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MASS SPECTROMETRIC IDENTIFICATION OF NEW LIPID MEDIATORS

新脂质介质的质谱鉴定

基本信息

批准号：
6862725
负责人：
MICHAEL BALAZY
金额：
$ 18.87万
依托单位：
NEW YORK MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-03-01 至 2007-02-28
项目状态：
已结题

项目摘要

DESCRIPTION (Applicant's abstract): The overall aim of this application is to characterize new mechanisms of biological membrane injury resulting form infection with bacterial endotoxin (LPS). The role of free radicals in LPS-induced endotoxemia is becoming well established, however, little is known about the processes involved in the damage to biomembrane lipids by nitrogen dioxide (NO2) radical (a product of nitric oxide oxidation). We have developed a new methodology based on electrospray tandem mass spectrometry, which allows identification and quantification of specific lipid products formed by the reaction of NO2 with arachidonic acid. Preliminary studies have revealed that this reaction generates a complex mixture of lipids containing characteristic products: trans isomers of arachidonic acid and lipids containing nitrogen-carbon bond (nitroeicosanoids). In addition, plasmalogen phospholipids reacted with NO2, which resulted in complete removal of this group of lipids and generation of 1 -lyso-phospholipids. We hypothesize that increased production of NO generates NO2. which is a key radical that targets arachidonic acid and phospholipids. thereby causing membrane injury. Specific aims are to: 1) study relationships between the magnitude of trans-arachidonic acid generation and other markers of free radical damage (isoprostaglandin, nitrite/nitrate, nitrotyrosine); 2) examine the nitration of arachidonic acid and the effects of nitroeicosanoids on NO and cGMP levels in tissues; 3) characterize modifications of plasmalogen phospholipids in endotoxemia. In order to address the role of NO, L-NMA, a NO synthase inhibitor will be used to prevent generation of NO. Uric acid was shown to scavenge NO2, and thus serve as a good probe to study effects of NO2 in LPS-induced injury. Thus these probes will be used to determine the role of NO and NO2 in arachidonic acid isomerization, nitration and plasmalogen degradation. We anticipate that in the long term the proposed studies will provide a foundation for a rational design of new strategies for development of new drugs (inhibitors of lipid isomexization and nitration), and therapies to treat symptoms of sepsis related to the N02-induced cytotoxicity.

描述（申请人的摘要）：本申请的总体目的是表征生物膜损伤的新机制，细菌内毒素（LPS）感染。自由基的作用脂多糖诱导的内毒素血症已被证实，然而，氮对生物膜脂质的破坏过程二氧化物（NO2）自由基（一氧化氮氧化产物）。我们已经开发一种基于电喷雾串联质谱的新方法，对由脂质体形成的特定脂质产物的鉴定和定量 NO2与花生四烯酸的反应。初步研究表明，该反应产生含有特征性的脂质的复杂混合物产品：花生四烯酸的反式异构体和含有氮-碳键（硝基类二十烷）。此外，缩醛磷脂与NO2反应，导致这组脂质被完全去除和1 -溶血磷脂的产生。我们假设 NO的产生产生NO2。这是一种针对花生四烯酸酸和磷脂。从而导致膜损伤。具体目标是： 1)研究反式花生四烯酸的大小与自由基损伤的产生和其它标志物（异前列腺素，亚硝酸盐/硝酸盐，硝基酪氨酸）; 2）检查花生四烯酸的硝化硝基类二十烷酸对组织中NO和cGMP水平的影响; 3）表征内毒素血症中缩醛磷脂的修饰。在为了说明NO的作用，将使用NO合酶抑制剂L-NMA来尿酸被证明可以消除NO2，因此可以为研究NO2在LPS损伤中的作用提供了良好的探针。因此这些将使用探针来确定NO和NO2在花生四烯酸中的作用。异构化、硝化和缩醛磷脂降解。我们预计，长远而言，建议的研究将为合理的设计提供基础开发新药（脂质抑制剂）的新策略异构化和硝化），以及治疗脓毒症相关症状的疗法 NO2诱导的细胞毒性。