PPARs in CYP450 Dependent Regulation of Kidney Function

CYP450 中 PPAR 的肾功能依赖性调节

基本信息

批准号：
7459642
负责人：
Matthew Douglas Breyer
金额：
$ 13.41万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7459642
关键词：
2,4-thiazolidinedione Alleles Androgen Receptor Arachidonic Acids Binding Blood Pressure Blood Vessels Carbon Class Cytochrome P450 Duct (organ) structure Epithelial Epoxy Compounds Family Family member Fibrates Goals Human Hydroxylation Hypertension Ion Transport Kidney Ligands Link Lipids Lipoxygenase Mediating Metabolism Mineralocorticoids Mixed Function Oxygenases Molecular Molecular Target Mus Mutation Nephrons Nuclear Receptors Object Attachment PPAR gamma PTGS1 gene PTGS2 gene Pathway interactions Peroxisome Proliferator-Activated Receptors Prostaglandin-Endoperoxide Synthase Regulation Renal function Role Sodium Chloride System Testing Thiazolidinediones Unsaturated Fatty Acids absorption arachidonate blood pressure regulation cyclooxygenase 1 cyclooxygenase 2 design fatty acid metabolism gene therapy man novel response

项目摘要

The demonstration of hypertension in mice lacking Cytochrome P450 4a14 provides unequivocal evidence linking the CYP450 system with blood pressure control. Although other evidence implicates Cytochrome P450 derived arachidonate metabolites (CYP450-AA metabolites) as mediating both renal microvascular effects and effects on renal salt absorption, identification of a molecular target of CYP450-AA metabolites has remained elusive. Abnormalities in activation of nuclear receptors including mineralocorticoid and androgen receptors are well-established causes of hypertension in man. More recently mutations in another group of nuclear receptors, the peroxisome proliferator activated receptors (PPARs), have also been found to result in human hypertension. PPARs have also been shown both to transcriptionally modulate the expression of CYP450s and also bind and be activated by CYP450 AA metabolites. This goal of this project is to test the hypothesis that PPARgamma are not only key target of CYP450 AA metabolites, mediating both the epithelial and microvascular effects of this family of compounds, but also modulate the expression of CYP450 epoxygenases. The studies proposed in Specific aim 1: will examine the interaction between CYP450s and PPARgamma in regulating renal epithelial ion transport, using the Cre/Lox system to conditionally delete a "floxed" PPARgamma allele from the mouse collecting duct and other nephron segments. The potential of CYP450 derived arachidonate metabolites as PPARgamma ligands will also be studied. Specific Aim 2 will examine the role PPARgamma in modulating CYP450 AA epoxygenase products (EETs) and DHETs in modulating vascular tone and blood pressure. Through these studies we hope to establish a novel molecular pathway contributing to the regulation of blood pressure by CYP450s.

缺乏细胞色素P450 4A14的小鼠中高血压的演示提供了明确的将CYP450系统与血压控制联系起来的证据。尽管其他证据表明，细胞色素P450衍生的蛛网膜盐代谢产物（CYP450-AA代谢产物）是介导肾脏微血管效应和对肾脏盐吸收的影响，鉴定CYP450-AA代谢物的分子靶标的鉴定，难以释放。包括盐皮质激素和雄激素受体在内的核受体激活异常是人类高血压的良好原因。最近，还发现了另一组核受体，过氧化物酶体增殖物激活受体（PPARS）的突变，也会导致人类高血压。 PPAR也已显示出转录调节CYP450s的表达，并通过CYP450 AA代谢产物结合并激活。该项目的这个目标是检验以下假设：ppargamma不仅是CYP450 AA代谢产物的关键靶标，从而介导了这种化合物家族的上皮和微血管效应，还调节了CYP450上氧化酶的表达。特定目标1中提出的研究将使用CRE/LOX系统从小鼠收集管和其他肾肾脏段从有条件地删除“ Floxed” Ppargamma等位基因的CRE/LOX系统在调节肾上皮离子转运方面的相互作用。还将研究CYP450衍生的蛛形代谢产物作为ppargamma配体的潜力。特定的目标2将检查PPARGAMMA在调节CYP450 AA环氧酶产物（EET）和DHET中的作用，并在调节血管张力和血压调节中的作用。通过这些研究，我们希望建立一种新型的分子途径，从而导致CYP450的血压调节。