Role of Eicosanoids in Renal Function

类二十烷酸在肾功能中的作用

• 批准号: 8326682
• 负责人: Nancy J. Brown
• 金额: $ 160.5万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8326682
• 关键词: Address; African American; Agonist; Albuminuria; Alkane 1-monooxygenase; Alleles; Anabolism; Animal Model; Animals; Antihypertensive Agents; Arachidonic Acids; Area; Attenuated; Basic Science; Biochemical; Biochemistry; Biological; Biology; Biometry; Blood Pressure; Blood Vessels; Body Fluids; Boston; CYP2C9 gene; CYP4A11 gene; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Caucasians; Caucasoid Race; Cellular biology; Cerebrum; Chronic; Clinical; Clinical Management; Clinical Research; Complications of Diabetes Mellitus; Cytochrome P450; DNA Sequence; DNA Sequencing Facility; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Diet; Disease; Distal; Diuretics; Early Diagnosis; Early treatment; Eicosanoids; Electrophysiology (science); Elements; Enzymatic Biochemistry; Enzymes; Epidemiologist; Evaluation; Fenofibrate; Functional disorder; Funding; Future; Gene Structure; Gene Targeting; Generations; Genes; Genetic; Genetic Research; Genetic Variation; Genome; Genomics; Genotype; Goals; Health; Home environment; Homologous Gene; Human; Human Genetics; Hydroxyeicosatetraenoic Acids; Hydroxylation; Hypertension; Individual; Institutes; Institution; Insulin; Interest Group; Intervention; Kidney; Kidney Diseases; Knockout Mice; Knowledge; Laboratories; Lead; Leadership; Ligands; Mediating; Mediator of activation protein; Medical; Metabolic; Metabolic syndrome; Microarray Shared Resource; Mixed Function Oxygenases; Modeling; Molecular; Molecular Biology; Molecular Genetics; Morbidity - disease rate; Mus; Nature; Nephrons; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Organ; Pathway interactions; Pharmacogenetics; Pharmacology and Toxicology; Phenotype; Physicians; Physiological; Physiology; Plasma; Play; Population; Positioning Attribute; Prevalence; Property; Protein Isoforms; Proteins; Public Health Schools; Publications; Publishing; Rattus; Regulation; Renal Hypertension; Renal function; Research; Research Personnel; Resources; Role; Running; Scientist; Site; Sodium; Solid; System; Talents; Technology; Translating; Translational Research; Tubular formation; United States National Institutes of Health; Universities; Up-Regulation; Urine; Variant; Wisconsin; Work; base; blood pressure regulation; clinical Diagnosis; clinically relevant; cohort; cytochrome P-450 CYP2C subfamily; db/db mouse; diabetic; experience; familial hypertension; genetic association; hemodynamics; human disease; insight; insulin sensitivity; insulin sensitizing drugs; interdisciplinary approach; interest; kidney vascular structure; loss of function; medical schools; meetings; member; mortality; mouse model; multidisciplinary; next generation; normotensive; novel strategies; prevent; professor; protective effect; receptor; renal tubular transport; research study; response; salt intake; socioeconomics; tool; tool development; vasoconstriction

The kidney plays a key role in the control of body fluid volume and composition, and tubular and/or hemodynamic dysfunction are common features of diseases such as hypertension and diabetes. The renal P450 arachidonic acid (AA) monooxygenase biosynthesizes hydroxy- and epoxy-AA derivatives that are known to modulate tubular transport and vascular reactivity. Animal models of P450 gene dysfunction confirmed the physiological importance of these enzymes, characterized their pathophysiological roles, and provided insights into the mechanism of action of their metabolites. Studies of the pathophysiological roles of human P450s identified associations between P450 gene variants with hypertension, the progression of renal disease, and with components of metabolic syndrome. This application proposes to build upon these studies and to address: a) mechanisms by which the P450-eicosanoids regulate renal tubular transport and vascular reactivity, b) the role of P450s in human hypertension and renal complications of diabetes, and c) the molecular basis of these pathophysiological roles. To achieve these goals, we developed a multidisciplinary approach for studies of P450-isoform specific phenotypes at the cellular, organ and whole animal levels, the analysis of associations between alterations in human P450 gene structure/expression and disease, and for clinical studies of their metabolic and functional consequences. Cyp2c and Cyp4a knockout mice will be used to study gene-dependent changes in: a) renal EET and/or 20-HETE synthase expression, b) tubular transport and/or vascular reactivity, and c) systemic blood pressure and the progression of renal disease. Associations between CYP2C8/2C9 or CYP4A11 genotypes with blood pressure, insulin sensitivity, and urine and plasma EET and 20-HETE levels will be explored to define pathophysiological correlations between variant alleles, AA epoxidation/hydroxylation, and individual responses to changes in dietary salt intake, the administration of diuretics, or peroxisomal proliferator activated receptor (alpha) ligands. Our long term goals are to provide a molecular understanding of role(s) of P450 eicosanoids in renal physiological, their mechanism and site of action, and relevance to human disease. These are needed for the development of meaningful approaches for: a) the unequivocal definition of human pathophysiological significance, and b) future pharmacological targeting, and clinical diagnosis and intervention.

肾脏在控制体液容量和成分方面发挥着关键作用，肾小管和/或血流动力学功能障碍是高血压和糖尿病等疾病的常见特征。肾脏 P450 花生四烯酸 (AA) 单加氧酶生物合成羟基和环氧-AA 衍生物，已知这些衍生物可调节肾小管转运和血管反应性。 P450 基因功能障碍的动物模型证实了这些酶的生理重要性，表征了它们的病理生理作用，并提供了对其代谢物作用机制的见解。对人类 P450 病理生理学作用的研究确定了 P450 基因变异与高血压、肾病进展以及代谢综合征组成部分之间的关​​联。本申请旨在以这些研究为基础，并解决：a) P450-类二十烷酸调节肾小管转运和血管反应性的机制，b) P450 在人类高血压和糖尿病肾脏并发症中的作用，以及 c) 分子基础这些病理生理学作用。为了实现这些目标，我们开发了一种多学科方法，用于在细胞、器官和整个动物水平上研究 P450 亚型特异性表型，分析人类 P450 基因结构/表达的改变与疾病之间的关联，并对其进行临床研究。代谢和功能的后果。 Cyp2c 和 Cyp4a 敲除小鼠将用于研究以下方面的基因依赖性变化：a) 肾脏 EET 和/或 20-HETE 合酶表达，b) 肾小管转运和/或血管反应性，以及 c) 全身血压和肾病进展疾病。将探索 CYP2C8/2C9 或 CYP4A11 基因型与血压、胰岛素敏感性、尿液和血浆 EET 和 20-HETE 水平之间的关联，以确定变异等位基因、AA 环氧化/羟基化以及个体对膳食盐摄入量变化的反应之间的病理生理学相关性、给予利尿剂或过氧化物酶体增殖物激活受体（α）配体。我们的长期目标是提供对 P450 类二十烷酸在肾脏生理学中的作用、其机制和作用位点以及与人类疾病的相关性的分子理解。这些对于开发有意义的方法是必要的：a）人类病理生理学意义的明确定义，b）未来的药理学靶向、临床诊断和干预。