PHAGOCYTE RESOLVING METABOLISM

炎症通常是自我限制的，当“不受控制”时会导致组织损伤和器官损伤。 功能障碍。分解阶段是从急性炎症到稳态的一系列重要的细胞过程，即缓解期，人们普遍认为它是一个被动的过程1、2、3。在这个实验室，新的证据表明，分解是一个积极的过程，发现了新的专门的脂类介质(LM)，我们称之为解毒素和二十二碳三烯(保护素)，它们限制了炎症和组织损伤中的关键事件。现在很清楚的是，在分辨率范围内平衡新颖的光密度计是至关重要的。该项目的重点是利用中介-脂质组学和体内模型系统地阐明进一步的代谢(可能是失活)途径。在正在进行的工作中，我们发现解毒素，即RvE1和二十二碳三烯10，17-dt，积极地对小鼠和 人中性粒细胞(PMN)。我们将重点关注代谢转换这些LM的途径，并测试以下假设： 解决需要及时分解促进分解的脂质介体的代谢。解决方案和 二十二碳三烯是一种内源性抗炎信号，可以暂时地对促炎通路进行反调节，并控制中性粒细胞的运输以达到消退的目的。这些新型内源性抗炎介质的局部失活对缓解期至关重要。 为此，我们提出了四个具体的目标，包括：1.建立RV和DT代谢产物在体内和人PMN中的分解结构和途径；2.确定RV和DT转化途径可操作的分解区间(S)；3.确定新的RvE1和10，17-DT代谢产物与人PMN的作用；4.肾移植排斥和保护研究。 该项目的长期目标有两个：a)阐明参与分解-炎症的LM的失活途径；b)向临床医生提供这些基本分解途径的生化图(S)，了解这些途径可以改进当前的治疗方法。

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.