Resolution Mechanisms in Acute Inflammation: Resolution Pharmacology

描述（由申请人提供）：在许多人类疾病（例如炎症性肠病、败血症、多器官损伤和衰竭）中，从急性炎症损伤到消退或慢性化的进展仍然无法预测。我们最近的研究结果表明，局部炎症的解决涉及主动解决电路，产生一种新的有效的专业促解决介体（SPM）。SPM由脂质介质（LM）的不同结构家族组成，包括源自必需ω-3脂肪酸的消退素、保护素和maresins。新型SPM是有效的抗炎药，也刺激凋亡中性粒细胞的摄取，微生物的遏制和吞噬细胞和粘膜上皮细胞的清除。这些发现揭示了迫切的临床需要导航分辨率，以建立解决药理学的基本机制。为了解决这一健康使命，一个多学科的专家团队在这个项目中组装，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的重点是阐明急性炎症的程序化解决方案，重点是LM，SPM和新治疗的解决药理学。正在进行的研究产生了一个总体假设，由四个高度互补的综合项目与协同方法进行测试。解决的整体新的假设是：Resolvins，protectins和maresins构成了一个新的属SPM的时间调节内源性抗炎和促消退途径。SPM通过调节白细胞反应、增强粘膜防御和细菌遏制来控制消退，这些分子事件可以用于新的消退药理学来治疗疾病。该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分辨率代谢组，SPM的立体控制合成及其在分辨率，抗炎和清除途径中的特定机制。选定的合成SPM将按比例放大，以使用实验疾病模型在分辨率药理学核心中证明其独特的体内作用模式。我们的总体目标是提出新的解决方案。

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.