Novel Pathways of Eicosanoid Metabolism

类二十烷酸代谢的新途径

• 批准号: 9445135
• 负责人: Claus Schneider
• 金额: $ 32.17万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9445135
• 关键词: Affect; Anabolism; Analgesics; Anti Inflammatory Analgesics; Anti-Inflammatory Agents; Anti-inflammatory; Arachidonic Acids; Aspirin; Asthma; Autacoids; Blood Platelets; Chemicals; Clinical; Clinical Research; Cytochrome P450; Data; Diclofenac; Dinoprostone; Eicosanoid Metabolism Pathway; Eicosanoids; Enzymes; Evaluation; Event; FMO1; Failure; Fatty Acids; Fever; Flavins; Flushing; Genetic; Hepatocyte; Hormones; Human; Human body; In Vitro; Inflammation; Inflammatory; Injectable; Label; Lactones; Leukotrienes; Lipids; Lipoxygenase; Liver; Measurement; Mediator of activation protein; Metabolic; Metabolic Pathway; Metabolism; Mixed Function Oxygenases; Modeling; Mus; Nature; Nicotinic Acids; Pain; Parents; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Physiological; Plasma; Platelet Activation; Process; Prostaglandin D2; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Prostaglandins I; Publishing; Recombinants; Resistance; Role; Signal Transduction; Site; Source; Subcellular Fractions; Testing; Thromboxane B2; Thromboxanes; Time; Tissues; Tylenol; Urine; Work; base; clinical practice; cyclic ketone; eicosanoid metabolism; experimental study; functional group; genetic manipulation; in vivo; indexing; knockout animal; man; mastocytosis; mouse model; novel; oxidation; translational impact; urinary; volunteer

Prostaglandins and other eicosanoids are derived from cyclooxygenase, lipoxygenase, and cytochrome P450 oxygenation of arachidonic acid. Eicosanoids serve as important lipid autacoids (local hormones) to signal and regulate inflammation, fever, pain, and other physiological and pathophysiological processes. The fleeting nature of prostaglandins and other eicosanoids in vivo precludes in most cases their direct quantitative measurement at the sites of their formation. Instead, urinary metabolites have been established as convenient, reliable, and non-invasive markers for the formation of eicosanoids during physiological and pathophysiological events. Likewise, these markers are used to assess the effects and efficacy of anti-inflammatory drugs and other medications used to modulate their biosynthesis. Here, we will test the hypothesis that prostaglandin D2 (PGD2), when formed in unusually high amounts, is metabolized in part to 11- dehydro-thromboxane B2 (11d-TxB2). This hypothesis is based on re-interpretation of published data and preliminary studies that show parallel formation of a urinary metabolite of PGD2, PGD- M, and 11d-TxB2, and metabolism of labeled PGD2 to labeled 11d-TxB2 in mice. The same metabolic pathway is hypothesized to be involved in the metabolism of other eicosanoids, including PGE2 and 15-deoxy-∆ -PGJ2. We will test the hypothesis in three specific aims. In 12,14 aim 1 we will analyze the time course of formation of the urinary metabolites PGD-M, 11d-TxB2, and 2,3-dinor-TxB2 in human models of increased formation of PGD2. In specific aim 2 we will use pharmacologic and genetic mouse models to provide a mechanistic analysis of the transformation of PGD2 to 11d-TxB2. In specific aim 3 we will use recombinant enzymes and liver tissue fractions to identify the enzyme(s) involved in the novel metabolic pathway. Together, these studies will lead to a re-evaluation of the utility of urinary metabolites for the quantitative analysis of their parent prostaglandins and eicosanoids. There is immediate clinical and translational relevance for the usefulness of these markers in the assessment of anti-platelet therapy.

前列腺素和其他二十烷基类化合物来源于花生四烯酸的环氧合酶、脂氧合酶和细胞色素P450的氧化。二十烷类化合物是重要的类脂类化合物(局部激素)，用来发出信号并调节炎症、发热、疼痛和其他生理和病理生理过程。前列腺素和其他二十烷类化合物在体内的短暂性质，在大多数情况下排除了在其形成部位进行直接定量测量的可能性。相反，尿代谢物已被确定为在生理和病理生理事件中形成二十烷类化合物的方便、可靠和非侵入性的标记物。同样，这些标记物也被用来评估抗炎药和其他用于调节其生物合成的药物的效果和疗效。在这里，我们将检验一种假设，即前列腺素D2(PGD2)当形成异常高的量时，部分代谢为11-脱氢-血栓素B2(11d-TxB2)。这一假说是基于对已发表的数据和初步研究的重新解释，这些研究表明在小鼠体内平行形成了PGD2、PGD-M和11d-TxB2的尿代谢物，并将标记的PGD2代谢成标记的11d-TxB2。同样的代谢途径被认为参与了其他二十烷类化合物的代谢，包括前列腺素E_2和15-脱氧-∆-前列腺素J_2。我们将在三个具体目标上检验这一假设。在12，14目标1中，我们将分析在人体PGD2形成增加的模型中，尿代谢物PGD-M、11d-TxB2和2，3-dior-TxB2的形成时间过程。在具体目标2中，我们将使用药理学和遗传学的小鼠模型来提供PGD2向11d-TxB2转化的机制分析。在具体目标3中，我们将使用重组酶和肝组织组分来鉴定参与新代谢途径的酶(S)。总之，这些研究将导致重新评估尿代谢物对其母体前列腺素和二十烷类化合物进行定量分析的效用。对于这些标记物在抗血小板治疗评估中的有效性，有直接的临床和翻译相关性。