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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.

该项目测试了血小板中缺乏EP 2受体表达和功能的假设，白细胞改变腺苷酸环化酶/环磷酸腺苷（cAMP）途径的稳态，阿司匹林加重呼吸道疾病（AERD）的致病机制。以下情况需要书面陈述：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（CD 62 P）和促进整合素亲合力。当与中性粒细胞结合时，血小板也可形成白三烯（LT）C4（半胱氨酰白三烯（cys-LT）的母体）来自嗜中性粒细胞衍生的LTA 4。我们有发现阿司匹林加重呼吸道疾病（AERD）受试者的血小板显著增加，相对于来自正常和阿司匹林耐受的血小板，哮喘（ATA）对照。结果，外源性PGE 2和选择性EP 2激动剂都不能在体外阻断AERD患者的血小板活化或血小板-白细胞的形成集料.此外，来自AERD个体的外周血样品含有数倍高的血小板-白细胞聚集体的频率高于正常和阿司匹林耐受性ATA对照样品，这表明在体内减少EP 2信号传导的功能结果，炎症和cys-LT的产生。此外，EP 2受体表达的缺陷延伸到来自AERD个体的外周血白细胞，伴随有表达缺陷的mRNA编码EP 4受体;这两个缺陷逆转阿司匹林治疗。目标1是确定前列腺素E2受体的EP 2亚型在血小板上的功能缺陷的后果， AERD的病理生理学目的2：探讨EP 2和EP 4受体缺失对脑缺血的影响外周血白细胞中5-脂氧合酶（5-LO）通路活性的信号传导，以及用阿司匹林治疗可以纠正这种缺陷。目的3是表征表观遗传变异的程度， EP受体，经典和新型CysLTRs，以及AERD中的相关候选效应物。