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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：
10517922
负责人：
Joshua A Boyce
金额：
$ 65.65万
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 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10517922
关键词：
Affinity Agonist Alveolar Antibodies Arachidonate 5-Lipoxygenase Arachidonic Acids Aspirin Asthma Binding Biology Blood Platelets Blood Vessels Bronchoconstriction Cells Clinical DNA-Binding Proteins Dinoprostone Disease Drug Targeting Eicosanoids Event Extravasation Functional disorder G-Protein-Coupled Receptors Genetic HMGB1 gene Human Hypersensitivity Immunologics Inflammation Interleukins Leukotriene C4 Leukotriene D4 Ligand Binding Lung Lymphoid Cell Mediating Mediator Microsomes Modeling Molecular Mus Myeloid Cells Nose Parents Pathology Pathway interactions Patients Phenotype Physiological Physiology Platelet Activation Play Property Prostaglandins Reaction Receptor Signaling Refractory Regulation Respiratory System Role Signal Transduction Sinus Site Syndrome Testing Therapeutic Tissues Transgenic Mice airway inflammation antagonist aspirin-exacerbated respiratory disease asthma exacerbation autocrine base cell type cellular targeting chronic rhinosinusitis cysteinyl leukotriene receptor cysteinyl leukotriene receptor 2 cysteinyl-leukotriene desensitization human subject immunopathology in vivo innovation insight leukotriene-C4 synthase lipid mediator mast cell novel novel therapeutics pharmacologic polyposis preference prevent programs receptor receptor expression receptor for advanced glycation endproducts recruit respiratory respiratory smooth muscle response therapeutic development therapeutic target tool translational potential

项目摘要

Summary/Abstract This application for renewed support continues its focus on the mechanisms responsible for aspirin sensitivity, a defining feature of aspirin exacerbated respiratory disease (AERD). AERD is a debilitating clinical syndrome characterized by severe sinonasal and bronchial inflammation resulting in chronic rhinosinusitis with nasal polyposis (CRSwNP) and asthma, respectively. Few therapeutic options exist, and none have disease modifying properties. Our proposal focuses on a unique, platelet-driven mechanism through which endogenous cysteinyl leukotrienes (cysLTs), specifically the parent cysLT LTC4, elicits biased signaling through the type 2 cysLT receptor (CysLT2R) on platelets and other cell types to drive immunopathology through IL-33. The central hypotheses are that LTC4 signals at CysLT2R to promote respiratory type 2 inflammation by inducing the expression and release of interleukin 33 (IL-33) by both direct and indirect mechanisms. A corollary hypothesis is that AERD involves a significant pathogenetic contribution from an autocrine LTC4/CysLT2R-mediated platelet activation pathway that provides IL-33 and other mediators that contribute to respiratory tract T2I and drive aspirin sensitivity. We use a complementary approach with molecular tools, a unique set of transgenic mice, and tissues and cells from carefully phenotyped human subjects to test the core hypotheses and validate the biology across species. The studies should reveal new potential strategies for therapeutic development that are based on a novel underlying mechanism,

摘要/文摘