ANG II AND AVP ISORECEPTORS IN BLOOD PRESSURE

血压中的 ANG II 和 AVP 异受体

基本信息

批准号：
6125874
负责人：
NELSON RUIZ-OPAZO
金额：
$ 29.66万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-12-15 至 2002-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6125874
关键词：
angiotensin /renin /aldosterone hypertension angiotensin II angiotensin receptor animal population genetics arginine vasopressin blood pressure developmental genetics gene expression gene targeting genetically modified animals hormone regulation /control mechanism immunocytochemistry laboratory mouse laboratory rat neuropeptide receptor protein localization protein structure function

项目摘要

Vasopressin (AVP) and angiotensin II (AngII) hormonal systems modulate a variety of physiologic functions affecting multiple organ systems. Of singular importance, is their role in blood pressure regulation. Our long term objective is to dissect the specific contribution of novel AngII and AVP receptors in blood pressure regulation in normal and pathophysiological states. Several isoreceptors for both AngII and AVP have been recently characterized. Of these, the dual AngII/AVP receptor, isolated by us, elucidates novel information providing the bases for new hypotheses and questions. In this research proposal, we will test the following hypotheses: 1) Based on the detected abundance and assignment by immunocytochemical localization of the AngII/AVP receptor polypeptide to renal epithelial cells of the outer medullary thick ascending limb tubules and inner medullary collecting ducts, we hypothesize that the AngII/AVP receptor is a prominent renal physiologic target for AngII and AVP, and therefore plays an important role in salt- water balance and blood pressure regulation; 2) Based on the elucidation of functional significant mutations in the Dahl Salt-Sensitive rat AngII/AVP receptor, we hypothesize that the AngII/AVP receptor is a genetic determinant for salt-sensitive hypertension in the Dahl Salt- Sensitive hypertensive rat. Accordingly, the following specific aims are prioritized: I) Dissection of potential pathophysiologic involvement of the AngII/AVP receptor in hypertension 1A) Assessment of the specific contribution(s) of N119S and C163R substitutions to the increased sensitivity to Ang II and AVP and enhanced Gs-coupling observed in the Dahl S AngII/AVP receptor; 1B) Genetic cosegregation analysis of the AngII/AVP receptor with blood pressure and renal pathology in an F2 (Dahl S male x Dahl R female) cohort comprised of male and female rats in order to determine whether the mutant AngII/AVP receptor cosegregates with high blood pressure and/or with hypertensive renal disease. II) Dissection of physiologic role of the AngII/AVP receptor: 2A) Tissue specific, spatial and temporal expression patterns in development of the AngII/AVP receptor gene, establishing a foundation for assessing its function in an integrated biologic experimental system as in the gene targeting experiments proposed below. 2B) Targeted disruption of the AngII/AVP receptor gene in mice in order to define its physiologic role in an integrated biologic experimental system. These studies will elucidate the physiologic role of the AngII/AVP receptor and will define the status of the AngII/AVP receptor as a candidate hypertension susceptibility gene, thus paving the way for the direct assessment of the mechanistic role of this receptor in salt-sensitive hypertension and its role in the development of hypertension in selective human populations.

加压素（AVP）和血管紧张素II（Angii）激素系统调节影响多器官系统的多种生理功能。至关重要的是它们在血压调节中的作用。我们的长期目标是剖析新颖的特定贡献正常和病理生理状态。 ANGII和AVP的几种异感受器最近被描述了。其中，双重ANGII/AVP 我们隔离的受体阐明了提供的新信息新假设和问题的基础。在这项研究建议中，我们将检验以下假设：1）基于检测到的丰度和通过Angii/AVP的免疫细胞化学定位分配受体多肽到外髓的肾上皮细胞较厚的上升肢小管和内髓质收集管道，我们假设ANGII/AVP受体是一种突出的肾脏生理学 ANGII和AVP的目标，因此在盐中起重要作用水平和血压调节； 2）基于阐明 DAHL盐敏感大鼠功能性显着突变 ANGII/AVP受体，我们假设Angii/AVP受体是一个达尔盐中盐敏感性高血压的遗传决定因素敏感高血压大鼠。因此，以下特定目标优先考虑：i）解剖潜在的病理生理参与高血压1A中的Angii/AVP受体的评估 N119S和C163R取代的特定贡献对ANG II和AVP的敏感性提高，并增强GS耦合在Dahl S Angii/AVP受体中观察到； 1b）遗传性cosegrigation 用血压和肾脏分析ANGII/AVP受体由F2（Dahl s Male X Dahl R雌性）中的病理学组成雄性和雌性大鼠是为了确定突变体Angii/AVP是否受体高血压和/或高血压肾脏疾病。 ii）ANGII/AVP生理作用的解剖受体：2a）特异性，空间和时间表达模式在Angii/AVP受体基因的开发中，建立基础用于评估其在集成的生物学实验系统中的功能如下面提出的基因靶向实验所示。 2b）目标为了定义小鼠中Angii/AVP受体基因的破坏在综合生物实验系统中的生理作用。这些研究将阐明ANGII/AVP受体的生理作用并将将Angii/AVP受体的状态定义为候选者高血压敏感性基因，因此为直接铺平了道路评估该受体在盐敏感的机械作用高血压及其在高血压发展中的作用选择性人群。