Eicosanoid Networks in Aspirin Hypersensitivity

阿司匹林过敏中的类二十烷酸网络

基本信息

批准号：
10062848
负责人：
Joshua A Boyce
金额：
$ 54.98万
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：
2017
资助国家：
美国
起止时间：
2017-12-04 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10062848
关键词：
Adherence Airway Resistance Antibodies Arachidonate 5-Lipoxygenase Arachidonic Acids Aspirin Asthma Automobile Driving Blood Blood Platelets Cells Clinical Cyclooxygenase Inhibitors Dermatophagoides farinae Dinoprostone Disease Dose Effector Cell Eicosanoids Enzymes Functional disorder Funding HMGB1 Protein Homeostasis Hypersensitivity Inflammation Inflammation Mediators Leukotriene C4 Leukotriene Production Lymphoid Cell Mediating Modeling Molecular Mouse Strains Mucous Membrane Mus Nasal Polyps Nose Parents Pathogenicity Pathologic Pathway interactions Patients Pattern Pharmaceutical Preparations Pharmacology Phenotype Physiological Platelet Activation Play Polyps Production Prostaglandins Pyroglyphidae Reaction Recurrence Respiratory Mucosa Respiratory System Role SELP gene Salicylic Acids Signal Transduction Sinus Syndrome System Testing Therapeutic Therapeutic Effect Tissues Transgenic Mice aspirin-exacerbated respiratory disease autocrine clinical phenotype cyclooxygenase 2 cysteinyl leukotriene receptor 2 cysteinyl-leukotriene cytokine eosinophilic inflammation granulocyte human subject immunopathology innate immune pathways leukotriene-C4 synthase mast cell mouse PGE synthase 1 mouse model novel overexpression platelet function polyposis receptor receptor for advanced glycation endproducts respiratory response rhinosinusitis therapeutic target

项目摘要

Project Summary Aspirin-exacerbated respiratory disease (AERD) is a common, severe idiopathic disorder characterized by asthma, recurrent nasal polyposis, and marked eosinophilic inflammation of the sinonasal and bronchial mucosa. The disease is consistently associated with markedly dysregulated cysteinyl leukotriene production, and with cryptic over-activation of platelets. This proposal will focus on understanding how these two features drive the pathophysiology of the disease. The central hypothesis is that an autocrine, LTC4-mediated platelet activation pathway plays a critical role in driving the exaggerated type 2 immunopathology associated with AERD, and is central to pathognomonic reactions to ASA. Platelet-associated CysLT2R and HMGB1 are each necessary for these features. A corollary hypothesis is that neutralization of platelet HMGB1 by salicylic acid (SA) contributes to the therapeutic effect of ASA therapy in AERD. We will use newly created transgenic mice, a novel model of AERD, and cells and tissues from carefully characterized human subjects to test the hypothesis. The studies proposed will reveal potential causative mechanisms in AERD and identify therapeutic targets that could restore normal homeostasis, and are the first to integrate CysLT2R into AERD pathophysiology.

项目摘要阿司匹林呼吸道疾病（AERD）是一种常见的，严重的特发性疾病以哮喘，复发性鼻多息护物和明显的嗜酸性炎症为特征鼻窦和支气管粘膜。该疾病始终与白细胞三烯产生的白细胞蛋白酶失调，血小板过度活化。这建议将重点放在理解这两个特征如何推动其病理生理学疾病。中心假设是自分泌LTC4介导的血小板激活途径在推动与AERD相关的夸张的2型免疫病理学方面起着至关重要的作用并且是对ASA的病理反应的核心。血小板相关的Cyslt2r和HMGB1 这些功能都是必要的。推论假设是血小板中和水杨酸（SA）的HMGB1有助于ARD中ASA治疗的治疗作用。我们将使用新创建的转基因小鼠，一种新型AERD模型，以及来自精心表征人类受试者以检验假设。提出的研究将揭示 AERD中的潜在致病机制并确定可以恢复的治疗靶标正常的稳态，并且是第一个将Cyslt2R整合到AERD病理生理学中的人。