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：
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
项目类别：
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

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.