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结果将一群紧密联系在一起的 对多不饱和脂肪酸氧化有共同兴趣的有经验的研究人员进行研究 重点研究二十烷类化合物和相关化合物的药理、生物化学和生物学。的目标是 这项研究是为了确定新的靶点的治疗方法的发展，以调节形成，代谢， 以及二十烷类化合物和相关化合物在人体内的生物活性。 研究表明，含氧多不饱和脂肪酸在人体生理中起着重要作用。 和病理生理学。因此，对氧化脂肪酸物种形成的药理学操纵 为预防或治疗与这些化合物相关的病理生理过程提供了机会。 然而，在分子水平上，对影响形成和作用的因素有透彻的了解 二十烷类化合物和相关化合物的含量仍然难以捉摸。 该中心包括五个研究项目和两个核心，将提供对 含氧多不饱和脂肪酸，在人类中以酶或非酶方式衍生 生理学和病理生理学。我们研究计划的一个优势是，提出的项目整合了Basic 药理学、生物化学和分子生物学方法以及涉及人类的翻译研究。 项目1将确定参与形成新型甘油-前列腺素(PGs)的生化途径。 从2-花生四烯基甘油中，检测它们在细胞和组织中的生成，并表征它们在 活着。项目2将检验PGD2受体是中枢炎症的关键调节剂这一假设。 神经系统采用了多种体外和体内模型。项目3的基础是扑热息痛 抑制血红素蛋白催化的脂质过氧化，并将确定这一作用的分子基础。在……里面 此外，研究还将评估以对乙酰氨基酚为基础的疗法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，来源于 过氧化的多不饱和脂肪酸，介导氧化应激的不利影响。项目4将重点放在 该化合物在体内形成的机制并表征了新的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得到精确的定义，并导致 形成含有复杂环状结构的未描述的生物活性产物。这些 研究将利用在磷脂酰乙醇胺中酯化的DNA，磷脂酰乙醇胺是这种脂肪酸的一种生物相关形式。 这项研究计划中包括的研究人员在科学和智力上都是高度整合的。 在与花生四烯酸和花生四烯酸的氧化有关的许多方面的研究方面都非常有经验 其他多不饱和脂肪酸。预计拟议的项目将大大推进我们的 了解二十烷类化合物和相关化合物的药理和生物学。

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.