Mechanisms and Consequences of Defective E Prostanoid Receptor Signaling 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。

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.