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

• 批准号: 8195747
• 负责人: Joshua A Boyce
• 金额: $ 52.16万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195747
• 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

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.

该项目测试了以下假说：缺乏EP2受体的表达和功能 白细胞改变腺苷环化酶/环磷酸腺苷(CAMP)途径的动态平衡 阿司匹林加重呼吸道疾病(AERD)的致病机制。血小板是人体必需的 肺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)和促进整合素亲和力。当血小板与中性粒细胞结合时，也会形成白三烯。 (Lt)C4(半胱氨酸白三烯(Cys-LTs)的母体)来自中性粒细胞来源的LTA4。我们有 发现患有阿司匹林加重呼吸道疾病(AERD)的受试者的血小板显著 与正常和阿司匹林耐受者的血小板相比，PGE2的Gs连锁EP2受体表达不足 哮喘(ATA)对照。因此，外源性PGE2和选择性EP2激动剂都不能 体外阻断AERD患者的血小板活化，或血小板-白细胞的形成 集合体。此外，AERD患者的外周血液样本中的AERD含量要高出几倍 血小板-白细胞聚集率高于正常和阿司匹林耐受性ATA对照组的样本， 提示体内EP2信号减弱的功能结果可能增强了这两个组织 炎症和Cys-LT的产生。此外，EP2受体表达的缺陷延伸到 AERD患者外周血白细胞伴有表达缺陷 编码EP4受体的信使核糖核酸；这两种缺陷都可通过阿司匹林治疗而逆转。目标1是确定 前列腺素E_2受体EP2亚型功能缺陷对高血压病患者血小板功能的影响 AERD的病理生理学。目的2是确定EP2和EP4受体缺陷的后果 外周血白细胞中5-脂氧合酶(5-LO)途径活性的信号转导 缺乏症可以通过服用阿司匹林来纠正。目标3是描述表观遗传变异的程度。 AERD中的EP受体、经典的和新的CysLTRs以及相关的候选效应因子。