Chemical Synthesis and Lipid Peroxidation Analytical Core

该计划项目的总体目标是评估高密度脂蛋白功能障碍对增加动脉粥样硬化风险的三种情况的贡献：家族性高胆固醇血症、慢性肾脏疾病和类风湿性关节炎。这些条件似乎共有的高密度脂蛋白功能障碍的一个机制是存在氧化应激，这导致了本项目的主要假设之一：在这些条件下，高密度脂蛋白的过氧化导致其功能障碍。Core C将通过测量高密度脂蛋白中各种脂质过氧化产物的水平并提供试剂来直接测试这些氧化产物对高密度脂蛋白功能障碍的贡献，从而帮助这一努力。核心C有三个目标：1)合成两类化合物，这两类化合物将用于所有三个项目。第一类是合成的异前列腺素产品，包括含有磷脂的F2-异前列腺素、伽马酮醛(异丁香素/异缩酮)，以及项目3将主要使用的非活性类似物。第二类化合物将是所有3个项目都将使用的除醛化合物及其非活性类似物。2)利用质谱学技术对临床和动物样品中的脂质过氧化产物进行定量。这些产品将包括F2-异前列腺素、异胡萝卜素-赖氨酸加合物、异胡芦巴黄素-PE加合物和丙二醛-赖氨酸交联物。这项服务将由所有3个项目使用。3)定量测定给予水杨胺、4-水杨胺、戊基吡哆胺和戊基吡哆醇等化合物的小鼠血浆中醛清除剂及其非活性类似物的水平。这项服务将由所有3个项目使用。

The overall aim of the program project is to assess the contribution of HDL dysfunction to three conditions that increase risk for atherosclerosis: familial hypercholesterolemia, chronic kidney disease, and rheumatoid arthritis. One mechanism of HDL dysfunction that these conditions appear to share is the presence of oxidative stress, which has led to one of the main hypotheses in this program: that peroxidation of HDL in these conditions causes it to become dysfuncfional. Core C will assist in this endeavor by measuring levels of various products of lipid peroxidation in HDL and by providing reagents to directly test the contribution of these oxidized products to HDL dysfunction. Core C has three aims: 1) To synthesize two classes of compounds that will be utilized in all 3 Projects. The first will be synthetic isoprostane products including F2-isoprostane containing phospholipids, gamma-ketoaldehydes (isolevuglandin/isoketal), and inactive analogs which will be used primarily by project 3. The second class of compounds will be aldehyde scavengers and their inactive analogs which will be used by all 3 projects. 2) To quantify lipid peroxidation products in clinical and animal samples using mass spectrometric techniques. These products will include F2-isoprostane, isolevuglandin-lysine-adducts, isolevuglandin-PE adducts, and MDA-lysine crosslinks. This service will be utilized by all 3 Projects. 3) To quantify plasma levels of aldehydes scavengers and their inactive analogs in mice administered these compounds which include salicylamine, 4-salicylamine, pentylpyridoxamine, and pentylpyridoxine. This service will be utilized by all 3 projects.