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,