FUNCTIONAL SIGNIFICANCE OF CYTOCHROME P450 CYCLOOXYGENASE

细胞色素 P450 环加氧酶的功能意义

• 批准号: 6653341
• 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: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6653341
• 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-羟基乙酸烯酸（20-Hete）是关键肾脏结构的主要eicosanoid，它在调节肾血管和管状功能的调节中是必不可少的组成部分。鉴于20-HETE对肾功能的重要性，在确定eicosanoid的肾脏作用的深度和广度时，这些控制和活性的因素的识别和表征占据了高度优先级。环氧酶（COX-1和COX 2）和一氧化氮合酶（NOS）已被确定为分别对20-HETE代谢和生产的调节核心。三个目标将解决COX的重要重要性，而肾脏中的20位级别和活动的重要性。 AIM 1的AII输注模型的高血压模型，以确定影响20-HETE的生产和生物学活性的细胞因子，NO和COX（1和-2）的可能相互作用。 AIM 2利用了高盐摄入对无生产和低盐摄入对皮质Cox-2表达的相对选择性的影响，以研究其对皮质中20-Hete代谢物的20-Hete组织水平和生物学活性谱的单独影响。 AIM 3解决了糖皮质激素对TAL中COX-2表达的强大负面影响，以定义涉及TNF和COX-2（以及可能是Inos）后肾上腺后的相互作用，并将其中一个或多个因素与CYP450 AA代谢的假定抑郁症相关联，以与肾功能的变化有关。