Research Center for Pharmacology and Drug Toxicology

药理学和药物毒理学研究中心：新机制和药理学 多不饱和脂肪酸氧化的后果汇集了一个紧密结合的群体， 经验丰富的研究人员，对多不饱和脂肪酸氧化有共同的兴趣， 专注于类花生酸和相关化合物的药理学、生物化学和生物学。的目标 这项研究是为了确定新的治疗目标，以调节形成，代谢， 以及类二十烷酸和相关化合物在人体中的生物活性。 研究表明，含氧多不饱和脂肪酸物种在人体生理中起着重要作用 和病理生理学。因此，对脂肪酸的氧化物质的形成的药理学操作 提供了预防或治疗与这些化合物相关的病理生理过程的机会。 尽管如此，在分子水平上彻底了解影响形成和作用的因素， 类二十烷酸和相关化合物的合成仍然是难以捉摸的。 该中心包括五个研究项目和两个核心，将提供重要的见解， 人体中酶促或非酶促衍生的多不饱和脂肪酸的含氧物质 生理学和病理生理学。我们的研究计划的一个优势是，拟议的项目整合了基本的 药理学、生物化学和分子生物学方法以及涉及人类的转化研究。 项目1将定义参与形成新的甘油基-胡萝卜素（PG）的生化途径 从2-花生四烯酸甘油，检查它们在细胞和组织中的生成，并表征它们在 vivo.项目2将检验PGD 2受体是中枢神经系统炎症的关键调节剂这一假设。 神经系统使用各种体外和体内模型。项目3建立在对乙酰氨基酚 抑制血红素蛋白催化的脂质过氧化，并将确定这种作用的分子基础。在 此外，研究将评估对乙酰氨基酚为基础的方案对人体脂质过氧化的抑制作用 蛛网膜下腔出血4-羟基壬烯醛是一种生物活性脂质， 过氧化多不饱和脂肪酸，介导氧化应激的不利影响。项目4将侧重于 该化合物在体内形成的机制和表征新的HNE加合物。项目5将测试 假设二十二碳六烯酸的氧化可以在人类中精确定义，并导致 形成迄今为止未描述的、具有生物活性的、含有复杂环状结构的产物。这些 研究将利用在磷脂酰乙醇胺中酯化的DNA，磷脂酰乙醇胺是该脂肪酸的生物学相关形式。 包括在这个研究计划中的调查人员在科学和智力上都是高度综合的 并且在与花生四烯酸的氧化有关的研究的许多方面都非常有经验， 其它多不饱和脂肪酸。预计拟议的项目将大大促进我们的 了解类花生酸及其相关化合物的药理学和生物学。

The Research Center for Pharmacology and Drug Toxicology: Novel Mechanisms and Pharmacological Consequences of Polyunsaturated Fatty Acid Oxygenation brings together a tightly-knit group of experienced investigators with a shared interest in polyunsaturated fatty acid oxygenation to undertake research focused on the pharmacology, biochemistry, and biology of eicosanoids and related compounds. The goal of this research is to identify new targets for the development of therapies to modulate the formation, metabolism, and biological activities of eicosanoids and related compounds in humans. Studies suggest that oxygenated polyunsaturated fatty acid species play an important role in human physiology and pathophysiology. Thus, pharmacological manipulation of the formation of oxidized species of fatty acids provides the opportunity to prevent or treat pathophysiological processes associated with these compounds. Nonetheless, a thorough understanding, at the molecular level, of factors influencing the formation and actions of eicosanoids and related compounds remains elusive. This Center comprises five research projects and two cores that will provide important insights into the role of oxygenated species of polyunsaturated fatty acids, derived either enzymatically or non-enzymatically, in human physiology and pathophysiology. A strength of our research program is that proposed projects integrate basic pharmacological, biochemical and molecular biological approaches with translational studies involving humans. Project 1 will define biochemical pathways involved in the formation of novel glyceryl-prostaglandins (PGs) from 2-arachidonylglycerol, examine their generation in cells and tissues, and characterize their metabolism in vivo. Project 2 will test the hypothesis that PGD2 receptors are critical modulators of inflammation in the central nervous system using a variety of in vitro and in vivo models. Project 3 builds on findings that acetaminophen inhibits heme protein-catalyzed lipid peroxidation and will determine the molecular basis for this effect. In addition, studies will evaluate the inhibition of lipid peroxidation by acetaminophen-based regimens in humans with subarachnoid hemorrhage. 4-hydroxynonenal is a bioactive lipid derived from the fragmentation of peroxidized polyunsaturated fatty acids that mediates adverse effects of oxidant stress. Project 4 will focus on mechanisms by which this compound is formed in vivo and characterize novel HNE adducts. Project 5 will test the hypothesis that the oxidation of docosahexaenoic can be precisely defined in humans and leads to the formation of here-to-fore undescribed, biologically active, products containing complex cyclic structures. These studies will utilize DNA esterified in phosphatidylethanolamine, a biologically relevant form of this fatty acid. The investigators included in this research proposal are highly integrated both scientifically and intellectually and are extremely experienced in a number of facets of research related to the oxygenation of arachidonate and other polyunsaturated fatty acids. It is anticipated that the projects proposed will significantly advance our understanding of the pharmacology and biology of eicosanoids and related compounds.