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:
  • 金额:
    $ 35.03万
  • 依托单位:
  • 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

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

项目成果

期刊论文数量(0)
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Nancy Brown其他文献

Nancy Brown的其他文献

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{{ truncateString('Nancy Brown', 18)}}的其他基金

Human Hypertension and P450 Co-Hydroxylases and Epoxygenases
人类高血压与 P450 辅羟化酶和环氧合酶
  • 批准号:
    8326677
  • 财政年份:
  • 资助金额:
    $ 35.03万
  • 项目类别:
Human Hypertension and P450 Co-Hydroxylases and Epoxygenases
人类高血压与 P450 辅羟化酶和环氧合酶
  • 批准号:
    8521251
  • 财政年份:
  • 资助金额:
    $ 35.03万
  • 项目类别:
Human Hypertension and P450 Co-Hydroxylases and Epoxygenases
人类高血压与 P450 辅羟化酶和环氧合酶
  • 批准号:
    8111792
  • 财政年份:
  • 资助金额:
    $ 35.03万
  • 项目类别:
Human Hypertension and P450 Co-Hydroxylases and Epoxygenases
人类高血压与 P450 辅羟化酶和环氧合酶
  • 批准号:
    8379574
  • 财政年份:
  • 资助金额:
    $ 35.03万
  • 项目类别:

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