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Human Hypertension and P450 Co-Hydroxylases and Epoxygenases

人类高血压与 P450 辅羟化酶和环氧合酶

基本信息

批准号：
7758891
负责人：
Nancy Brown
金额：
$ 35.03万
依托单位：
VANDERBILT UNIVERSITY
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：
2009-09-05 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7758891
关键词：
Acids Address Affect African American Agonist Aldosterone Alkane 1-monooxygenase Alleles Amiloride Androgens Animal Model Animals Antihypertensive Agents Arachidonic Acids Asians Attenuated Biological Markers Blood Pressure Blood Vessels Body Fluids CYP4A11 gene Cardiovascular system Caucasians Caucasoid Race Cerebrum Cessation of life Clinical Research Complications of Diabetes Mellitus Congestive Heart Failure Cytochrome P450 Cytosine Data Development Diabetes Mellitus Disease Diuretics Early Diagnosis Economics Eicosanoids End stage renal failure Enzymes Epithelial Excretory function Experimental Models Functional disorder Future Gender Gene Structure Genes Genetic Genetic Polymorphism Genetic Variation Genotype Ghana Goals Health Homologous Gene Human Hydroxyeicosatetraenoic Acids Hydroxylation Hypertension Individual Injury Insulin Resistance Intervention Kidney Kidney Diseases Knock-out Knockout Mice Lead Ligands Medical Metabolic Metabolic syndrome Mixed Function Oxygenases Molecular Morbidity - disease rate Mus Myocardial Infarction Natriuresis Nephrosclerosis Organ Peroxisome Proliferator-Activated Receptors Phenotype Physiological Plasma Play Population Study Prevalence Production Protein Isoforms Proteins Proteinuria Renal Hypertension Renal function Renin Rodent Rodent Model Role Serine Site Sodium Sodium Channel Sodium Chloride Stroke Testing Thymidine Tubular formation United States Urine Variant Vasoconstrictor Agents Vasodilation Vasodilator Agents base blood pressure regulation clinical Diagnosis genetic epidemiology hemodynamics human disease improved inhibitor/antagonist insight insulin sensitivity interdisciplinary approach kidney vascular structure loss of function men mortality novel strategies prevent receptor renal tubular transport response salt intake urinary vasoconstriction

项目摘要

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.

肾脏在控制体液的体积和组成，管状和/或