Active transmembrane water cycling kinetics: A Cellular Metabolic 1H MR Biomarker

活性跨膜水循环动力学：细胞代谢 1H MR 生物标志物

• 批准号: 8445710
• 负责人: James Alvin Balschi
• 金额: $ 32.09万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445710
• 关键词: ATP phosphohydrolase; ATPase inhibitory protein; Acute Kidney Failure; Affect; Area; Basic Science; Biological Markers; Biological Models; Bolus Infusion; Carrier Proteins; Cell Size; Cell Volumes; Cell membrane; Cell physiology; Cell surface; Cells; Cellular Membrane; Contrast Media; Coronary Arteriosclerosis; Data; Data Analyses; Diffusion; Drug Kinetics; Equilibrium; Evaluation; Functional Imaging; Goals; Gold; Heart; Heart failure; Human; Image; Individual; Ion Pumps; Ion Transport; Ischemia; Kidney; Kinetics; Link; Magnetic Resonance; Magnetic Resonance Imaging; Mammalian Cell; Maps; Measurement; Measures; Mediating; Membrane; Membrane Proteins; Metabolic; Metabolism; Methods; Modeling; Mole the mammal; Myocardium; Na(+)-K(+)-Exchanging ATPase; Noise; Organism; Ouabain; Patients; Permeability; Phospholipids; Physiological; Population; Proton-Translocating ATPases; Rattus; Reagent; Relaxation; Reporting; Resolution; Severities; Signal Transduction; Site; Skeletal Muscle; Solutions; Spectrum Analysis; Speed; System; Techniques; Testing; Time; Tissues; Transmembrane Transport; Vesicle; Water; Water Movements; Yeasts; aqueous; base; extracellular; heart metabolism; imaging modality; in vivo; inhibitor/antagonist; malignant breast neoplasm; molecular imaging; novel; osteosarcoma; outcome forecast; prognostic; programs; public health relevance; response; standard measure; symporter; water channel; water diffusion

DESCRIPTION (provided by applicant): Water transport across plasma membranes is a fundamental cellular function. Net water movement in response to an osmotic gradient changes cell volume. Steady-state exchange of water molecules (water cycling), with no net flux or volume change, occurs by passive diffusion through the phospholipid bilayer and via membrane proteins. In a very exciting discovery, we have found that steady-state water exchange correlates with the activity of the yeast cellular membrane major ion transport protein, the P-type H+-ATPase. We also have preliminary data from the heart that water exchange correlates with Na+,K+-ATPase activity. Na+,K+-ATPase is present in almost all mammalian cells. This discovery was made using MR relaxography (MRR) with steady-state extracellular relaxation reagent (RRe) to distinguish intra- and extracellular water signals by their longitudinal time constant (T1) values (1H2O T1 MRR/RRe). Two-site exchange analysis determines trans-membrane water exchange kinetics in terms of the mean intracellular water lifetime (¿i) and intra- and extracellular water fractions (Vi and Ve). The inverse ¿i (¿i-1) is the first order rate constant for water efflux. Our results show that ¿i-1 or water cycling reveals membrane protein mediated activities. The long-term objective of this application is to develop 1H2O T1 MRR measured water exchange as a high-resolution molecular imaging method for metabolic transport activity. First, we pursue the basic science to reveal the causal mechanisms that link water exchange kinetics and membrane transport activity. The model system will be the isolated perfused heart with steady-state RRe concentration ([RRe]). These RRe are contrast agents currently used in human MRI studies. Imaging versions of 1H2O T1 MRR measurements with steady-state [RRe] will be implemented and used as gold standard measures of ¿i-1, Vi and Ve to establish the accuracy/precision of the same parameters obtained from bolus [RRe] Dynamic-Contrast-Enhanced -MRI (non-steady state [RRe]) measurements, which are already in use. Finally, we will measure and compare ¿i-1 and Vi with steady state and bolus [RRe] in the in vivo rat heart. This project will begin to elucidate the factors affecting ¿i-1 magnitude and assess its potential use as a novel cellular metabolic transport activity 1H MRI biomarker. This biomarker would benefit from the high signal and spatial resolution of 1H MRI, thus allowing high resolution functional imaging. Existing shutter-speed DCE-MRI studies have reported anatomically accurate parametric ¿i maps of human osteosarcoma/skeletal muscle and malignant breast tumors. Other patho-physiological states, e.g., ischemia, heart failure and acute renal failure may also have altered ¿i-1. For example, acute renal failure involves loss of renal transport activity (and likely, water fluxes). Potentially our method will define the severity of metabolic damage, which will likely correlate with prognosis.

描述(申请人提供)：水通过质膜运输是一种基本的细胞功能。渗透梯度引起的净水分运动改变了细胞体积。水分子的稳态交换(水循环)，没有净通量或体积变化，通过磷脂双层和通过膜蛋白的被动扩散发生。在一个非常令人兴奋的发现中，我们发现稳态水交换与酵母细胞膜主要离子转运蛋白P型的活性相关 H+-ATPase。我们也有来自心脏的初步数据，水交换与Na+，K+-ATPase活性有关。Na+，K+-ATPase几乎存在于所有哺乳动物细胞中。这一发现是通过使用稳态细胞外松弛试剂(RRE)的MR松弛成像(MRR)来区分细胞内和细胞外水分信号的纵向时间常数(T1)值(1H2O T1 MRR/RRE)得出的。双位交换分析根据平均细胞内水寿命(？i)和细胞内外水分数(Vi和Ve)确定跨膜水交换动力学。倒数i(i-1)是一阶速率 水外流的常量。我们的结果表明，i-1或水循环显示了膜蛋白介导的活性。 这一应用的长期目标是开发1H2O T1 MRR测量的水交换作为一种高分辨率的代谢转运活动的分子成像方法。首先，我们追求基础科学，以揭示水交换动力学和膜转运活动之间的因果机制。模型系统将是具有稳态RRE浓度([RRE])的隔离灌流心脏。这些RRE是目前用于人类MRI研究的造影剂。将实施具有稳态[RRE]的1H2O T1 MRR测量的成像版本，并将其用作I-1、Vi和Ve的黄金标准测量，以确定已在使用的团注[RRE]动态对比度增强MRI(非稳态[RRE])测量获得的相同参数的准确性/精确度。最后，我们将测量和比较稳态和团注[RRE]在活体大鼠心脏中的I-1和Vi。 该项目将开始阐明影响I-1大小的因素，并评估其作为一种新的细胞代谢转运活性1H MRI生物标记物的潜在用途。这一生物标志物将受益于1H MRI的高信号和空间分辨率，从而允许高分辨率功能成像。现有的快门速度DCE-MRI研究报告了人体骨肉瘤/骨骼肌和恶性乳腺肿瘤的解剖学上准确的参数图。其他病理生理状态，如缺血、心力衰竭和急性肾功能衰竭也可能改变了i-1。例如，急性肾功能衰竭涉及肾脏转运活动的丧失(可能还包括水通量)。我们的方法可能会定义代谢损伤的严重程度，这可能与预后相关。