Eicosanoid Networks in Aspirin Hypersensitivity

摘要/摘要 这项重新提供支持的申请继续把重点放在负责 阿司匹林敏感性，阿司匹林的一个定义特征加剧了呼吸系统疾病(AERD)。AERD 是一种衰弱的临床综合征，以严重的鼻腔和支气管炎为特征。 分别导致慢性鼻窦炎鼻息肉病(CRSwNP)和哮喘。一些 治疗方案是存在的，但没有一种具有改善疾病的特性。我们的建议侧重于 一种独特的、由血小板驱动的机制，通过这种机制，内源性半胱氨酰白三烯(CysLTs)， 特别是亲本cysLT LTC4，通过2型cysLT受体诱导偏向信号 (CysLT2R)在血小板和其他细胞类型上，通过IL-33驱动免疫病理学。中环 假设CysLT2R上的LTC4信号通过以下方式促进呼吸道2型炎症 直接和间接诱导IL-33的表达和释放 机械装置。一个推论是，AERD与一种重要的致病因素有关 自分泌LTC4/CysLT2R介导的血小板激活途径的贡献 IL-33和其他促进呼吸道T2I和驱动阿司匹林敏感性的介质。我们 使用与分子工具互补的方法，一组独特的转基因小鼠，以及 来自仔细表型的人类受试者的组织和细胞来检验核心假说和 验证跨物种的生物学。这些研究应该揭示出新的潜在战略 基于一种新的潜在机制的治疗开发，

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,