PHOSPHOLIPASE ACTIVATION IN ASPIRIN INTOLERANT ASTHMA

描述 (摘自申请者摘要)候选人：Esther Langmack，医学博士， 是宾夕法尼亚大学肺/重症监护研究员 科罗拉多州。朗马克博士的背景包括研究经验和 在酶生物化学、免疫学和哮喘领域发表论文。 她的整个职业目标是研究脂质衍生介质在 哮喘大发作时炎症的发展和持续 学术医疗中心。她的赞助人是萨利·温泽尔博士，她有广泛的 研究白三烯在哮喘中的作用的经验。这项研究 建议：半胱氨酰白三烯(CLT)在病理生理学中起关键作用 哮喘，特别是阿司匹林不耐受哮喘。 然而，起始酶(磷脂酶(S)、5-脂氧合酶(5-LO)) 阿司匹林耐受哮喘患者CLT的产生及其机制 它被激活的背后是未知的。需要解决的具体假设 在这一建议中，花生四烯酸底物的增加 在存在环氧合酶抑制的情况下，被磷脂酶释放， 在阿司匹林不耐受患者中通过5-LO促进CLT的快速产生 哮喘患者。增加花生四烯酸底物也有助于 非5-LO的其他炎性脂质介质的过量生产 途径产物，如HETE、脂蛋白和血小板激活因子， 导致炎症通路的广泛激活。相对的 参与AA释放的两种主要磷脂酶的贡献， 分泌型磷脂酶A2(SPLA2)和胞浆磷脂酶A2(CPLA2)； AIA中AA释放和AA衍生的介体产量将被确定。 5-LO抑制对AA衍生谱的体内影响 将对友邦保险产生的调解人进行评估。这项提议将进一步 对脂类介体生成步骤的理解 炎症状态和这些介质的变化，可能 发生在5-LO抑制后。这些发现不仅将改善 了解阿司匹林不耐受哮喘，但将澄清规则 在许多其他炎症条件下的脂质介体。这个 研究环境：国家犹太医学研究中心是一个 国际公认的机构致力于以下领域的研究 过敏、免疫学、肺部内科和传染病。Dr。 朗马克在这个项目上的合作者包括罗伯特·墨菲博士、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 脂质介体分析。(摘要结束)

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)