Pathophysiologic and therapeutic mechanisms of aspirin exacerbated respiratory d*

描述（由申请人提供）：支持哮喘和过敏性疾病合作研究中心（AADCRC）拨款的这一提案侧重于阿司匹林加重呼吸道疾病（AERD）的机制基础，AERD是一种独特的临床综合征，占严重哮喘和复发性鼻息肉患者的比例不成比例。AERD与摄入非选择性环氧合酶（考克斯）抑制剂的特征性临床反应、持续升高的半胱氨酰白三烯（cys-LT）生成（尤其是在阿司匹林反应期间）和选择性气道对白三烯E4（LTE 4）（最稳定和最丰富的cys-LT）的高反应性相关。我们已经发现了LTE 4诱导肺部炎症（需要P2 Y12受体和血小板）和血管渗漏（需要推定的新型LTE 4受体GPR 99）的分子途径。我们还发现，AERD患者的白细胞在考克斯-2表达和考克斯-2依赖性前列腺素E2（维持AERD体内平衡所必需的）生成方面存在缺陷，并且这种缺陷在对阿司匹林脱敏后逆转。我们还发现AERD患者的血小板和白细胞缺乏PGE 2的EP 2受体。一个具有互补技能的高度成就的研究人员团队将应用细胞，分子和整个动物策略，结合概念验证临床试验，以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.博伊斯，PI）关注EP 2受体缺陷的生理和功能后果，并确定其表观遗传基础。项目2（Y. Kanaoka，PI）将验证GPR 99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、P2 Y12和血栓烷）的需求以引发生理反应。项目3（E. Israel，PI）将确定P2 Y12拮抗作用对阿司匹林临床反应严重程度的功效，以及阿司匹林治疗恢复考克斯-2依赖性PGE 2产生的机制。该委员会的协调工作通过一个行政核心得到加强。

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.