Novel Lipid Mediators in Human Neutrophil Signal Transduction in Resolution

人中性粒细胞信号转导中的新型脂质介质的分辨率

• 批准号: 7676065
• 负责人: JOHN A BADWEY
• 金额: $ 29.93万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7676065
• 关键词: 1,2-diacylglycerol; Abbreviations; Acute; Adherence; Adhesions; Affect; Affinity; Anabolism; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Area; Aspirin; Autologous; Bacteria; Binding; Biochemical; Biochemistry; Biomedical Engineering; Cell Communication; Cells; Cellular biology; Chemotactic Factors; Chemotaxis; Condition; Congenital Abnormality; Data; Defect; Diglycerides; Disease; Dissociation; Docosahexaenoic Acids; Eicosapentaenoic Acid; Enzymatic Biochemistry; Epithelial; Exhibits; F-Actin; Family; Functional disorder; Generations; Genetic; Human; Implant; In Vitro; Infection; Inflammation; Inflammatory; Injury; Investigation; Knock-out; Knowledge; Leukocytes; Lipoxin Receptors; Lipoxins; Localized; MAPK14 gene; Mediator of activation protein; Methods; Microscopy; Modeling; Molecular Biology; Monomeric GTP-Binding Proteins; Mus; Mutation; Numbers; Omega-3 Fatty Acids; Operative Surgical Procedures; Pathway interactions; Patients; Pattern; Periodontitis; Peroxides; Phagocytosis; Phosphatidylinositols; Phosphoproteins; Phosphorylation; Plastics; Play; Polymers; Post-Translational Protein Processing; Process; Production; Protein Dephosphorylation; Protein Isoforms; Protein phosphatase; Proteins; Proteomics; Reaction; Reconstructive Surgical Procedures; Regulation; Research; Resolution; Role; Second Messenger Systems; Series; Shapes; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Site; Sphingosine; Stress; Structure-Activity Relationship; Superoxides; Surface; Techniques; Testing; Therapeutic; Tissue Engineering; Tissues; Trauma; analog; arachidonate; base; chemokine; craniofacial; cytokine; improved; inhibitor/antagonist; inorganic phosphate; insight; killings; lipid mediator; lipoxin A4; neutrophil; novel; polymerization; prevent; protein expression; receptor; receptor downregulation; research study; response; scaffold; second messenger

Studies in this Research Center have shown that human cells convert arachidonate and omega-3 fatty acids into highly potent, anti-inflammatory agents that promote the resolution of inflammation[e.g., resolvins, docosatrienes (DT), lipoxins]. Biosynthesis of these lipid mediators (LM) requires cell-cell interactions and is highly influenced by the presence of cytokines and aspirin. These mediators inhibit certain functional responses of neutrophils (PMN) in vitro and prevent influx of leukocytes in several models of acute inflammation including peridontal destruction. While receptors for some of these LM have been identified, the signaling pathways employed by these receptors remain largely unknown. Experiments presented in this proposal are aimed at filling this gap. Specifically, this sub-Project focuses on four unexplored areas of the signal transduction pathways in PMN. These are: (1) identifying receptors for the resolvins and DT in PMN and elucidating the signal transduction pathways that become activated when these receptors are occupied; (2) determining how resolvins and DT each impact the p38-MAPK cascade in PMN and the exact function(s) of leukocyte specific protein 1 (LSP1) in this pathway; (3) determine the biochemical basis for the reduced phosphorylation of LSP 1 in PMN from patients with localized aggressive periodontitis (LAP) and establish if this is responsible for the PMN functional defects in LAP, and (4) establish the functional responses of PMN that are altered by resolvins and DT, and evaluate the therapeutic potential of these compounds in tissue bioengineering implant studies for use in reconstructive craniofacial surgery. Techniques of biochemistry (enzymology), molecular biology (knockout experiments, protein expression), cell biology (IF microscopy) and animal pathophysiology (tissue bioengineering) will be employed in these investigations. These studies should provide new mechanistic insights into the beneficial effects of aspirin and omega-3 fatty acids on a variety of inflammatory diseases, and may result in new therapies to treat these conditions.

该研究中心的研究表明，人体细胞可将花生四烯酸和 omega-3 脂肪酸转化为高效抗炎剂，促进炎症消退[例如消退素、二十二碳三烯 (DT)、脂氧素]。这些脂质介质 (LM) 的生物合成需要细胞与细胞之间的相互作用，并且受到细胞因子和阿司匹林存在的高度影响。这些介质在体外抑制中性粒细胞 (PMN) 的某些功能反应，并在包括牙周破坏在内的几种急性炎症模型中防止白细胞流入。虽然其中一些 LM 的受体已被识别，但这些受体所采用的信号传导途径仍然很大程度上未知。本文中介绍的实验 提案旨在填补这一空白。具体来说，该子项目重点关注中性粒细胞信号转导途径的四个未探索领域。这些是：（1）鉴定PMN中的resolvins和DT的受体，并阐明当这些受体被占据时被激活的信号转导途径； (2) 确定解析素和 DT 如何各自影响 PMN 中的 p38-MAPK 级联以及白细胞特异性蛋白 1 (LSP1) 在该途径中的确切功能； (3) 确定局部侵袭性牙周炎 (LAP) 患者 PMN 中 LSP 1 磷酸化减少的生化基础，并确定这是否是 LAP 中 PMN 功能缺陷的原因，(4) 确定由消解素和 DT 改变的 PMN 功能反应，并评估这些药物的治疗潜力 用于重建颅面手术的组织生物工程植入物研究中的化合物。这些研究将采用生物化学（酶学）、分子生物学（敲除实验、蛋白质表达）、细胞生物学（IF显微镜）和动物病理生理学（组织生物工程）技术。这些研究应该为阿司匹林和 omega-3 脂肪酸对各种炎症性疾病的有益作用提供新的机制见解，并可能产生治疗这些疾病的新疗法。