬细胞。项目1将检验以下新假设： 在自限性炎症期间，渗出物中新的抗炎和促分解介质的局部产生增强了对凋亡细胞和微生物的清除，以便及时化解。溶血素、保护素和树脂素是一种新发现的SPM属，它们在时间上控制PMN和巨噬细胞的反应，这是组织分解和恢复内稳态所必需的。为解决这一问题，提出了3个具体目标： 1)确定分解蛋白和保护素(SPM)生物合成在分解过程中的时间关系。我们将通过SPM和项目2和3确定自限拆分中涉及的关键事件；2)在拆分过程中激活新的树脂素和解析剂。MAR具有较强的抗炎和促消炎作用。这一目标将以项目4的MAR生物合成和立体化学为重点，并将在核心C的人类疾病模型中建立促进分解和保护作用，以及3)分解中的松脂和分解素对吞噬细胞反应的影响。在这里，我们将鉴定SPM具有促进小鼠和人吞噬细胞分解、清除吞噬细胞的抗微生物活性。综合这些结果，将确定新型SPM在消炎方面的作用。

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.