Pathophysiologic and Therapeutic Mechanisms of Aspirin Exacerbated Respiratory Disease

总体摘要/摘要 这个哮喘和过敏性疾病合作研究中心(AADCRC)继续关注 呼吸道2型免疫病理学(T2I)的机制基础，特别是在阿司匹林加重的情况下 呼吸道疾病(AERD)，一种独特的临床综合征，占不成比例的 患有严重哮喘和复发性慢性鼻窦炎并鼻息肉病(CRSwNP)的个人。在 在当前的支持期，我们在上皮性基底细胞中发现了明显的表观遗传印记异常 (BC)CRSwNP和AERD的功能和分化，其中一些是由Strong， 持续信号通过白介素4受体α(IL-4Rα)和一些通过改变的Wnt/Notch信号。 我们在CRSwNP组织中发现了肥大细胞(MC)的显著增殖，特别是在患有 AERD，部分由一种新的、转录和细胞荧光分析上独特的MC群体驱动，该群体具有高 增殖率。我们现在有强有力的证据表明MC-间质的相互作用推动了许多病理生理学 这些相互作用受IL-4Rα和IL-4R的协同作用调节。 33/ST2信号轴。一个由经验丰富、技能互补的调查人员组成的紧密互动的团队将 应用细胞、分子和整体动物策略，结合概念验证临床试验 确定这些发现的机制基础，它们与疾病病理生理学的相关性，以及它们的 对治疗的顺从性。项目1(J.Boyce，Pi)侧重于呼吸道的发育起源 MCs与基质细胞的相互作用如何决定MC的发育和功能，并被IL-4Rα改变 以及MC如何通过涉及IL-6和IL-6的前馈环驱动改变的基质细胞功能。 白血病抑制因子。项目2(N.Barrett，Pi)的重点是表观遗传学 BC的重新编程与IL-4Rα信号相结合，推动BC异常增生和感觉异常成为一种疾病- 引发机制。项目3(T.Laidlaw，PI)将比较IL-4Rα阻断和IL-33的疗效 一项机制证明的安慰剂对照试验中的阻断，重点是恢复BC功能和 抑制MC的增殖和活化。这些项目由各自的核心支持 管理(核心A)和整合基因组学(核心B)。

Overall Summary/Abstract This Asthma and Allergic Disease Cooperative Research Center (AADCRC) continues its focus on the mechanistic basis of respiratory tract type 2 immunopathology (T2I), particularly in aspirin-exacerbated respiratory disease (AERD), a distinctive clinical syndrome that accounts for a disproportionate percentage of individuals with severe asthma and recurrent chronic rhinosinusitis with nasal polyposis (CRSwNP). In the current period of support, we discovered marked epigenetically imprinted abnormailites in epithelial basal cell (BC) function and differentiation underlying CRSwNP and AERD, some of which are driven by strong, persistent signaling through the interleukin 4 receptor alpha (IL-4Rα) and some by altered Wnt/Notch signaling. We identified dramatic hyperplasia of mast cells (MCs) in CRSwNP tissue, especially from individuals with AERD, driven in part by a novel, transcriptionally and cytofluorographically distinct MC population with a high rate of proliferation. We now have strong evidence that MC-stromal interactions drive many pathophysiologic features of respiratory T2I, and that these interactions are regulated by synergistic inputs from IL-4Rα and IL- 33/ST2 signaling axes. A tightly interactive team of accomplished investigators with complementary skills will apply cellular, molecular, and whole animal strategies, combined with a proof-of-concept clincal trial to determine the mechanistic basis for these findings, their relevance to disease pathophysiology, and their amenability to therapy. Project 1 (J. Boyce, PI) focuses on the the developmental origins of respiratory tract MCs, how their interactions with stromal cells dictate MC development and function and are altered by IL-4Rα signaling, and how MCs drive altered stromal cell function through a feed-forward loop involving IL-6 and leukemia inhibitory factor. Project 2 (N. Barrett, PI) focuses on the mechanisms by which epigenetic reprogramming of BCs combines with IL-4Rα signaling to drive BC dysplasia and sensecence as a disease- causing mechanism. Project 3 (T. Laidlaw, PI) will compare the efficacy of IL-4Rα blockade with IL-33 blockade in a proof of mechanism placebo controlled trial, focusing on restoration of BC function and suppression of MC hyperplasia and activation. The Projects are supported by respective Cores for Adminstration (Core A), and Integrative Genomics (Core B).