Pathophysiologic and therapeutic mechanisms of aspirin exacerbated respiratory d*

描述(由申请人提供)：这项支持哮喘和过敏性疾病合作研究中心(AADCRC)赠款的提案侧重于阿司匹林加重呼吸系统疾病(AERD)的机制基础，AERD是一种独特的临床综合征，在严重哮喘和复发性鼻息肉患者中占不成比例的比例。AERD与摄入非选择性环氧合酶抑制剂(COX)的典型临床反应、半胱氨酰白三烯(Cys-LTs)的持续增加(尤其是在阿司匹林反应期间)以及对白三烯E4(LTE4)的选择性气道高反应有关，白三烯E4是最稳定和含量最丰富的Cys-LTs。我们发现了LTE4引起肺部炎症(需要P2Y12受体和血小板)和血管渗漏(需要一种新的LTE4受体GPR99)的分子途径。我们还发现，AERD患者的白细胞显示出COX-2和COX-2依赖的前列腺素E2(维持AERD动态平衡所必需的)表达的缺陷，并且这种缺陷随着阿司匹林的脱敏而逆转。我们还发现AERD患者的血小板和白细胞缺乏PGE2的EP2受体。一支具有互补技能的高水平研究人员团队将应用细胞、分子和整体动物策略，结合概念验证临床试验，确定这些发现的细胞和分子基础，它们与疾病病理生理学的相关性，以及它们对治疗的适应性。项目1(J.Boyce，PI)专注于EP2受体缺乏的生理和功能后果，并确定其表观遗传学基础。项目2(Y.Kanaoka，PI)将验证GPR99的身份和功能，并确定其对脱敏的敏感性及其对下游效应物(血小板、P2Y12和血栓烷)的需求，以引发生理反应。项目3(E.以色列，PI)将确定P2Y12拮抗剂对阿司匹林临床反应的严重程度的疗效，以及阿司匹林治疗恢复COX-2依赖的PGE2生成的机制。通过一个行政核心，加强了AADCRC的协调。

DESCRIPTION (provided by applicant): This Proposal for support of an Asthma and Allergic Disease Cooperative Research Center (AADCRC) grant is focused on the mechanistic basis of aspirin-exacerbated respiratory disease (AERD), a distinctive clinical syndrome that accounts for a disproportionate percentage of individuals with severe asthma and recurrent nasal polyps. AERD is associated with both characteristic clinical reactions to ingestion of nonselective inhibitors of cyclooxygenase (COX), persistently elevated generation of the cysteinyl leukotrienes (cys-LTs), especially during reactions to aspirin, and selective airway hyperresponsivness to leukotriene E4 (LTE4), the most stable and abundant of the cys-LTs. We have discovered a molecular pathway through which LTE4 induces pulmonary inflammation (requiring P2Y12 receptors and platelets) and vascular leak (requiring a putative novel LTE4 receptor, GPR99). We have also discovered that leukocytes from individuals with AERD display a defect in expression of COX-2 and COX-2-dependent generation of prostaglandin E2 (essential to maintain homeostasis in AERD), and that this reverses with desensitization to aspirin. We have also found that platelets and leukocytes from individuals with AERD lack the EP2 receptor for PGE2. A team of highly accomplished investigators with complementary skills will apply cellular, molecular, and whole animal strategies, combined with a proof-of-concept clinical trial to determine the cellular and molecular basis for these findings, their relevance to disease pathophysiology, and their amenability to therapy. Project 1 (J. Boyce, PI) focuses on the physiologic and functional consequences of EP2 receptor deficiency, and determines its epigenetic basis. Project 2 (Y. Kanaoka, PI) will verify the identity and function of GPR99 and determine its susceptibility to desensitization and its requirement for downstream effectors (platelets, P2Y12, and thromboxane) to elicit physiologic responses. Project 3 (E. Israel, PI) will determine the efficacy of P2Y12 antagonism on the severity of clinical reactions to aspirin, and the mechanism by which aspirin treatment restores COX-2-dependent PGE2 generation. The coordination of the AADCRC is enhanced by an administrative Core.