Regulation of Pulmonary Prostaglandins by Leukotriene E4

白三烯 E4 对肺前列腺素的调节

基本信息

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
项目类别：
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

项目摘要

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. ?? ?? ?? ??

该提案旨在确定半胱氨酰白三烯 (cys-LT) 最稳定的配体白三烯 (LT)E4 激活肥大细胞 (MC) 并促进肺部炎症的机制和受体。大量历史信息支持 LTE4 独特受体的存在。我们发表的研究表明，LTE4 是最有效的 cys-LT，无论是在体外促进人类 MC 增殖，还是在体内增强气道炎症，并且它通过以下方式激活人类 MC：机制独立于 CysLT1R 和 CysLT2R。我们的初步研究强烈表明，P2Y12 受体（一种二磷酸腺苷响应性 GPCR）也是 LTE4 反应性受体（以下称为 P2Y12/CysLT3R），介导 LTE4 对体外 MC 和体内肺部病理学的影响。中心假设是 LTE4 是 cys-LT 在其已知受体上最弱的激动剂，是促进过敏性粘膜炎症最相关的 cys-LT。一个推论假设是，LTE4 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)（以下称为“P2Y12/CysLT3R”）介导的。目标 1 使用体外方法证明 P2Y12/CysLT3R 是真正的 LTE4 反应性受体。目标 2 试图证明 P2Y12/CysLT3R 解释了 LTE4 在体内肺部的显着促炎作用，并确定了这种作用的重要细胞靶标。预计这些发现将对哮喘病理生理学和治疗产生直接影响。 ?? ?? ?? ??