Regulation of Pulmonary Prostaglandins by Leukotriene E4

白三烯 E4 对肺前列腺素的调节

• 批准号: 7895671
• 负责人: Joshua A Boyce
• 金额: $ 39.77万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895671
• 关键词: 1-Phosphatidylinositol 3-Kinase; Abbreviations; Accounting; Address; Adenosine Diphosphate; Affinity; Agonist; Allergens; Allergic; Allergic Reaction; Antibodies; Arachidonate 5-Lipoxygenase; Arachidonic Acids; Arts; Aspirin; Asthma; Biochemical; Biology; Bone Marrow; Bronchoconstriction; Cell Proliferation; Cells; Chemicals; Chemosensitization; Clinical Research; Complex; Dendritic Cells; Dermatophagoides; Development; Drug Delivery Systems; Edema; Employee Strikes; Energy Transfer; Extracellular Signal Regulated Kinases; Fc Receptor; Fluorescein-5-isothiocyanate; Fluorescence Resonance Energy Transfer; Fluorescence-Activated Cell Sorting; Functional disorder; G-Protein-Coupled Receptors; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic; Histidine; Histidine Decarboxylase; Human; Hydroxyeicosatetraenoic Acids; Hypersensitivity; IgE; Image; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory; Insulin-Like-Growth Factor I Receptor; Interleukins; Isothiocyanates; Leukotriene E4; Leukotrienes; Ligand Binding Domain; Ligands; Lung; Lung diseases; Lysophospholipids; MEKs; Macrophage Inflammatory Proteins; Mediating; Mediator of activation protein; Methodology; Microscopy; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Molecular; Mononuclear; Mouse Strains; Mucositis; Mus; Oral; Ovalbumin; Pathology; Pathway interactions; Periodic acid Schiff stain method; Peroxisome Proliferator-Activated Receptors; Pertussis Toxin; Pharmacology; Phosphotransferases; Pneumonia; Polymerase Chain Reaction; Process; Prostaglandin D2; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Proteins; Publishing; Pulmonary Function Test/Forced Expiratory Volume 1; Pyroglyphidae; Receptor Protein-Tyrosine Kinases; Regulation; Role; Sampling; Side; Small Interfering RNA; Stem Cell Factor; Translating; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Work; airway hyperresponsiveness; airway inflammation; cell type; cellular targeting; cysteinyl-leukotriene; drug efficacy; in vivo; inhibitor/antagonist; interleukin 9 receptor; leukotriene-C4 synthase; light scattering; lysophosphatidic acid; mast cell; novel; progesterone 11-hemisuccinate-(2-iodohistamine); prostaglandin D receptor; prostaglandin R2 D-isomerase; protein tyrosine kinase PYK2; receptor; response; small hairpin RNA; tool

This proposal seeks to determine the mechanisms and receptors by which leukotriene (LT)E4, the most stable ligand of the cysteinyl leukotrienes (cys-LTs), activates mast cells (MCs) and promotes pulmonary inflammation. An abundance of historical information supports the existence of a distinct receptor for LTE4 Our published studies demonstrate that LTE4 is the most potent cys-LT for both for human MC proliferation in vitro and potentiation of airway inflammation in vivo, and it activates human MCs by a mechanism independent of CysLT1R and CysLT2R. Our Preliminary Studies strongly indicate that the P2Y12 receptor, an adenosine diphosphate-responsive GPCR, is also the LTE4-reactive receptor (hereafter termed P2Y12/CysLT3R) mediating the effects of LTE4 on MCs in vitro and on lung pathology in vivo. The central hypothesis is that LTE4, the weakest agonist of the cys-LTs at their known receptors, is the most relevant cys-LT for promoting allergic mucosal inflammation. A corollary hypothesis is that the actions of LTE4 are mediated by a previously unrecognized cys-LT-reactive G protein-coupled receptor (GPCR), hereafter referred to as "P2Y12/CysLT3R". Aim 1 uses in vitro approaches to prove that P2Y12/CysLT3R is a true LTE4-reactive receptor. Aim 2 seeks to prove that P2Y12/CysLT3R accounts for the striking proinflammatory effects of LTE4 in the lung in vivo, and to identify the essential cellular targets of this effect. The findings are expected to have immediate implications for asthma pathophysiology and treatment. ?? ?? ?? ??

该提议旨在确定白三烯（LT）E4（半胱氨酰白三烯（cys-LT）的最稳定配体）激活肥大细胞（MC）并促进肺部炎症的机制和受体。大量的历史信息支持存在一个独特的受体LTE 4我们发表的研究表明，LTE 4是最有效的cys-LT的人MC增殖在体外和增强气道炎症在体内，它激活人MC的CysLT 1 R和CysLT 2 R的独立机制。我们的初步研究强烈表明，P2 Y12受体，腺苷二磷酸响应GPCR，也是LTE 4反应性受体（以下称为P2 Y12/CysLT 3R）介导的LTE 4对MC在体外和肺病理学在体内的影响。中心假设是LTE 4，cys-LT在其已知受体上的最弱激动剂，是促进过敏性粘膜炎症的最相关的cys-LT。一个必然的假设是，LTE 4的作用是由以前未被识别的cys-LT反应性G蛋白偶联受体（GPCR）介导的，下文称为“P2 Y12/CysLT 3R”。目的1通过体外实验证明P2 Y12/CysLT 3R是一个真正的LTE 4反应性受体。目的2试图证明P2 Y12/CysLT 3R解释LTE 4在体内肺中的显著促炎作用，并鉴定该作用的基本细胞靶点。这些发现有望对哮喘的病理生理学和治疗产生直接影响。 ?? ?? ?? ??