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）衍生的类二十烷在肾脏和血管功能调节以及血压控制中的作用。该项目为高血压领域的cyp20 -类胡萝卜素研究框架提供了范例和科学指导。该项研究与人类健康的相关性在最近的研究中得到了强调，这些研究表明，cyp20 -羟色胺与包括糖尿病、中风和高血压在内的心血管疾病之间存在分子和功能上的联系。这一建议建立在这个基础上，为这一领域的研究带来了新的概念和新的方向。它结合了血管和肾脏机制以及高血压的炎症成分，包括cypp衍生的二十烷类化合物、EETs和20-HETE以及两个不同的调节回路，肾素血管紧张素系统（RAS）和血红素加氧酶（HO）之间的相互作用。在三个项目中描述了这个主题。项目1侧重于cyp4a衍生的20-HETE与肾素血管紧张素系统的相互作用，并研究内皮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cyp2c44依赖性eet对皮质集管钠转运（上皮Na+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，通过调节脂肪细胞功能和脂联素水平来预防肥胖引起的高血压血管功能障碍的分子机制。这些项目将由三个核心提供支持：核心A提供行政支持。Core B提供基于LC-MS/ ms的类二十烷酸测量。Core C为动物研究提供分子、基因型和表型支持。本项目结合跨学科的方法，探索eet和HETEs的整合生物学，肾盐处理、血管内皮完整性和血管张力的关键调节剂，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.