Formation and Metabolism of 15-deoxy-delta-12, 14-prostaglandin J2 in Vivo

15-脱氧-δ-12, 14-前列腺素 J2 在体内的形成和代谢

• 批准号: 8053495
• 负责人: Klarissa D Jackson
• 金额: $ 0.57万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2011-05-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8053495
• 关键词: 9-deoxy-delta-9-prostaglandin D2; Alzheimer' s Disease; Apoptotic; Arachidonic Acids; Arterial Fatty Streak; Atherosclerosis; Biological Assay; Biological Markers; Biological Process; Cysteine; Data; Dehydration; Disease; Eicosanoids; Foam Cells; Foundations; Free Radicals; Functional disorder; Glutathione; Goals; Human; Inflammation; Inflammatory; Injury; Isoprostanes; Ligands; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Metabolic; Metabolism; Methodology; Methods; Oxidants; Oxidative Stress; PPAR gamma; Pathway interactions; Physiological; Process; Production; Prostaglandin D2; Prostaglandin-Endoperoxide Synthase; Proteins; Public Health; Rattus; Relative (related person); Reporting; Research; Role; Sulfhydryl Compounds; Testing; Urine; cyclopentenone; in vivo; interest; nonhuman primate; oxidant stress; peroxidation; response; urinary

DESCRIPTION (provided by applicant): 15-deoxy-delta-12,14-prostaglandin J2 (15-d-PGJ2) is a highly reactive cyclopentenone eicosanoid generated from the dehydration of cyclooxygenase(COX)-derived prostaglandin D2 (PGD2). We have obtained data supporting the contention that. In addition to the COX pathway, 15-d-PGJ2 can be generated from the dehydration of PGD2-like compounds, termed D2-isoprostanes (IsoPs), which are formed from the free radical-catalyzed peroxidation of arachidonic acid under settings of oxidative stress. This is relevant because 15-d-PGJ2 has been postulated as an important mediator of a wide variety of biological processes. Its diverse bioactivities are largely attributed to the presence of a reactive polyunsaturated carbonyl moiety on its prostane ring that is a substrate for Michael addition with thiol-containing biomolecules, such as glutathione and cysteine residues on proteins. 15-d-PGJ2 has been shown to possess anti-proliferative and pro-apoptotic activity. Some of its activity may relate to the observation that it is a ligand for peroxisome proliferator-activated receptor-gamma. Additionally, 15-d-PGJ2 has been reported to be present in significant amounts in human atherosclerotic lesions and to reside in foam cells, suggesting an important role for it in modulating inflammatory and apoptotic responses. Despite great interest in its bioactivity, the extent to which 15-d-PGJ2 is formed in vivo and the mechanisms that regulate its formation are unclear. The overall goal of the proposed research is to determine the extent to which 15-d-PGJ2 is formed in vivo and examine the mechanisms that regulate it formation. We hypothesize that both the COX and IsoP pathways contribute to the formation of 15-d-PGJ2 in vivo. To test this hypothesis, we will develop mass spectrometric methodologies to measure the major urinary metabolite of 15-d-PGJ2 as a biomarker of its endogenous production. The following specific aims are thus proposed: I.) Determine the metabolic fate of 15-d-PGJ2 in the rat and identify its major urinary metabolite; II.) Compare the metabolism of 15-d-PGJ2 in rats and humans; and III.) Examine the contributions of the COX and IsoP pathways to the formation of 15- d-PGJ2 in vivo. As a result of being generated through the COX and IsoP pathways in vivo, 15-d-PGJ2 may mediate various physiological and pathophysiological processes involved in inflammation and oxidant injury. It is clear that diseases associated with inflammation and/or oxidative injury, such as atherosclerosis, Alzheimer's disease, and cancer, pose a tremendous public health burden on our nation. In this context, studies examining the formation and metabolism of 15-d-PGJ2 will lay the foundation for understanding its role in the pathophysiology of these and related diseases.

描述（申请人提供）： 15-脱氧-δ-12,14-前列腺素 J2 (15-d-PGJ2) 是一种高反应性环戊烯酮类二十烷酸，由环氧合酶 (COX) 衍生的前列腺素 D2 (PGD2) 脱水生成。我们已经获得了支持这一论点的数据。除了 COX 途径外，15-d-PGJ2 还可以通过 PGD2 样化合物的脱水产生，称为 D2-异前列腺素 (IsoPs)，这些化合物是在氧化应激条件下由自由基催化的花生四烯酸过氧化形成的。这是相关的，因为 15-d-PGJ2 已被认为是多种生物过程的重要介质。其多样化的生物活性很大程度上归因于其前列腺烷环上存在反应性多不饱和羰基部分，该部分是与含硫醇生物分子（例如蛋白质上的谷胱甘肽和半胱氨酸残基）进行迈克尔加成的底物。 15-d-PGJ2 已被证明具有抗增殖和促凋亡活性。它的一些活性可能与它是过氧化物酶体增殖物激活受体-γ 的配体这一观察结果有关。此外，据报道，15-d-PGJ2 在人类动脉粥样硬化病变中大量存在，并驻留在泡沫细胞中，这表明它在调节炎症和细胞凋亡反应中发挥着重要作用。尽管人们对其生物活性非常感兴趣，但 15-d-PGJ2 在体内形成的程度以及调节其形成的机制尚不清楚。本研究的总体目标是确定 15-d-PGJ2 在体内形成的程度并检查调节其形成的机制。我们假设 COX 和 IsoP 途径都有助于体内 15-d-PGJ2 的形成。为了检验这一假设，我们将开发质谱方法来测量 15-d-PGJ2 的主要尿液代谢物，作为其内源性产生的生物标志物。因此提出以下具体目标： I.) 确定 15-d-PGJ2 在大鼠体内的代谢命运并鉴定其主要尿代谢物； II.) 比较 15-d-PGJ2 在大鼠和人类中的代谢； III.) 检查 COX 和 IsoP 途径对体内 15-d-PGJ2 形成的贡献。由于在体内通过 COX 和 IsoP 途径产生，15-d-PGJ2 可能介导炎症和氧化损伤等各种生理和病理生理过程。显然，与炎症和/或氧化损伤相关的疾病，例如动脉粥样硬化、阿尔茨海默病和癌症，给我们国家带来了巨大的公共卫生负担。在这种背景下，检查 15-d-PGJ2 的形成和代谢的研究将为了解其在这些疾病及相关疾病的病理生理学中的作用奠定基础。