Mechanisms and Consequences of Defective E Prostanoid Receptor Signaling in AERD

AERD 中 E 类前列腺素受体信号传导缺陷的机制和后果

基本信息

批准号：
8915315
负责人：
Joshua A Boyce
金额：
$ 14.81万
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：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8915315
关键词：
Adenylate Cyclase Agonist Allergens Allergic Animal Model Arachidonate 5-Lipoxygenase Arachidonic Acids Aspirin Asthma Avidity Binding Blood Platelets Blood specimen Breathing Bronchoconstriction Cells Characteristics Cyclic AMP Defect Dinoprostone Disease Disease model Dose EP4 receptor Effector Cell Enzymes Epigenetic Process Forced expiratory volume function Frequencies Functional disorder Generations Homeostasis Immune response In Vitro Individual Inflammation Integrins Leukocytes Leukotriene A4 Leukotriene C4 Leukotriene E4 Leukotrienes Link Lung Lung diseases Mediating Mediator of activation protein Messenger RNA Organ P-Selectin Parents Pathogenesis Pathway interactions Phase Platelet Activation Play Pneumonia Production Prostaglandin E Receptor Prostaglandins Proteins Receptor Signaling Relative (related person)Role SELP gene Sampling Signal Transduction Testing Therapeutic Tissues Vascular remodeling base cysteinyl leukotriene receptor cysteinyl-leukotriene eosinophil epigenetic variation granulocyte in vitro activity in vivo mRNA Expression neutrophil novel peripheral blood prevent prostaglandin EP2 receptor receptor receptor coupling receptor expression receptor function respiratory response urinary

项目摘要

This project tests the hypotheses that deficient EP2 receptor expression and function in platelets and leukocytes alters homeostasis of the adenylyl cyclase/cyclic adenosine monophosphate (cAMP) pathway as a disease-causing mechanism in aspirin exacerbated respiratory disease (AERD). Platelets are required for granulocyte recruitment in animal models of pulmonary inflammation, binding to leukocytes via P-selectin (CD62P) and facilitating integrin avidity. When bound to neutrophils, platelets can also form leukotriene (LT)C4 (the parent of the cysteinly leukotrienes (cys-LTs)) from neutrophil-derived LTA4. We have discovered that platelets from subjects with aspirin exacerbated respiratory disease (AERD) are markedly deficient in expression of the Gs-linked EP2 receptor for PGE2 relative to platelets from normal and aspirin-tolerant asthmatic (ATA) controls. As a result, neither exogenous PGE2 nor a selective EP2 agonist can block activation of platelets from individuals with AERD in vitro, or the formation of platelet-leukocyte aggregates. Moreover, peripheral blood samples from individuals with AERD contain several fold higher frequencies of platelet-leukocyte aggregates than do samples from normal and aspirin-tolerant ATA controls, suggesting a functional result of diminished EP2 signaling in vivo that could enhance both tissue inflammation and the generation of cys-LTs. Furthermore, the defect in EP2 receptor expression extends to peripheral blood leukocytes from individuals with AERD, accompanied by concomitantly defective expression of mRNA encoding EP4 receptors; both defects are reversed by aspirin treatment. Aim 1 is to determine the consequences of defects in the function of the EP2 subtype of prostaglandin E2 receptor on platelets in the pathophysiology of AERD. Aim 2 is to determine the consequences of deficient of EP2 and EP4 receptor signaling on 5-lipoxygenase (5-LO) pathway activity in peripheral blood leukocytes and whether the deficiency is corrected by treatment with aspirin. Aim 3 is to characterize the extent of epigenetic variation in EP receptors, classical and novel CysLTRs, and associated candidate effectors in AERD.

该项目测试血小板中 EP2 受体表达和功能缺陷的假设白细胞改变腺苷酸环化酶/环磷酸腺苷 (cAMP) 途径的稳态阿司匹林加剧呼吸道疾病（AERD）的致病机制。需要血小板肺部炎症动物模型中粒细胞的募集，通过 P-选择素与白细胞结合 (CD62P) 并促进整合素亲和力。当与中性粒细胞结合时，血小板也可以形成白三烯 (LT)C4（半胱氨酸白三烯 (cys-LTs) 的母体）来自中性粒细胞衍生的 LTA4。我们有发现患有阿司匹林加剧呼吸系统疾病（AERD）的受试者的血小板显着降低相对于正常和阿司匹林耐受的血小板，PGE2 的 Gs 连接 EP2 受体的表达存在缺陷哮喘（ATA）控制。因此，外源性 PGE2 和选择性 EP2 激动剂都不能体外阻断 AERD 患者血小板的激活，或血小板白细胞的形成聚合体。此外，AERD 患者的外周血样本中含有数倍的血小板-白细胞聚集的频率比正常和阿司匹林耐受 ATA 对照样品的频率高，表明体内 EP2 信号减弱的功能结果可以增强两种组织炎症和 cys-LT 的产生。此外，EP2受体表达的缺陷延伸至来自 AERD 患者的外周血白细胞，同时伴有表达缺陷编码EP4受体的mRNA；这两种缺陷都可以通过阿司匹林治疗来逆转。目标 1 是确定前列腺素 E2 受体 EP2 亚型功能缺陷对血小板的影响 AERD 的病理生理学。目标 2 是确定 EP2 和 EP4 受体缺乏的后果外周血白细胞中 5-脂氧合酶 (5-LO) 通路活性的信号传导以及是否缺陷可以通过阿司匹林治疗来纠正。目标 3 是表征表观遗传变异的程度 EP 受体、经典和新型 CysLTR 以及 AERD 中的相关候选效应器。