Resolution Mechanisms in Acute Inflammation: Resolution Pharmacology

描述(申请人提供)：在许多人类情况下(例如炎症性肠病、败血症、多器官损伤和衰竭)，从急性炎症性侮辱到消退或慢性化的进展仍然无法预测。我们最近的发现表明，局部炎症的消退涉及到主动的消解回路，产生一类新的有效的专门化前消解介质(SPM)。SPM由不同的脂类介体(LM)结构家族组成，包括必需的omega-3脂肪酸衍生的解毒素、保护素和软脂素。新型SPM是一种有效的抗炎药物，它还可以刺激中性粒细胞对凋亡的摄取、微生物的遏制以及吞噬细胞和粘膜上皮细胞对它们的清除。这些发现揭示了临床上迫切需要导航解析以建立解析药理学的基本机制。为了解决这一健康使命，在这个项目中组建了一个多学科的专家团队，将使用系统的方法来阐明自限实验系统中的细胞和分子机制。我们的团队和整个项目专注于阐明急性炎症的程序性消解，重点是LM、SPM和用于新治疗的消解药理学。正在进行的研究产生了一个总体假设，并通过四个具有高度互补性的综合项目和协同方法进行了检验。整个新的假说是：溶血素、保护素和松脂素构成了一种新的SPM，它在时间上调节内源性抗炎和促消解途径。SPM通过调节白细胞反应、增强粘膜防御和细菌抑制来控制拆分，这些分子事件可以被利用于新的拆分药理学来治疗疾病。这个P01团队由4个项目、2个科学核心和一个咨询单位组成，专注于建立LM-拆分代谢组、SPM的立体控制合成及其在拆分、抗炎和清除途径中的特定机制。选定的合成SPM将被放大，以使用实验疾病模型在体内演示其独特的作用模式。我们的大目标是在解决问题上提出新的治疗方法。

DESCRIPTION (provided by applicant): In many human conditions (e.g. inflammatory bowel disease, sepsis, multi-organ injury and failure), the progression from acute inflammatory insult to either resolution or chronicity remains impossible to predict. Our recent findings indicate that resolution of local inflammation involves active resolution circuits that generate a novel genus of potent Specialized Pro-Resolving Mediators (SPM). SPM are comprised of distinct structural families of lipid mediators (LM) including resolvins, protectins and maresins derived from essential omega-3 fatty acids. Novel SPM that are potent anti-inflammatories also stimulate uptake of apoptotic neutrophils, microbial containment and their clearance by phagocytes and mucosal epithelia. These findings reveal an urgent clinical need to navigate resolution to establish fundamental mechanisms in resolution pharmacology. To address this health mission, a multidisciplinary team of experts is assembled in this program project that will use a systematic approach to elucidate cellular and molecular mechanisms in self-limited experimental systems. Our team and overall project is focused on elucidating programmed resolution of acute inflammation with an emphasis on LM, SPM and resolution pharmacology for new treatments. Ongoing studies give rise to an overarching hypothesis tested by four highly complementary integrated projects with synergistic approaches. The overall novel hypothesis addressed is: Resolvins, protectins and maresins constitute a new genus of SPM that temporally regulate endogenous anti inflammatory and pro-resolving pathways. SPM govern resolution via regulated leukocyte responses, enhanced mucosal defense and bacterial containment these molecular events can be harnessed for novel resolution pharmacology to treat diseases. This P01 team consists of 4 projects, 2 scientific cores and an advisory unit focused on establishing LM-resolution metabolome, stereo-controlled synthesis of SPM and their specific mechanisms in resolution, anti-inflammatory and clearance pathways. Selected synthetic SPM will be scaled-up for demonstration of their unique mode of action in vivo in a resolution pharmacology core using experimental disease models. Our broad goal is to bring forth new treatments in resolution.