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. ?? ?? ?? ??

该建议旨在确定白三烯（LT）E4（Cysteinyl Leukotrienes（CYS-LTS））的机制和受体，激活肥大细胞（MCS）并促进肺部炎症。大量的历史信息支持LTE4独特的受体的存在，我们的发表研究表明，LTE4是人类MC在体外的MC增殖和Vivo中气道炎症增强的最有效的CYS-LT，并且它通过独立于Cyslt1r和Cyslt2r的机制来激活人MC。我们的初步研究强烈表明，P2Y12受体是一种二磷酸腺苷反应性GPCR，也是LTE4反应受体（以下称为P2Y12/CYSLT3R），介导LTE4对LTE4对MCS Intidro和Vivo的肺病理学的影响。中心假设是，LTE4是其已知受体中CYS-LTS最弱的激动剂，是促进过敏性粘膜炎症的最相关的CYS-LT。推论假设是LTE4的作用是由先前未识别的Cys-LT反应G蛋白偶联受体（GPCR）介导的，此后称为“ P2Y12/CYSLT3R”。 AIM 1使用体外方法证明P2Y12/CYSLT3R是真正的LTE4反应受体。 AIM 2试图证明P2Y12/CYSLT3R解释了LTE4在体内肺中LTE4的引人注目的促炎作用，并确定了这种作用的基本细胞靶标。这些发现预计对哮喘病理生理学和治疗有直接的影响。 ？ ？ ？ ？