Resolution Mechanisms in Acute Inflammation: Resolution Pharmacology

急性炎症的消退机制：消退药理学

• 批准号: 8641129
• 负责人: Charles Nicholas Serhan
• 金额: $ 136.06万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8641129
• 关键词: Abbreviations; Accounting; Acute; Address; Agonist; Alzheimer' s Disease; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Area; Aspirin; Asthma; Awareness; Biochemical; Boxing; CD59 Antigen; Cardiovascular system; Caring; Chemicals; Chronic; Clinical; Coin; Communication; Communities; Containment; Development; Diabetes Mellitus; Disease; Disease model; Docosahexaenoic Acids; Eicosapentaenoic Acid; Epithelial; Epithelial Cells; Epithelium; Event; Failure; Family; Funding; Future; Glossary; Goals; Grant; Health; Healthcare; Homeostasis; Human; Immunosuppression; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Injury; Interdisciplinary Study; Invaded; Knowledge; LOX gene; Laboratories; Lead; Learning; Length of Stay; Leukocytes; Leukotrienes; Lipids; Lipoxins; Lipoxygenase; Liquid Chromatography; Mediator of activation protein; Medicine; Microbe; Mission; Molecular; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of General Medical Sciences; Natural Immunity; Omega-3 Fatty Acids; Operative Surgical Procedures; Oral; Organ; Organic Synthesis; Organism; Pathway interactions; Patient Care; Performance; Phagocytes; Phagocytosis; Pharmacology; Phase; Physiological; Principal Investigator; Process; Prostaglandins; Public Health; Research Infrastructure; Research Personnel; Resolution; Role; Sepsis; Series; Signal Transduction; Structure; Surface; System; Testing; Therapeutic; Tissues; Translations; Trauma; United States National Institutes of Health; Work; Yang; base; clinical practice; design; economic impact; effective therapy; experience; human disease; human tissue; improved; in vivo; injured; insight; lipid mediator; macrophage; meetings; microbial; mimetics; multidisciplinary; neuroprotectin D1; neutrophil; novel; novel strategies; novel therapeutic intervention; pre-clinical; prevent; programs; repaired; response; scale up; small molecule; tandem mass spectrometry; uptake

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.

描述（由申请人提供）：在许多人类病症（例如炎症性肠病、脓毒症、多器官损伤和衰竭）中，从急性炎症损伤到消退或慢性的进展仍然无法预测。我们最近的研究结果表明，局部炎症的消退涉及主动消退回路，该回路产生一类新的有效的专门促消退介质（SPM）。 SPM 由不同结构的脂质介质 (LM) 家族组成，包括衍生自必需 omega-3 脂肪酸的分解素、保护素和 maresins。新型 SPM 是有效的抗炎药，还能刺激凋亡中性粒细胞的摄取、微生物的抑制以及吞噬细胞和粘膜上皮的清除。这些发现揭示了临床迫切需要引导分辨率以建立分辨率药理学的基本机制。为了完成这一健康使命，该计划项目组建了一个多学科专家团队，该团队将使用系统方法来阐明自限性实验系统中的细胞和分子机制。我们的团队和整个项目致力于阐明急性炎症的程序化解决方案，重点是 LM、SPM 和新疗法的解决药理学。正在进行的研究提出了一个总体假设，并通过四个高度互补的综合项目和协同方法进行了检验。总体上提出的新颖假设是：消解素、保护素和 maresins 构成了 SPM 的一个新属，可暂时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分辨率，这些分子事件可用于新的分辨率药理学来治疗疾病。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具体机制。选定的合成 SPM 将进行放大，以使用实验疾病模型在分辨率药理学核心中展示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法。