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.
New magnetic resonance methods are being developed to non-invasively determine the state of cellular metabolism of the heart and other tissues. These methods may allow the measurement of viable heart tissue of patients suffering from coronary artery disease and heart failure. This information may be prognostic and guide therapy aimed at saving the heart muscle.
| Luptak, Ivan; Sverdlov, Aaron L; Panagia, Marcello et al. (2018) Decreased ATP production and myocardial contractile reserve in metabolic heart disease. J Mol Cell Cardiol 116:106-114 |
| Rowland, Benjamin; Merugumala, Sai K; Liao, Huijun et al. (2016) Spectral improvement by fourier thresholding of in vivo dynamic spectroscopy data. Magn Reson Med 76:978-85 |
