Pathophysiologic and Therapeutic Mechanisms of Aspirin Exacerbated Respiratory Disease

摘要/Abstract 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（T2 I）的机制基础，特别是在阿司匹林加重的 呼吸道疾病（AERD），一种独特的临床综合征，占不成比例的百分比， 患有严重哮喘和复发性慢性鼻窦炎伴鼻息肉病（CRSwNP）的个体。在 本研究期间，我们在上皮基底细胞中发现了明显的表观遗传印迹异常， (BC)CRSwNP和AERD的功能和分化，其中一些是由强大的， 通过白细胞介素4受体α（IL-4 R α）的持续信号传导和一些通过改变的Wnt/Notch信号传导。 我们在CRSwNP组织中发现了肥大细胞（MCs）的显著增生，特别是在患有CRSwNP的个体中。 AERD，部分由一种新的、转录和细胞荧光学上不同的MC群体驱动， 扩散率。我们现在有强有力的证据表明MC-基质相互作用驱动许多病理生理学改变， 呼吸T2 I的特征，并且这些相互作用由来自IL-4 R α和IL-2 R α的协同输入调节。 33/ST 2信号轴。一个由具有互补技能的资深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， 对治疗的顺从性项目1（J.博伊斯，PI）侧重于呼吸道的发育起源 MC，它们与基质细胞的相互作用如何决定MC的发育和功能，并被IL-4 R α改变 信号，以及MC如何通过涉及IL-6和IL-10的前馈回路驱动改变的基质细胞功能。 白血病抑制因子项目2（北）Barrett，PI）专注于表观遗传的机制， BC的重编程与IL-4 R α信号传导结合，驱动BC发育异常和作为疾病的衰老。 成因机制项目3（T. Laidlaw，PI）将比较IL-4 R α阻断与IL-33 在机制验证安慰剂对照试验中进行阻断，重点是恢复BC功能， 抑制MC增生和活化。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).