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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.

项目概要阿司匹林急性呼吸道疾病 (AERD) 是一种常见的严重特发性疾病其特征为哮喘、复发性鼻息肉病和明显的嗜酸性粒细胞炎症鼻窦和支气管粘膜。该疾病始终与显着相关半胱氨酰白三烯的产生失调，以及血小板的神秘过度激活。这该提案将侧重于了解这两个特征如何驱动病理生理学疾病。中心假设是自分泌、LTC4 介导的血小板激活途径在驱动与 AERD 相关的夸大 2 型免疫病理学方面发挥着关键作用，并且是 ASA 病理反应的核心。血小板相关 CysLT2R 和 HMGB1 都是这些功能所必需的。一个推论假设是中和血小板水杨酸 (SA) 的 HMGB1 有助于 ASA 治疗 AERD 的治疗效果。我们将使用新创建的转基因小鼠、一种新的 AERD 模型以及来自仔细描述人类受试者的特征来检验这一假设。拟议的研究将揭示 AERD 的潜在致病机制并确定可以恢复的治疗靶点正常体内平衡，并且是第一个将 CysLT2R 整合到 AERD 病理生理学中的人。