Integrating novel mechanisms controlling sodium excretion and blood pressure

总体--项目摘要 该计划项目赠款(PPG)的长期目标是生成有关流动性如何的新信息- 电解质平衡受到调节，因此有助于控制血压。我们的研究主要集中在 内皮素-1(ET-1)及其相关受体ETA和ETB的机制。之前的研究来自 项目组的研究人员揭示了该系统在控制肾脏处理盐分方面的重要作用 水平衡、肾血流动力学控制和血压调节。调查人员已经 证明这一系统的缺陷会导致高血压，高血压对饮食中的盐摄入量高度敏感。 这是一个复杂而强大的系统，平衡了ETB的血管扩张和促钠尿作用。 受体具有血管收缩促炎作用，可激活ETA受体。探查两个肾脏 主要在集合管中的管状作用以及血流动力学效应代表了一种不同的方法。 这是这个PPG独一无二的。我们提议的节目有几个主要主题，试图阐明小说 钠处理的肾脏控制机制。在项目1中，我们有证据表明ET-1有助于 血压的昼夜节律，因此我们将探索ET-1如何影响不同时期的钠排泄 一天中的几次。项目2将仔细研究肾小管液体流动的改变是如何与 不同的体液容量状态调节收集管道系统内ET-1的产生及其如何 受初级纤毛、多囊蛋白和其他介体调节。项目3的最新发现是 展示了一个独特的调控系统，涉及收集中NOS1的乙酰化和脱乙酰化 影响钠处理和盐依赖的血压变化的导管。此外，两个号码都是1 和NOS3在集合管的主细胞中表达，因此我们提出了一个新的假说 这两种酶调节细胞功能的不同方面。此外，项目2和项目3 研究集合管中的NOS1和NOS3如何调节ET-1的产生和作用。最后， 有两个核心支持这个PPG：管理核心和动物和分析核心。行政部门 CORE管理和协调整个PPG活动，提供财务会计和预算支持， 安排和安排PPG调查人员的会议，管理统计分析和数据 管理活动。核心B，动物和分析核心，负责管理繁殖和 在所有三个项目中对啮齿动物进行基因分型。总而言之，这些研究有望揭示出重要的 调节途径，将有助于我们了解体液电解质和血压在健康和 在疾病中。

OVERALL – PROJECT SUMMARY The long-term goal of this Program Project Grant (PPG) is to generate new information about how fluid- electrolyte balance is regulated and thus contributes to blood pressure control. Our studies largely focus on mechanisms related to endothelin-1 (ET-1) and its associated receptors, ETA and ETB. Previous studies from investigators on the project team revealed a significant role for this system in controlling renal handling of salt and water balance, control of renal hemodynamics, and blood pressure regulation. Investigators have demonstrated that defects in this system results in hypertension that is highly sensitive to dietary salt intake. This is a complicated yet powerful system that balances the vasodilatory and pro-natriuretic actions of the ETB receptor with the vasoconstrictor pro-inflammatory effects of ETA receptor activation. Exploring both renal tubular actions, primarily in the collecting duct, along with hemodynamic effects represents a diverse approach that is unique to this PPG. Our proposed program has several major themes that seek to elucidate novel mechanisms of renal control of sodium handling. In Project 1, we have evidence that ET-1 contributes to circadian regulation of blood pressure, and so we will explore how ET-1 impacts sodium excretion at different times of day. Project 2 will closely examine how alterations in renal tubular fluid flow that are associated with varying body fluid volume status modulate production of ET-1 within the collecting duct system and how it is regulated by the primary cilia, polycystins and other mediators. Recent findings from Project 3 have demonstrated a unique regulatory system involving acetylation and deacetylation of NOS1 in the collecting duct that impacts sodium handling and salt-dependent changes in blood pressure. Furthermore, both NOS1 and NOS3 are expressed in principal cells of the collecting duct, and so we have proposed a novel hypothesis whereby these two enzymes are regulating different aspects of cellular function. In addition, Projects 2 and 3 investigate how NOS1 and NOS3 in the collecting duct modulate both ET-1 production and actions. Finally, two cores support this PPG: the administrative core and the animal and analytical core. The administrative core manages and coordinates overall PPG activities, provides financial accounting and budgetary support, schedules and arranges meetings of PPG investigators, and manages statistical analysis and data management activities. Core B, the animal and analytical core, is responsible for managing breeding and genotyping for rodents in all three projects. In conclusion, these studies are expected to uncover important regulatory pathways that will aid our understanding of fluid-electrolyte and blood pressure control in health and in disease.