Stable Isotope Approaches to the Understanding of Potassium Homeostasis

稳定同位素方法了解钾稳态

基本信息

批准号：
10592405
负责人：
JANG H. YOUN
金额：
$ 20.46万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-15 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10592405
关键词：
Acute Address Affect Aldosterone Animals Biochemical Blood Brain Buffers Cardiovascular Physiology Cardiovascular system Cells Chronic Collaborations Communication Development Dietary Potassium Elements Epinephrine Equilibrium Event Excretory function Exercise Future Grant Half-Life Homeostasis Hormone secretion Hypokalemia In Vitro Incubated Individual Inductively Coupled Plasma Mass Spectrometry Institution Insulin Intake Intracellular Fluid Isotopes Kidney Life Measurement Measures Methodology Methods Modeling Molecular Muscle Na(+)-K(+)-Exchanging ATPase Nature Neurophysiology - biologic function Organ Pancreas Patients Plasma Play Potassium Potassium Channel Probability Radioactive Tracers Radioactivity Rattus Regulation Renal Tissue Role Sampling Signal Transduction Skeletal Muscle Technology Text Time Tissues Tracer Universities Variant Work analytical method extracellular heart function hyperkalemia improved in vivo innovation neuromuscular function novel strategies novel therapeutics pancreatic juice stable isotope tool

项目摘要

Project Summary Potassium (K+) homeostasis is critical for normal cardiovascular and neuromuscular function, and disturbances in K+ homeostasis (e.g., hyperkalemia) can lead to life-threatening cardiovascular events. Extracellular K+ homeostasis is maintained by renal and extrarenal mechanisms. The kidneys have a remarkable capacity to regulate K+ excretion to match K+ intake, playing the major role in maintaining chronic K+ balance. In addition, extrarenal tissues (mainly skeletal muscle, the major K+ store) provide K+ buffering capacity by shifting K+ between the extracellular and intracellular fluids. Furthermore, gut sensing of dietary K+ appears to generate signals for regulating renal K+ excretion and extrarenal K+ shift. Thus, extracellular K+ homeostasis involves multiple organs and tissues, their adaptation to dietary K+ intake, and crosstalk among them. Despite marked progress in this field in recent decades, many critical issues concerning K+ homeostatic mechanisms remain unresolved due to a lack of appropriate methodology. A main limitation in studies of extracellular K+ homeostasis is an inability to quantify K+ fluxes in vivo. Although previous studies quantified K+ fluxes using 86Rb, a radioactive tracer for K+, radioactivity exposure and short half-life of 86Rb have limited its use to in vitro studies. Stable isotopes of a wide range of elements have been used to quantify fluxes of various substrates or blood constituents in vivo. However, in spite of the existence of two stable isotopes of K+ in nature (39K, 93.3% and 41K, 6.7%), this approach has not been applied to the study of K+ homeostasis in vivo due to analytical limitations. Dr. John Higgins, a geochemist at Princeton University, developed analytical methods for determining the ratio of stable K+ isotopes (41K/39K) in natural samples using inductively coupled plasma mass spectrometry. This state-of-the-art technology provides the opportunity to determine K+ fluxes in vivo using stable isotopes (i.e., without using radioactive tracers). The objective of the current proposal is to develop and validate this new approach for estimating whole-body K+ fluxes in vivo and extend it to assess K+ transport activities in individual tissues. If successfully developed, these new cutting-edge approaches will open new doors to answering important questions and filling gaps in K+ homeostatic mechanisms in vivo. These stable isotope approaches will be highly innovative, as they allow whole-body and in vitro K+ flux analyses that were infeasible with any conventional approaches, including those with 86Rb.

项目摘要钾（K+）稳态对于正常的心血管和神经肌肉功能至关重要，并且 K+稳态（例如高钾血症）的扰动会导致威胁生命的心血管事件。细胞外K+稳态通过肾脏和外部机制维持。肾脏有一个了不起的调节K+排泄以匹配K+摄入量的能力，在维持慢性K+平衡方面发挥了主要作用。在另外，外部组织（主要是骨骼肌，主要的K+商店）通过移动提供K+缓冲能力 k+在细胞外和细胞内流体之间。此外，饮食K+的肠道感知似乎会产生调节肾脏K+排泄和肾外K+移位的信号。因此，细胞外K+稳态涉及多个器官和组织，它们适应饮食K+摄入量以及其中的串扰。尽管有标记近几十年来，该领域的进展，有关K+稳态机制的许多关键问题仍然存在由于缺乏适当的方法，未解决。细胞外K+稳态研究的主要局限性是无法在体内量化K+通量的一种。尽管以前的研究使用86RB量化了K+通量，但一种放射性 K+的示踪剂，放射性暴露和86RB的半衰期限制了其在体外研究中的用途。稳定的多种元素的同位素已用于量化各种基材或血液的通量体内成分。然而，尽管存在两个稳定的同位素在本质上（39K，93.3％和41K） 6.7％），由于分析局限性，这种方法尚未应用于体内K+稳态的研究。普林斯顿大学的地球化学家约翰·希金斯（John Higgins）博士开发了用于确定比率的分析方法使用电感耦合等离子体质谱法中天然样品中稳定的K+同位素（41K/39K）的体形。这最先进的技术提供了使用稳定同位素在体内确定K+通量的机会（即不使用放射性示踪剂）。当前建议的目的是开发和验证这一新的在体内估算全身K+通量的方法，并将其扩展以评估个体中的K+运输活动组织。如果成功开发，这些新的尖端方法将为回答打开新的门重要的问题和体内K+稳态机制中的空白。这些稳定的同位素方法将是高度创新的，因为它们允许全身和体外K+通量分析，而这些分析与任何有关传统方法，包括具有86RB的方法。