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 - 项目摘要 该计划项目赠款（PPG）的长期目标是生成有关流体方式的新信息 电解质平衡受到调节，从而有助于血压控制。我们的研究主要关注 与内皮素-1（ET-1）及其相关接收器ETA和ETB相关的机制。先前的研究 项目团队的调查人员揭示了该系统在控制盐分处理盐中的重要作用 水平，肾脏血流动力学的控制和血压调节。调查人员有 证明该系统中的缺陷导致高血压对饮食盐摄入高度敏感。 这是一个复杂而强大的系统，可以平衡ETB的血管舒张作用 ETA受体激活的血管收缩促炎作用的受体。探索两个肾脏 管状作用主要在收集管中，以及血液动力学作用代表潜水员方法 这是该PPG独有的。我们提出的计划有几个主要主题，旨在阐明小说 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 昼夜节律调节血压，因此我们将探讨ET-1在不同的情况下如何影响钠极端 一天的时间。项目2将密切研究肾块茎流体流的变化如何与 各种体液体积状态状态变化调制收集管系统中ET-1的产生以及它的方式 由原发性纤毛，多囊和其他介体调节。项目3的最新发现有 展示了涉及乙酰化和NOS1脱乙酰化的独特调节系统 影响钠处理和血压的盐依赖性变化的管道。此外，均NOS1 NOS3在收集管的主要细胞中表达，因此我们提出了一种新的假设 这两种酶正在调节细胞功能的不同方面。此外，项目2和3 研究收集管中的NOS1和NOS3如何调节ET-1的产生和作用。最后， 两个核心支持此PPG：行政核心，动物和分析核心。行政核心 核心管理并协调整体PPG活动，提供财务会计和预算支持， PPG调查人员的时间表和安排会议，并管理统计分析和数据 管理活动。动物和分析核心核心核心负责管理育种和 在所有三个项目中的啮齿动物的基因分型。总之，这些研究有望发现重要的 调节途径将有助于我们对健康和血压控制的理解以及 在疾病中。