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：
8435953
负责人：
Joshua A Boyce
金额：
$ 45.22万
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：
2002
资助国家：
美国
起止时间：
2002-08-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8435953
关键词：
Affinity Alleles Allergens Allergic rhinitis Anabolism Antibodies Antigen-Presenting Cells Antigens Apoptotic Aspergillus fumigatus Asthma Attenuated Backcrossings C Type Lectin Receptors C57BL/6 Mouse Cells Clinical Dendritic Cells Dendritic cell activation Dermatophagoides farinae Development Disease Dose Employee Strikes Enzymes Eosinophilia Epithelial Cells Functional disorder Funding G alpha q Protein G-Protein-Coupled Receptors Generations Genetic Transcription Goblet Cells Hematopoietic Homologous Gene House Dust Mite Allergens Hypersensitivity ITGAM gene ITGAX gene Immune response Immune system Impairment In Vitro Inbred BALB C Mice Inflammation Inhalant dose form Interleukin-10 Interleukin-6 Intranasal Administration Knock-out Lead Leukotriene D4 Ligands Lung Lung Inflammation Mannans Mediating Metaplasia Microglia Mus Nucleotides Pathway interactions Phagocytosis Pharmaceutical Preparations Phase Phenotype Phosphorylation Physiological Pneumonia Production Protein Isoforms Protein Kinase C Proteins Pyroglyphidae Receptor Signaling Role Signal Transduction Stimulus T-Cell Activation T-Lymphocyte Tumor Necrosis Factor-alpha Uridine Diphosphate allergic response autocrine base cell type cellular targeting cysteinyl leukotriene receptor cysteinyl-leukotriene cytokine desensitization insight interleukin-23 leukotriene-C4 synthase lipid mediator macrophage mast cell migration mouse dectin-2 paracrine prevent public health relevance purinoceptor P2Y6 receptor receptor function release of sequestered calcium ion into cytoplasm response

项目摘要

DESCRIPTION (provided by applicant): This application for continued support focuses on the role of the type 6 purinergic (P2Y6) receptor in the pathophysiology of house dust mite (HDM) allergen-induced pulmonary inflammation. In the previous funding cycle, we discovered that P2Y6 receptors, which are high affinity G protein-coupled receptors (GPCRs) for uridine diphosphate (UDP), cross-regulate the functions of the type 1 receptor for cysteinyl leukotrienes (cys- LTs), CysLT1R. We now demonstrate that P2Y6 receptors are major negative regulators of pulmonary inflammation induced by the intranasal administration of an extract (Df) from the HDM Dermatophagoides farinae. Repetitive intranasal administration of low doses of an extract (Df) from the HDM to C57BL/6 or BALB/c mice causes robust peribronchial and perivascular eosinophilia, goblet cell metaplasia, and a mixed T helper (Th)2, Th1, and Th17-type immune response in the lungs. The Th2 component of this response depends strongly on the expression of CysLT1R by dendritic cells (DCs), and the ability of DCs to generate cys-LTs. We have found the mice bearing a conditional knockout of the p2ry6 allele (p2ry6 (flox/flox);cre/+ mice, hereafter referred to as p2ry6-/- mice) develop markedly exacerbated peribronchial/perivascular inflammation compared with identically treated littermate p2ry6 (flox/flox) controls (hereafter referred to as +/+ mice) after receiving intranasal Df. Preliminary studies suggest that P2Y6 receptors control separate but distinct aspects of the phenotype through control of T cell and DC activation, respectively, with an especially important role in regulating CysLT1R-dependent Th2 priming by DCs. The primary hypothesis of this proposal that P2Y6 receptors inhibit the development of allergen-induced pulmonary inflammation through separate effects on Th2 priming by DCs at sensitization and on activation of T cells in the effector phase of the same response. A corollary hypothesis is that P2Y6 receptors exert control over the endogenous cys-LT-CysLT1R dependent pathway for Th2 priming by DCs via a PKC-dependent mechanism. The proposed studies will provide insight into the mechanisms by which common allergens elicit Th2 responses at sensitization, and may also provide a basis for developing effective pharmacologic agents that could attenuate Th2 sensitization by blocking CysLT1R without the off-target effects of blocking inhibitory signaling through P2Y6 receptors.

描述（由申请人提供）：持续支持的申请重点介绍了6型嘌呤能（P2Y6）受体在房屋粉尘螨（HDM）过敏蛋白诱导的肺部炎症的病理生理学中的作用。在上一个资金周期中，我们发现P2Y6受体是尿苷二磷酸盐（UDP）的高亲和力G蛋白偶联受体（GPCR），对Cysteinyl Leukotrienes（Cys-LTS）的1型1型受体的功能进行了交叉调节。现在，我们证明P2Y6受体是由HDM Dermatophagoiides farinae的提取物（DF）引起的肺部炎症的主要负调节剂。从HDM到C57BL/6或BALB/C小鼠对低剂量的提取物（DF）的重复施用会导致稳健的周性嗜酸性嗜酸性嗜酸性嗜酸性嗜酸性症，杯状细胞元素，以及混合的T Helper（Th）2，Th1，Th1，Th1，Th17- th17- th17-型免疫响应。该响应的Th2分量在很大程度上取决于树突状细胞（DC）的Cyslt1R的表达，以及DC产生CYS-LTS的能力。我们发现，具有有条件敲除P2RY6等位基因的小鼠（P2RY6（Flox/Flox）； Cre/+小鼠，此后称为P2RY6 - / - 小鼠）出现明显恶化的周围炎性细胞/血管周围炎症，与相同治疗的p2 rox/Flittermate+ Flittmate（+ Flitsmate）（Flox/flox）（+ Flox/Flox）（+）（+ MIN）（erse）（+ MIR）（+）接受鼻内DF。初步研究表明，P2Y6受体分别通过控制T细胞和DC激活来控制表型的单独但不同方面，在调节DC的CYSLT1R依赖性Th2启动中特别重要。该提议的主要假设是，P2Y6受体通过对DC在敏化时对Th2启动的单独影响和在相同反应的效应阶段激活T细胞的Th2启动，抑制过敏原诱导的肺部炎症的发展。推论假设是，P2Y6受体对内源性Cys-LT-Cyslt1R依赖性途径对DC通过PKC依赖性机制进行TH2启动的途径。拟议的研究将洞悉通用过敏原在致敏时引起Th2反应的机制，并可能为开发有效的药理学剂提供基础，这些药理剂可以通过阻断Cyslt1R来减轻TH2敏化，而不会通过P2Y6受体通过封闭抑制性信号的非目标效应。