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.

性状（由申请人提供）：15-脱氧-δ-12，14-前列腺素J2（15-d-PGJ 2）是一种高度反应性的环戊烯酮类花生酸，由环氧合酶（考克斯）衍生的前列腺素D2（PGD 2）脱水产生。我们已经获得了支持这一论点的数据。除了考克斯途径外，15-d-PGJ 2还可以通过PGD 2样化合物（称为D2-异前列腺素（IsoPs））的脱水产生，这些化合物是在氧化应激条件下自由基催化的花生四烯酸过氧化反应形成的。这是相关的，因为15-d-PGJ 2已被假定为多种生物过程的重要介质。其多样的生物活性在很大程度上归因于其前列烷环上存在反应性多不饱和羰基部分，该部分是与含巯基生物分子（如蛋白质上的谷胱甘肽和半胱氨酸残基）进行Michael加成的底物。15-d-PGJ 2已被证明具有抗增殖和促凋亡活性。它的一些活性可能与观察到它是过氧化物酶体增殖物激活受体-γ的配体有关。此外，15-d-PGJ 2已被报道存在于人类动脉粥样硬化病变中的显着量，并驻留在泡沫细胞，这表明它在调节炎症和凋亡反应的重要作用。尽管对15-d-PGJ 2的生物活性有很大的兴趣，但其在体内形成的程度和调节其形成的机制尚不清楚。这项研究的总体目标是确定15-d-PGJ 2在体内形成的程度，并研究调节其形成的机制。我们假设考克斯和IsoP途径都有助于体内15-d-PGJ 2的形成。为了验证这一假设，我们将开发质谱方法来测量15-d-PGJ 2的主要尿代谢产物作为其内源性产生的生物标志物。因此，提出了以下具体目标：确定15-d-PGJ 2在大鼠中的代谢命运并鉴定其主要尿代谢物; II.）比较15-d-PGJ 2在大鼠和人中的代谢;和III.）检查考克斯和IsoP途径对体内15-d-PGJ 2形成的贡献。由于在体内通过考克斯和IsoP途径产生，15-d-PGJ 2可以介导炎症和氧化损伤中涉及的各种生理和病理生理过程。很明显，与炎症和/或氧化损伤相关的疾病，如动脉粥样硬化、阿尔茨海默病和癌症，给我们的国家带来了巨大的公共卫生负担。在这种情况下，研究15-d-PGJ 2的形成和代谢将为理解其在这些疾病和相关疾病的病理生理学中的作用奠定基础。