HORMONAL REGULATION OF BLOOD PRESSURE

描述(由申请人提供)：本计划项目资助的目标继续集中在细胞色素P450(CYP)衍生的二十烷酸类化合物在调节肾脏和血管功能以及控制血压方面的作用。该计划为高血压领域的CYP-二十烷类药物研究框架提供了范例和科学线索。这项研究与人类健康的相关性在项目调查人员和其他人最近的研究中得到了强调，这些研究证明了CYP-二十糖与包括糖尿病、中风和高血压在内的心血管疾病之间的分子和功能联系。这一建议建立在此基础上，为这一研究领域带来了新的概念和新的方向。它结合了高血压的血管和肾脏机制以及炎症成分，包括CYP衍生的二十烷基类化合物、EETs和20-HETE之间的相互作用，以及两个不同的调节电路，肾素-血管紧张素系统(RAS)和血红素加氧酶(HO)。这一主题在三个项目中得到了描述。项目1主要研究20-HETE和肾素血管紧张素系统之间的相互作用，并研究血管内皮细胞ACE在20-HETE介导的血管功能障碍和高血压中的作用。项目2研究了K+摄入和血管紧张素II在调节依赖于细胞色素P450的EETs对皮质集合管钠离子转运(上皮性钠离子通道)的抑制作用及其对高血压的影响。项目3确定了HO-1和EETs之间的相互作用调节脂肪细胞功能和脂联素水平以防止肥胖引起的高血压患者血管功能障碍发展的分子机制。这些项目将得到三个核心的支持：核心A提供行政支助。核心B提供了基于LC-MS/MS的二十烷类化合物的测量。核心C为动物研究提供分子、基因和表型支持。该计划项目结合跨学科方法，探索高血压和心血管疾病病理生理学中EETs和HETEs的综合生物学，它们是肾脏盐分处理、血管内皮完整性和血管张力的关键调节因子。 该项目的目标继续集中在细胞色素P450(CYP)衍生的二十烷类化合物在调节肾脏和血管功能以及控制血压方面的作用。该计划为高血压领域的CYP-二十烷类药物研究框架提供了范例和科学线索。这项研究与人类健康的相关性在项目调查人员和其他人最近的研究中得到了强调，这些研究证明了CYP-二十糖与包括糖尿病、中风和高血压在内的心血管疾病之间的分子和功能联系。这一建议建立在此基础上，为这一研究领域带来了新的概念和新的方向。它结合了高血压的血管和肾脏机制以及炎症成分，包括CYP衍生的二十烷基类化合物、EETs和20-HETE之间的相互作用，以及两个不同的调节电路，肾素-血管紧张素系统(RAS)和血红素加氧酶(HO)。这一主题在三个项目中得到了描述。项目1主要研究20-HETE和肾素血管紧张素系统之间的相互作用，并研究血管内皮细胞ACE在20-HETE介导的血管功能障碍和高血压中的作用。项目2研究了K+摄入和血管紧张素II在调节依赖于细胞色素P450的EETs对皮质集合管钠离子转运(上皮性钠离子通道)的抑制作用及其对高血压的影响。项目3确定了HO-1和EETs之间的相互作用调节脂肪细胞功能和脂联素水平以防止肥胖引起的高血压患者血管功能障碍发展的分子机制。这些项目将得到三个核心的支持：核心A提供行政支助。核心B提供了基于LC-MS/MS的二十烷类化合物的测量。核心C为动物研究提供分子、基因和表型支持。该计划项目结合跨学科方法，探索高血压和心血管疾病病理生理学中EETs和HETEs的综合生物学，它们是肾脏盐分处理、血管内皮完整性和血管张力的关键调节因子。在高血压和心血管疾病的病理生理学中。

DESCRIPTION (provided by applicant): The objective of this Program Project Grant continues to concentrate on the role of the cytochrome P450 (CYP)-derived eicosanoids in the regulation of renal and vascular function and in the control of blood pressure. This Program provided paradigms and scientific leads for a framework of CYP-eicosanoid research in the field of hypertension. The relevance ofthis research to human health is highlighted in recent studies by Program investigators and others demonstrating the molecular and functional association between CYP-eicosanolds and cardiovascular disease including diabetes, stroke and hypertension. This proposal builds on this foundation and brings novel concepts and new directions to this area of research. It incorporates the vascular and renal mechanisms and the inflammatory component of hypertension in terms of interactions between the CYP-derived eicosanoids, EETs and 20-HETE, and two distinct regulatory circuits, the renin-angiotensin system (RAS) and the heme oxygenases (HO). This theme is depicted in three projects. Project 1 focuses on the interactions between the CYP4A-derived 20-HETE and the renin angiotensin system and investigate the role of endothelial ACE in 20-HETE-mediated vascular dysfunction and hypertension. Project 2 examines the role of K+ intake and angiotensin II in regulating the inhibitory effect of CYP2C44-dependent EETs on sodium transport (epithelial Na+ channel) in the cortical collecting duct and its impact on hypertension. Project 3 determines the molecular mechanisms by which an interplay between HO-1 and EETs modulates adipocyte function and adiponectin levels to prevent the development of vascular dysfunction in obesity-induced hypertension. These projects will be supported by three Cores: Core A provides administrative support. Core B provides LC-MS/MS-based measurements of eicosanoids. Core C provides molecular, genotypic and phenotypic support for animal research. This Program Project combines interdisciplinary approach to explore the integrative biology of EETs and HETEs, key modulators of renal salt handling, vascular endothelial integrity and vascular tone, in the pathophysiology of hypertension and cardiovascular disease. The objective of this Program Project Grant continues to concentrate on the role of the cytochrome P450 (CYP)-derived eicosanoids in the regulation of renal and vascular function and in the control of blood pressure. This Program provided paradigms and scientific leads for a framework of CYP-eicosanoid research in the field of hypertension. The relevance ofthis research to human health is highlighted in recent studies by Program investigators and others demonstrating the molecular and functional association between CYP-eicosanolds and cardiovascular disease including diabetes, stroke and hypertension. This proposal builds on this foundation and brings novel concepts and new directions to this area of research. It incorporates the vascular and renal mechanisms and the inflammatory component of hypertension in terms of interactions between the CYP-derived eicosanoids, EETs and 20-HETE, and two distinct regulatory circuits, the renin-angiotensin system (RAS) and the heme oxygenases (HO). This theme is depicted in three projects. Project 1 focuses on the interactions between the CYP4A-derived 20-HETE and the renin angiotensin system and investigate the role of endothelial ACE in 20-HETE-mediated vascular dysfunction and hypertension. Project 2 examines the role of K+ intake and angiotensin II in regulating the inhibitory effect of CYP2C44-dependent EETs on sodium transport (epithelial Na+ channel) in the cortical collecting duct and its impact on hypertension. Project 3 determines the molecular mechanisms by which an interplay between HO-1 and EETs modulates adipocyte function and adiponectin levels to prevent the development of vascular dysfunction in obesity-induced hypertension. These projects will be supported by three Cores: Core A provides administrative support. Core B provides LC-MS/MS-based measurements of eicosanoids. Core C provides molecular, genotypic and phenotypic support for animal research. This Program Project combines interdisciplinary approach to explore the integrative biology of EETs and HETEs, key modulators of renal salt handling, vascular endothelial integrity and vascular tone, in the pathophysiology of hypertension and cardiovascular disease. ular tone, in the pathophysiology of hypertension and cardiovascular disease.