Integrating novel mechanisms controlling sodium excretion and blood pressure

整合控制钠排泄和血压的新机制

• 批准号: 9922350
• 负责人: DAVID M POLLOCK
• 金额: $ 225.97万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922350
• 关键词: ARNTL gene; Accounting; Acetylation; Adult; American; Angiotensins; Animal Model; Animals; Attention; Awareness; Biology; Blood Circulation; Blood Pressure; Blood Vessels; Body Fluids; Breeding; Businesses; Cardiovascular Diseases; Cardiovascular system; Cell physiology; Cilia; Clinical; Collecting Cell; Complement; Deacetylation; Defect; Disease; Duct (organ) structure; Ductal Epithelial Cell; Electrolyte Balance; Electrolytes; Elements; Endothelin; Endothelin Receptor Antagonist; Endothelin-1; Ensure; Enzymes; Equilibrium; Estrogens; Excretory function; Future; Genes; Genotype; Goals; Gonadal Steroid Hormones; HDAC1 gene; Health; Histone Deacetylase; Homeostasis; Human; Hypertension; Immune System Diseases; In Vitro; Inflammatory; Kidney; Kidney Diseases; Knowledge; Laboratories; Lead; Liquid substance; Mediating; Mediator of activation protein; Molecular; Monitor; NOS1 gene; NOS3 gene; Nitric Oxide; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Physiological; Population; Process; Production; Program Development; Program Research Project Grants; Receptor Activation; Regulation; Regulatory Pathway; Renin; Research Personnel; Risk; Risk Factors; Rodent; Role; Schedule; Scheme; Sex Differences; Signal Transduction; Sodium; Sodium Chloride; Statistical Data Interpretation; System; Techniques; Testing; Testosterone; Therapeutic; Time; Tubular formation; Variant; Vasoconstrictor Agents; Water; blood pressure regulation; cardiovascular risk factor; circadian; circadian pacemaker; circadian regulation; clinical development; combat; data management; dietary salt; fluid flow; gene function; hemodynamics; high salt diet; innovation; meetings; novel; programs; receptor; salt intake; saluretic; side effect; success; synergism

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.

总体而言——项目概要 该计划项目拨款 (PPG) 的长期目标是生成有关流体如何- 电解质平衡得到调节，从而有助于血压控制。 与内皮素-1 (ET-1) 及其相关受体、ETA 和 ETB 相关的机制。 项目团队的研究人员揭示了该系统在控制肾脏处理盐方面的重要作用 和水平衡、肾血流动力学控制和血压调节。 该系统的缺陷导致对膳食盐摄入高度敏感的高血压。 这是一个复杂而强大的系统，可以平衡 ETB 的血管舒张作用和促尿钠排泄作用 受体与ETA受体激活的血管收缩促炎作用。 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 这是本 PPG 所独有的，我们提出的计划有几个旨在阐明新颖的主题。 肾脏控制钠处理的机制 在项目 1 中，我们有证据表明 ET-1 有助于 血压的昼夜节律调节，因此我们将探讨 ET-1 如何影响不同时间的钠排泄 项目 2 将仔细检查肾小管液流的变化是如何与相关的。 不同的体液量状态调节集合管系统内 ET-1 的产生以及它是如何产生的 由初级纤毛、多囊蛋白和其他介质调节。项目 3 的最新发现表明。 一个独特的调节系统，涉及NOS1在收集过程中的乙酰化和脱乙酰化 此外，NOS1 还影响钠处理和盐依赖性血压变化。 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设 因此，这两种酶调节细胞功能的不同方面。此外，项目 2 和 3。 研究集合管中的 NOS1 和 NOS3 如何调节 ET-1 的产生和作用。 有两个核心支持该 PPG：管理核心以及动物和分析核心。 核心管理和协调 PPG 的整体活动，提供财务会计和预算支持， 安排和安排 PPG 研究人员的会议，并管理统计分析和数据 核心 B，即动物和分析核心，负责管理育种和管理活动。 总之，这些研究有望揭示所有三个项目中的啮齿动物基因分型。 监管途径将有助于我们了解健康和健康领域的液体电解质和血压控制 在疾病中。