P450 Monooxygenases and Renal Vascular Function

P450 单加氧酶和肾血管功能

基本信息

批准号：
7758889
负责人：
John D Imig
金额：
$ 23.72万
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/7758889
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 Cells 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 Diagnostic Disease Distal Diuretics Early Diagnosis Economics Eicosanoids Electrophysiology (science)Elements Enzymatic Biochemistry Enzymes Epidemiologist Evaluation Fenofibrate Functional disorder Funding Future Gene Structure Gene Targeting Generations Genes Genetic Genetic Research Genetic Techniques 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 Genetics Morbidity - disease rate Mus Nature Nephrons Non-Insulin-Dependent Diabetes Mellitus Nuclear Receptors Organ Outcome 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 Testing Therapeutic Translating Translational Research Tubular formation 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 in vivo 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 tool tool development 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.

肾脏在控制体液体积和成分以及管状和/或血液动力学功能障碍是高血压和糖尿病等疾病的常见特征。肾 P450花生四烯酸（AA）单加氧酶的生物合成羟基和环氧-AA衍生物是已知可以调节管状转运和血管反应性。 P450基因功能障碍的动物模型确认了这些酶的生理重要性，表征了它们的病理生理作用，并提供了有关其代谢产物作用机理的见解。研究的病理生理作用人类P450鉴定了P450基因变异与高血压的关联，肾脏疾病，以及代谢综合征的成分。本申请建议以这些为基础研究和解决：a）P450- eicosanoids调节肾小管运输和血管反应性，b）P450在糖尿病的人类高血压和肾脏并发症中的作用，C）这些病理生理作用的分子基础。为了实现这些目标，我们开发了一个多学科在细胞，器官和整个动物的P450-异型特异性表型的研究方法水平，对人P450基因结构/表达的改变与疾病，以及有关其代谢和功能后果的临床研究。 CYP2C和CYP4A淘汰赛小鼠将用于研究基因依赖性的变化：a）肾脏EET和/或20-HETE合酶表达， b）管状转运和/或血管反应性，c）全身血压和肾脏的进展疾病。 CYP2C8/2C9或CYP4A11基因型与血压，胰岛素敏感性，将探索尿液和血浆EET以及20-HETE水平以定义病理生理相关性在变异等位基因，AA环氧化/羟基化以及对饮食盐变化的各个反应之间摄入量，利尿剂或过氧化物酶体增生剂活化受体（alpha）配体。我们的长期目标是提供对肾脏中P450 eicosanoids作用的分子理解生理学，其机制和作用部位以及与人类疾病相关的。这些是需要的有意义的方法的发展：a）人类病理生理学的明确定义意义和b）未来的药理学靶向，以及临床诊断和干预。