FUNCTIONAL SIGNIFICANCE OF CYTOCHROME P450 CYCLOOXYGENASE

细胞色素 P450 环加氧酶的功能意义

• 批准号: 6578852
• 负责人: JOHN C MC GIFF
• 金额: $ 31.48万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-11-01 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6578852
• 关键词: adrenalectomy; angiotensin II; arachidonate; cytochrome P450; dietary sodium; eicosanoid metabolism; enzyme activity; enzyme mechanism; glucocorticoids; hormone regulation /control mechanism; hypertension; isolation perfusion; kidney function; laboratory rat; mass spectrometry; nitric oxide; nitric oxide synthase; nutrition related tag; prostaglandin endoperoxide synthase; protein protein interaction; tumor necrosis factor alpha; vasomotion

20-hydroxyeicosatetraenoic acid (20-HETE) is the principal eicosanoid of key renal structures where it serves an essential component in the regulation of renal vascular and tubular function. In view of the importance of 20-HETE to renal function, the identification and characterization of those factors that govern production and activity of 20-HETE assume a high priority as they determine the depth and breadth of the renal actions of the eicosanoid. Cyclooxygenases (COX-1 and COX 2) and nitric oxide synthases (NOS) have been identified as being central to the regulation of 20-HETE metabolism and production, respectively. Three Aims will address the postulated importance of COX and NO to 20-HETE levels and activities in the kidney. AIM 1 makes of the AII infusion model of hypertension to determine relationship and possible interactions of cytokines, NO and COX (both-1 and -2) that affect production and biological activities of 20-HETE. Aim 2 draws upon the relatively selective effect of high salt intake on NO production and low salt intake on cortical COX-2 expression in order to study their separate effects on 20-HETE tissue levels and spectrum of biological activities of 20-HETE metabolites in the cortex. AIM 3 addresses the powerful negative effect of glucocorticoids on COX- 2 expression in the TAL in order to define interactions involving TNF and COX-2 (and possibly iNOS) post-adrenal and to relate one or more of these factors to a postulated depression of CYP450 AA metabolism and to changes in renal function.

20-羟基二十碳四烯酸 (20-HETE) 是肾脏关键结构的主要类二十烷酸，是调节肾血管和肾小管功能的重要组成部分。鉴于 20-HETE 对肾功能的重要性，控制 20-HETE 产生和活性的那些因素的识别和表征具有高度优先性，因为它们决定了类二十烷酸肾脏作用的深度和广度。环加氧酶（COX-1 和 COX 2）和一氧化氮合酶 (NOS) 已被确定分别是 20-HETE 代谢和生产调节的核心。三个目标将解决 COX 和 NO 对肾脏中 20-HETE 水平和活动的假定重要性。 AIM 1 利用高血压的 AII 输注模型来确定影响 20-HETE 产生和生物活性的细胞因子、NO 和 COX（-1 和 -2）之间的关系和可能的相互作用。目标 2 利用高盐摄入量对 NO 产生的相对选择性影响和低盐摄入量对皮质 COX-2 表达的相对选择性影响，以研究它们对 20-HETE 组织水平和 20-HETE 代谢物生物活性谱的单独影响。皮质。 AIM 3 解决了糖皮质激素对 TAL 中 COX-2 表达的强大负面影响，以定义肾上腺后涉及 TNF 和 COX-2（可能还有 iNOS）的相互作用，并将这些因素中的一个或多个与假设的抑郁症联系起来。 CYP450 AA代谢及肾功能的变化。