PHAGOCYTE RESOLVING METABOLISM

炎症通常是自限性的，当“不受控制”时，会导致组织损伤和器官损伤。 功能障碍解决阶段是一系列基本的细胞过程，导致从急性炎症到稳态，即缓解，已被广泛认为是一个被动的过程1，2，3。在这个实验室中，新的证据表明，解决是一个积极的过程，与识别新的专门的脂质衍生介质（LM），我们称为resolvins和docosatrienes（protectins），限制炎症和组织损伤的关键事件。现在清楚的是，分辨率内的新LM的平衡是至关重要的。该项目的重点是使用介体脂质组学和体内模型系统阐明进一步代谢（可能失活）途径。在进行中的工作中，我们发现消退素，即RvE 1和二十二碳三烯10，17-DT，积极地反调节小鼠和 人中性粒细胞（PMN）。我们将专注于代谢转化这些LM的途径，并检验以下假设： 消退需要及时代谢分解促消退脂质介质。消退素和 二十二碳三烯是内源性抗炎信号，其在时间上反调节促炎性回路并控制PMN运输朝向消退。这些新的内源性神经递质的局部失活对于缓解是必不可少的。 为此，提出了四个具体目标，其中包括：目标1。建立Rv和DT衍生代谢物在体内和人PMN中的结构和途径; 2.识别Rv & DT转换途径起作用时的分辨率间隔; 3.确定新的RvE 1和10，17-DT衍生的代谢产物与人PMN的作用; 4.肾移植排斥和保护研究。 本项目的长期目标有2个方面：a）阐明参与消退-炎症的LM的灭活途径，以及B）为临床医生提供这些基本消退途径的生化图谱，了解这些图谱可以改善当前治疗。

Inflammation is usually self-limited and when "uncontrolled" leads to tissue damage and organ dysfunction. The resolution phase is a series of essential cellular processes that lead from acute inflammation to homeostasis, namely catabasis that has been widely believed to be a passive process 1, 2, 3. In this laboratory, new evidence has emerged indicating that resolution is an active process with the identification of novel specialized lipid-derived mediators (LM) we termed resolvins and docosatrienes (protectins) that limit key events in inflammation and tissue injury. It is now clear that the balance of novel LM within resolution is critical. The focus of this project is the systematic elucidation of further metabolic (likely inactivation) routes within resolution using mediator-lipidomics and in vivo models. In work in progress, we found that resolvins, namely, RvE1 and the docosatriene 10,17-DT, actively counter-regulate murine and human neutrophils (PMN). We will focus on the pathways that metabolically transform these LM and test the hypothesis that: Resolution requires timely metabolic breakdown of pro-resolving lipid mediators. Resolvins and docosatrienes are endogenous anti-inflammatory signals that temporally counter-regulate proinflammatory circuits and govern PMN traffic toward resolution. Local inactivation of these novel endogenous antiinflammatory mediators is essential for catabasis. To this end, four specific aims are proposed, which include: Aim 1. Establishing the structures and pathways of Rv and DT-derived metabolites in resolution in vivo and human PMN; 2. Identify the resolution interval(s) when Rv & DT transformation pathways are operative; 3. Determine the actions of the new RvE1 and 10,17-DT-derived metabolites with human PMN; 4. Renal transplant rejection and protection studies. Long-term goals for this project are 2-fold: a) to elucidate the inactivation pathways for LM involved in resolution-inflammation and b) to provide biochemical map(s) of these essential resolution pathways to clinicians, knowledge of which can improve current treatments.