CysLT and P2Y Receptors in Lung Inflammation

肺部炎症中的 CysLT 和 P2Y 受体

基本信息

批准号：
7846667
负责人：
Joshua A Boyce
金额：
$ 2.23万
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：
2009-06-05 至 2009-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7846667
关键词：
1-Phosphatidylinositol 3-Kinase ABCC1 gene Abbreviations Adenosine Diphosphate Adenosine Triphosphate Adenylate Cyclase Affinity Allergens Allergic Antibodies Arachidonate 5-Lipoxygenase Asthma BAC (bacterial artificial chromosome)Binding Bone Marrow Bronchi Bronchoalveolar Lavage Butyric Acids CREB1 gene Cell Count Cell Proliferation Cell physiology Cells Characteristics Chemicals Co-Immunoprecipitations Complex Connective Tissue Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic AMP-Responsive DNA-Binding Protein Cysteine Dendritic Cells Dimerization Diphosphates Disease Disulfide Linkage EGF gene Epidermal Growth Factor Epidermal Growth Factor Receptor Epithelial Event Exhibits Extracellular Signal Regulated Kinases Fibrosis Fluorescence Fluorescence Resonance Energy Transfer Funding G-Protein-Coupled Receptors Generations Green Fluorescent Proteins Growth Growth Factor Guanine Guanosine Triphosphate Heart Diseases Heterodimerization Human IgE Receptors Image Immune In Situ In Vitro Infection Injury Interleukin-4 Interleukins Intestines Knockout Mice Leukotriene C4 Leukotrienes Ligands Lipopolysaccharides Lung Lung Inflammation Lysophospholipids MAP Kinase Modules MEKs Macrophage Inflammatory Proteins Mediating Microscopy Mitogen-Activated Protein Kinases Mitogens Modeling Molecular Monocyte Chemoattractant Proteins Mouse Strains Mucositis Mus Nuclear Nucleotides Ovalbumin P-Glycoprotein Passive Cutaneous Anaphylaxis Pathway interactions Pertussis Toxin Phenotype Phospholipase A2 Phosphotransferases Platelet-Derived Growth Factor Receptor Play Pneumonia Polymerase Chain Reaction Process Proteins Proto-Oncogene Protein c-kit Receptor Cross-Talk Receptor Protein-Tyrosine Kinases Receptor Signaling Regulation Reporting Research Reverse Transcription Role Signal Transduction Single Nucleotide Polymorphism Stem Cell Factor Surface TNF gene Tissues Toll-like receptors Transactivation Transmembrane Domain Tumor Necrosis Factor-alpha Tumor Necrosis Factors Umbilical Cord Blood Uridine Diphosphate Uridine Triphosphate activating transcription factor airway hyperresponsiveness base chemokine common treatment cysteinyl leukotriene receptor 2 cysteinyl-leukotriene cytokine desensitization extracellular gamma-Aminobutyric Acid in vivo leukotriene D4 receptor leukotriene-C4 synthase lysophosphatidic acid mast cell mastocytosis nuclear factors of activated T-cells progenitor purinoceptor P2Y6 receptor receptor expression receptor function release of sequestered calcium ion into cytoplasm respiratory smooth muscle response small hairpin RNA tripolyphosphate

项目摘要

DESCRIPTION (provided by applicant): Mast cells (MCs) are important in allergic diseases, tissue injury, and protection from infections. MC numbers and their effector functions are dynamically regulated by constituents of the tissue microenvironment. This application for continued support focuses on the role of cysteinyl leukotrienes (cys-LTs) and their receptors in the regulation of MC function. During the last funding period, we recognized that human MCs (hMCs) expressed both of the known receptors for cys-LTs (CysLT1 and CysLT2 receptors), and defined different functions for each. We identified specific modulatory functions for IL-4 in regulating cys-LT-dependent signaling events as well as CysLT2 receptor expression, and defined differential and complementary functions for the two cys-LT receptors by developing null strains of mice. Our preliminary studies now demonstrate that cys-LTs play an unanticipated, essential role in mediating reactive mastocytosis in a model of allergen-induced pulmonary inflammation. Both leukotriene C4 synthase-null mice (which cannot generate cys-LTs) and CysLT1 receptor-null mice completely lack MCs in the inflamed epithelial surfaces of the bronchi. Moreover, we have demonstrated that both cys-LTs and a nucleotide, UDP, behave as co-mitogenic growth factors for hMCs in vitro, acting by a pathway that requires CysLT1 receptors, Gi proteins, and the ERK MAP kinase cascade. Finally, we demonstrate that CysLT1 receptors on MCs constitutively form heterodimers with CysLT2 receptors and with UDP- selective P2Y6 receptors, respectively, and that each heterodimer differentially regulates the function of the therapeutically relevant CysLT1 receptor. The Specific Aims are: 1. To determine the molecular basis and functional consequences of dimerization of P2Y6 and CysLT2 receptors with the CysLT1 receptor, and; 2. To define the mechanisms through which P2Y6/CysLT1 receptors amplify stem cell factor (SCF)-dependent growth of hMCs, and mediate reactive mastocytosis in vivo using newly developed null mouse strains. Project Narrative: This proposal seeks to understand how a class of chemicals called cysteinyl leukotrienes control the function of mast cells, a type of immune cell. Since both mast cells and cysteinyl leukotrienes are important in asthma and are also believed to be important in heart disease and other conditions, these studies are anticipated to reveal potential new treatments for these common diseases.

描述（由申请人提供）：肥大细胞（MC）在过敏性疾病，组织损伤和免受感染的保护中很重要。 MC数及其效应子功能受组织微环境的成分动态调节。这种持续支持的应用集中在白细胞三烯（CYS-LTS）及其受体在MC功能调节中的作用。在最后一个资金期间，我们认识到人MC（HMC）表达了Cys-LTS（Cyslt1和Cyslt2受体）的已知受体，并为每个受体定义了不同的功能。我们在调节Cys-LT依赖性信号事件以及CYSLT2受体表达中鉴定了IL-4的特定调节功能，并通过产生小鼠无效的小鼠菌株来定义两个CYS-LT受体的差异和互补功能。我们的初步研究现在表明，在过敏原诱导的肺部炎症模型中，CYS-LTS在介导反应性肥大症中起意外，至关重要。白三烯C4合酶无小鼠（无法产生Cys-LTS）和Cyslt1受体无小鼠完全缺乏支气管发炎的上皮表面中的MC。此外，我们已经证明了Cys-LTS和A核苷酸UDP都作为HMC在体外的共裂生长因子的作用，其作用于需要Cyslt1受体，GI蛋白和ERK MAP MAP MAP激酶级联的途径。最后，我们证明了MCS上的CYSLT1受体分别与CYSLT2受体和UDP-选择性P2Y6受体形成异二聚体，并且每个异二聚体都差异地调节了治疗相关的Cyslt1受体的功能。具体目的是：1。确定P2Y6和CYSLT2受体与Cyslt1受体的分子基础和功能后果，并且； 2。定义P2Y6/CYSLT1受体通过新开发的无小鼠菌株在体内介导的HMC的干细胞因子（SCF）依赖性生长的机制。项目叙述：该提案旨在了解一类称为Cysteinyl Leukotrienes的化学物质如何控制肥大细胞的功能，一种免疫细胞。由于肥大细胞和白细胞三烯在哮喘中都很重要，并且在心脏病和其他疾病中也很重要，因此预计这些研究会揭示这些常见疾病的潜在新疗法。