Project 1 : Novel Specialized Pro-Resolving Lipid Mediators

项目 1：新型专业化脂质调节剂

• 批准号: 8375334
• 负责人: Charles Nicholas Serhan
• 金额: $ 39.23万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8375334
• 关键词: Acute; Address; Anabolism; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Appearance; Biological Models; CD59 Antigen; Cause of Death; Cells; Clinical; Coin; Coupled; Disease; Eicosanoids; Escherichia coli; Event; Exudate; Family; Goals; Homeostasis; Human; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injury; Kidney; Knowledge; Link; Lipids; Mediator of activation protein; Microbe; Modeling; Molecular; Mus; Pathway interactions; Peritonitis; Phagocytes; Pharmacology; Population; Process; Production; Resolution; Role; Sepsis; Sterility; Stimulus; System; Testing; Tissues; Yeasts; Zymosan; antimicrobial; clinical practice; human disease; improved; in vivo; in vivo Model; indexing; lipid mediator; macrophage; microbial; neutrophil; novel; novel strategies; particle; programs; response; stereochemistry; tool; uptake

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.

局部急性炎症是保护性的，理想情况下应该是自限性的。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，与识别新的专门proresolving脂质衍生介质（SPM），我们创造了resolvins和protectins。这些局部介质具有有效的抗炎和促消退作用。现在很明显，在体内系统模型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液进行自限性与未消退炎症期间的消退组分进行系统阐明。使用这种方法，我们最近发现了一个新的脂质介质家族，称为maresins（解决炎症的巨噬细胞介质; MaR），它积极调节中性粒细胞（PMN）和巨噬细胞。项目1将检验以下新假设： 在自限性炎症过程中，渗出液中新型抗炎和促消退介质的局部产生增强了凋亡细胞和微生物的清除，以及时消退。Resolvins，protectins和maresins是一种新发现的SPM属，在时间上控制组织分解和恢复稳态所需的PMN和巨噬细胞反应。为解决这一问题，提出了三个具体目标： 1)确定消退过程中消退素和保护素（SPM）生物合成之间的时间关系。我们将确定与SPM和项目2和3的自限性决议所涉及的关键事件; 2）决议期间新maresins和resolvins的激活。MaR显示出有效的抗炎和促消退作用。该目标将重点关注项目4的MaR生物合成和立体化学，并将在具有核心C的人类疾病模型中建立促消退和保护作用，以及3）maresins和resolvins在消退中吞噬细胞反应中的影响。在这里，我们将确定SPM，加快分辨率，清除吞噬细胞抗微生物活性在小鼠和人类吞噬细胞。这些结果将共同确定新型SPM在炎症消退中的作用。