Convergence of the COX-2 and 5-lipoxygenase pathways
COX-2 和 5-脂氧合酶途径的融合
基本信息
- 批准号:7938289
- 负责人:
- 金额:$ 5.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-09-30 至 2010-08-31
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAnabolismAnti-Inflammatory AgentsAnti-inflammatoryArachidonate 5-LipoxygenaseArachidonic AcidsArterial Fatty StreakAspirinAsthmaAtherosclerosisAttenuatedBindingBinding SitesBiological ProcessBiologyCarbonCellsCommitDNA Sequence RearrangementDetectionDinoprostoneDiseaseEicosanoidsEndothelial CellsEnzymatic BiochemistryEnzymesEtiologyFamilyGenetic Crossing OverHumanHydrogen PeroxideHydroxyeicosatetraenoic AcidsInflammationInflammatoryInflammatory ResponseInterleukin-8IsoenzymesKineticsLeadLeukotriene A4LeukotrienesLightLinkLipoxinsLipoxygenaseLungMalignant NeoplasmsMediatingMediator of activation proteinMetabolismMusPathway interactionsPeritoneal MacrophagesPeroxidesPharmaceutical PreparationsPropertyProstaglandin D2Prostaglandin H2Prostaglandin-Endoperoxide SynthaseProstaglandinsPsoriasisReactionRegulationResolutionRouteSeriesSignal PathwaySingle ParentSubstrate SpecificityTestingTissuesTreatment Protocolsanalogangiogenesisarachidonic acid 5-hydroperoxidebasecancer typecyclooxygenase 1cyclooxygenase 2macrophagemast cellnovelnovel therapeutics
项目摘要
There is strong evidence for the induction of the inflammatory enzymes 5-lipoxygenase (5-LOX) and
cyclooxygenase-2 (COX-2) in atherosclerosis, asthma, and many types of cancer. Both enzymes mediate
the inflammatory response of these diseases through the synthesis of leukotrienes and prostaglandins,
respectively. The leukotriene and prostaglandin pathways have traditionally been viewed as independent
biosynthetic routes since the committed step toward either pathway is taken as the initial oxygenation of the
common substrate, arachidonic acid. This proposal is based on the finding that the 5-LOX product, 5S-
hydroxyeicosatetraenoic acid (5S-HETE), is a selective and highly efficient substrate for oxygenation by
COX-2 (but not by the COX-1 isozyme). The discovery of this novel substrate for COX-2 intimately links the
two eicosanoid pathways. The common 5-LOX/COX-2 product is a novel di-endoperoxide that is structurally
reminiscent of, but distinctly different from prostaglandin H2. In the first Specific Aim we propose to analyze
the enzymology of the conversion of arachidonic acid into the novel di-endoperoxide by establishing the
reaction kinetics, substrate specificity, and the structural basis for binding of 5-HETE in the COX-2 active
site. The enzymatic transformation of the di-endoperoxide product will be studied using RAW264.7 cells and
murine peritoneal macrophages, prototypical cells that expresses both 5-LOX and COX-2. Endogenous
formation of the novel eicosanoid and its family of metabolites will be assessed in mouse atherosclerotic
tissue. We will test the hypothesis that the novel di-endoperoxide (or its metabolites) possess anti-
inflammatory properties. Preliminary studies have shown that the di-endoperoxide attenuates the release of
interleukin-8 from stimulated mast cells and microvascular endothelial cells. The signaling pathways involved
in this interaction will be studied using the 5-LOX and COX-2 expressing HMC-1 human mast cell.
Characterization of the novel 5-LOX/COX-2 cross-over pathway will undoubtedly lead to an entirely new
understanding of the biology of 5-LOX and COX-2, and it will also shed new light on the etiology and
regulation of the inflammatory component of diseases like atherosclerosis, asthma, and cancer. These
studies could ultimately lead to new therapeutic regimens for the treatment of these diseases using
established anti-inflammatory medications.
有强有力的证据表明,炎症酶5-脂氧合酶(5-LOX)和
项目成果
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Claus Schneider其他文献
Claus Schneider的其他文献
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{{ truncateString('Claus Schneider', 18)}}的其他基金
Novel pathways in eicosanoid biosynthesis and metabolism
类二十烷酸生物合成和代谢的新途径
- 批准号:
10672176 - 财政年份:2022
- 资助金额:
$ 5.51万 - 项目类别:
Novel pathways in eicosanoid biosynthesis and metabolism
类二十烷酸生物合成和代谢的新途径
- 批准号:
10330785 - 财政年份:2022
- 资助金额:
$ 5.51万 - 项目类别:
Oxidative activation of the dietary cancer chemopreventive agent curcumin
膳食癌症化学预防剂姜黄素的氧化活化
- 批准号:
8601172 - 财政年份:2013
- 资助金额:
$ 5.51万 - 项目类别:
Oxidative activation of the dietary cancer chemopreventive agent curcumin
膳食癌症化学预防剂姜黄素的氧化活化
- 批准号:
9207754 - 财政年份:2013
- 资助金额:
$ 5.51万 - 项目类别:
Oxidative activation of the dietary cancer chemopreventive agent curcumin
膳食癌症化学预防剂姜黄素的氧化活化
- 批准号:
8435168 - 财政年份:2013
- 资助金额:
$ 5.51万 - 项目类别:
Pharmacokinetics and Metabolism of Oxidized Curcumin
氧化姜黄素的药代动力学和代谢
- 批准号:
8301157 - 财政年份:2012
- 资助金额:
$ 5.51万 - 项目类别:
Pharmacokinetics and Metabolism of Oxidized Curcumin
氧化姜黄素的药代动力学和代谢
- 批准号:
8540399 - 财政年份:2012
- 资助金额:
$ 5.51万 - 项目类别:
Convergence of the Cox-2 and 5-Lipoxygenase Pathways
Cox-2 和 5-脂氧合酶途径的融合
- 批准号:
8501525 - 财政年份:2007
- 资助金额:
$ 5.51万 - 项目类别:
Convergence of the COX-2 and 5-lipoxygenase pathways
COX-2 和 5-脂氧合酶途径的融合
- 批准号:
7541465 - 财政年份:2007
- 资助金额:
$ 5.51万 - 项目类别:
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