PHOSPHOLIPASE ACTIVATION IN ASPIRIN INTOLERANT ASTHMA

描述 （改编自申请人摘要）候选人：Esther Langmack，医学博士， 是美国密歇根大学肺部/重症监护研究员， 科罗拉多。 Langmack博士的背景包括研究经验和 酶生物化学、免疫学和哮喘领域的出版物。 她的总体职业目标是研究脂源性介质在 哮喘中炎症的发展和持续， 学术医疗中心 她的赞助商是莎莉·温泽尔博士，她有广泛的 研究白三烯在哮喘中作用的经验。 研究 建议：半胱氨酰白三烯（cLT）对病理生理学至关重要 尤其是阿司匹林不耐受性哮喘。 然而，初始酶（磷脂酶（s），5-脂氧合酶（5-LO）） 导致阿司匹林不耐受性哮喘患者产生cLT及其机制 其激活的背后是未知的。 要解决的具体假设 在该建议中，花生四烯酸底物增加 磷脂酶的释放，在环氧合酶抑制剂存在下， 在阿司匹林不耐受患者中， 哮喘患者 增加的花生四烯酸底物也促进了 非5-LO的其他炎症脂质介质的过度产生 途径产物，如HETE、脂氧素和血小板活化因子， 导致炎症途径广泛激活。 的相对 参与AA释放的两种主要磷脂酶的贡献， 分泌型磷脂酶A2（sPLA 2）和胞质型磷脂酶A2（cPLA 2）， AA释放和AA衍生的介质生产中，将被确定。 5-LO抑制对AA衍生的光谱的体内影响 将对AIA产生的调解员进行评估。 该提案将进一步 了解导致脂质介质产生的步骤， 炎症状态和这些介质的改变， 发生在5-LO抑制后。 这些发现不仅可以改善 了解阿司匹林不耐受性哮喘，但将阐明调节 脂质介质在许多其他炎症条件下，以及。 的 研究环境：国家犹太医学和研究中心是一个 国际公认的机构，致力于研究领域的 过敏、免疫学、肺医学和传染病。 博士 朗马克的合作者为这个项目包括博士罗伯特墨菲，博士。 克里斯蒂娜·莱斯利和杰伊·韦斯科特博士将分享他们在以下方面的专业知识： 脂质介质分析。 (End摘要）

DESCRIPTION (Adapted from applicant's abstract) The Candidate: Esther Langmack, M.D., is a Research Fellow in Pulmonary/Critical Care at the University of Colorado. Dr. Langmack's background includes research experience and publication in the areas of enzyme biochemistry, immunology, and asthma. Her overall career goal is to study the role of lipid-derived mediators in the development and perpetuation of inflammation in asthma at a major academic medial center. Her Sponsor is Dr. Sally Wenzel, who has extensive experience studying the role of leukotrienes in asthma. The research Proposal: Cysteinyl leukotrienes (cLTs) are critical to the pathophysiology of asthma, in general, and aspirin-intolerant asthma in particular. However, the initial enzyme (phospholipase(s), 5-lipoxygenase (5-LO)) leading to cLT production in aspirin-intolerant asthma and the mechanisms behind its activation are unknown. The specific hypothesis to be addressed in this proposal is that an increase in arachidonic acid substrate liberation by phospholipases, in the presence of cyclooxygenase inhibition, drives the rapid production of cLTs by 5-LO in aspirin-intolerant asthmatics. Increased arachidonic acid substrate also facilitates the overproduction of other inflammatory lipid mediators which are not 5-LO pathway products, such as HETEs, lipoxins, and platelet activating factor, leading to broad activation of inflammatory pathways. The relative contribution of the two main phospholipases involved in AA release, secretory phospholipase A2 (sPLA2) and cytosolic phospholipase A2 (cPLA2), to AA release and AA-derived mediator production in AIA, will be determined. The in vivo effect of 5-LO inhibition upon the spectrum of AA-derived mediators produced in AIA will be evaluated. This proposal will further understanding of the steps leading to the generation of lipid mediators in inflammatory conditions and the alteration of these mediators which may occur after 5-LO inhibition. These findings will not only improve the understanding of aspirin-intolerant asthma, but will clarify the regulation of lipid mediators in numerous other inflammatory conditions, as well. The Research Environment: National Jewish Medical and Research Center is an internationally recognized institution devoted to research in the areas of allergy, immunology, pulmonary medicine and infectious diseases. Dr. Langmack's collaborators for this project include Dr. Robert Murphy, Dr. Christina Leslie, and Dr. Jay Westcott, who will share their expertise in lipid mediator analysis. (End of Abstract)