Chemical Synthesis and Lipid Peroxidation Analytical Core

该项目的总体目标是评估HDL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。这些条件似乎共享的HDL功能障碍的一种机制是氧化应激的存在，这导致了该计划中的主要假设之一：在这些条件下HDL的过氧化导致其功能障碍。核心C将通过测量HDL中各种脂质过氧化产物的水平，并通过提供试剂来直接测试这些氧化产物对HDL功能障碍的贡献，来协助这一奋进。核心C有三个目标：1）合成两类化合物，用于所有3个项目。第一种将是合成异前列烷产品，包括含磷脂的F2-异前列烷、γ-酮醛（异丁香酮/异缩酮）和主要由项目3使用的无活性类似物。第二类化合物将是醛清除剂及其非活性类似物，将用于所有3个项目。2)使用质谱技术定量临床和动物样本中的脂质过氧化产物。这些产物将包括F2-异前列烷、异evuglandin-赖氨酸加合物、异evuglandin-PE加合物和MDA-赖氨酸交联。这三个项目都将使用这项服务。3)定量给予这些化合物（包括水杨胺、4-水杨胺、戊基吡哆胺和戊基吡哆辛）的小鼠中醛类清除剂及其非活性类似物的血浆水平。这三个项目都将使用这项服务。

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.