Research Center for Pharmacology & Drug Toxicology

描述（由申请人提供）：药理学和药物毒理学研究中心汇集了一组经验丰富的研究人员，他们对脂质氧化和氧化应激在疾病发病机制中的作用有共同的兴趣，并以此为基础确定治疗人类疾病的新药理学策略。该中心由五个研究项目和两个核心组成。 项目1中的拟议研究是我们在该中心先前研究的发展，该研究阐明了对乙酰氨基酚抑制血红素蛋白氧化还原循环诱导的脂质过氧化。我们的新研究将探讨对乙酰氨基酚和相关化合物通过抑制细胞色素c氧化还原循环诱导的心磷脂氧化来预防细胞凋亡的能力，心磷脂是细胞凋亡级联反应的重要组成部分。 项目2中的拟议研究由两个临床项目组成。其中一个项目将评价对乙酰氨基酚抑制蛛网膜下腔出血患者血红蛋白氧化还原循环诱导的脂质过氧化的能力，第二个项目将评价对乙酰氨基酚抑制接受心肺转流术患者血红蛋白和肌红蛋白诱导的氧化应激的能力。 项目3中的拟议研究将探索通过环氧合酶-2选择性氧化内源性大麻素以形成2-花生四烯酰乙醇酰胺和2-花生四烯酰甘油，以及低浓度非甾体抗炎药（NSAID）对它们的底物选择性抑制。“项目4中拟议的研究将探索治疗性调节内皮细胞四氢生物蝶呤水平的方法，作为预防一氧化氮合酶解偶联引起的氧化应激的一种手段。 项目5中的拟议研究将探索白三烯-A型脂肪酸环氧化物生物合成的潜在机制，这是形成促炎性白三烯和eoxins以及促分解脂氧素、resolvins、protectins和maresins的关键中间体。 相关性：预计这些研究将导致（a）有效的新药理学方法，以预防在诸如心肌梗塞和中风的情况下的凋亡性死亡以及在蛛网膜下腔出血和心肺转流手术的情况下的血红素蛋白介导的氧化损伤，（B）对NSAID的一些无法解释的作用的新认识，（c）通过提高四氢生物蝶呤的水平来改善血管功能的新治疗方法和（d）对潜在方法的新认识，所述潜在方法可调节消退素、保护素、脂氧素和maresins的形成。

DESCRIPTION (provided by applicant): The Research Center for Pharmacology and Drug Toxicology brings together a group of highly experienced investigators with a shared interest in the role of oxygenation of lipids and oxidative stress in disease pathogenesis as a basis for the identification of new pharmacologic strategies for treatment of human disease. The Center is comprised of five research projects and two cores. The proposed research in Project 1 is an evolution of our previous studies in the Center which elucidated that acetaminophen inhibits hemoprotein redox cycling induced lipid peroxidation. Our new studies will investigate the ability of acetaminophen and related compounds to prevent apoptosis by inhibiting cytochrome c redox cycling induced oxidation of cardiolipin, an essential component of the apoptotic cascade. The proposed research in Project 2 is comprised of two clinical projects. One will evaluate the ability of acetaminophen to inhibit hemoglobin redox cycling induced lipid peroxidation in patients with subarachnoid hemorrhage and the second project will evaluate the ability of acetaminophen to inhibit hemoglobin and myoglobin induced oxidative stress in patients undergoing cardiopulmonary bypass surgery. The proposed research in Project 3 will explore the selective oxygenation of endocannabinoids by cyclooxygenase-2 to form 2-arachidonoylethanolamide and 2-arachidonoylglycerol and their substrate- selective inhibition by low concentrations of non-steroidal anti-inflammatory drugs (NSAIDs). 'The proposed research in Project 4 will explore approaches to therapeutically modulate levels of endothelial cell tetrahydrobiopterin as a means to prevent oxidative stress due to uncoupling of nitric oxide synthase. The proposed research in Project 5 will explore the mechanisms underlying the biosynthesis of leukotriene-A type fatty acid epoxides, which are key intermediates in the formation of pro-inflammatory leukotrienes and eoxins and the pro-resolving lipoxins, resolvins, protectins, and maresins. RELEVANCE: It is anticipated that these studies will lead to (a) effective novel pharmacologic approaches to prevent apoptotic death in settings such as myocardial infarction and stroke and hemoprotein mediated oxidative damage in settings of subarachnoid hemorrhage and cardiopulmonary bypass surgery, (b) new insights into some of the unexplained actions of NSAID's, (c) new therapeutic approaches to improve vascular function by enhancing levels of tetrahydrobiopterin and (d) new insights into potential ways to pharmacologically modulate the formation of resolvins, protectins, lipoxins, and maresins.