Eicosanoid Networks in Aspirin Hypersensitivity

摘要/摘要 这一要求继续提供支助的申请继续侧重于负责以下方面的机制： 阿司匹林敏感性是阿司匹林加重呼吸道疾病（AERD）的一个定义性特征。AERD 是一种以严重的鼻窦和支气管炎症为特征的使人衰弱的临床综合征 分别导致慢性鼻窦炎伴鼻息肉病（CRSwNP）和哮喘。几 存在治疗选择，但没有一种具有疾病改善特性。我们的建议重点是 一种独特的血小板驱动机制，通过该机制，内源性半胱氨酰白三烯（cysLT）， 特别是母体cysLT LTC 4，通过2型cysLT受体引发偏见信号 （CysLT 2 R）在血小板和其他细胞类型上通过IL-33驱动免疫病理学。中央 假设是CysLT 2 R处的LTC 4信号通过以下途径促进呼吸道2型炎症： 通过直接和间接诱导白细胞介素33（IL-33）的表达和释放， 机制等一个必然的假设是，AERD涉及一个重要的致病因素， 自分泌LTC 4/CysLT 2 R介导的血小板活化途径的贡献， IL-33和其他介导呼吸道T2 I和驱动阿司匹林敏感性的介质。我们 使用分子工具的互补方法，一组独特的转基因小鼠， 组织和细胞从仔细表型人类受试者，以测试核心假设， 验证不同物种的生物学。这些研究应该揭示新的潜在战略， 基于新的潜在机制的治疗发展，

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,