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: 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
• 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

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.

该项目测试了缺乏EP2受体表达和血小板中的功能的假设 白细胞改变腺苷酸环化酶/环状腺苷一磷酸（CAMP）途径的稳态为 阿司匹林中引起疾病​​的机制加剧了呼吸道疾病（AERD）。需要血小板 肺部炎症动物模型中的粒细胞募集，通过p-选择素与白细胞结合 （CD62P）并促进整联蛋白的亲和力。当与中性粒细胞结合时，血小板也可以形成白细胞 （LT）C4（来自中性粒细胞衍生的LTA4的Cysteinly Liukotrienes（Cys-LTS）的母体）。我们有 发现来自阿司匹林受试者加重呼吸道疾病（AERD）的血小板明显 与正常和阿司匹林耐耐药的血小板相对于血小板的GS连接EP2受体的表达不足 哮喘（ATA）控制。结果，外源性PGE2和选择性EP2激动剂都不能 从体外AERD的个体或血小板 - 白细胞的形成中的血小板的阻滞激活 聚合。此外，来自AERD个体的外周血样本包含更高的几倍 血小板 - 白细胞骨料的频率比正常和耐阿司匹林ATA对照的样品 提示体内EP2信号传导降低的功能结果，可以增强两种组织 炎症和CYS-LT的产生。此外，EP2受体表达中的缺陷延伸至 来自AERD个体的外周血白细胞，伴随着表达 编码EP4受体的mRNA；两种缺陷都通过阿司匹林治疗逆转。目标1是确定 缺陷在Prostaglandin E2受体在血小板上的EP2亚型功能中的后果 AERD的病理生理学。 AIM 2是确定EP2和EP4受体不足的后果 对外周血白细胞中5-脂氧合酶（5-li）途径活性的信号传导 通过用阿司匹林治疗纠正缺陷。目标3是表征表观遗传变异的程度 EP受体，经典和新颖的Cysltr以及Aerd中相关的候选效应子。