My research program has two major thrusts. First, I have had a long-standing interest the impact of basic intermediary metabolism on human disease and in developing NMR and other physical methods to provide insights into cellular compartmentation, measurement of metabolic fluxes & flux control, and the influence of basic physiological parameters such as pH and cellular redox on metabolism in cells, tissues and whole organisms. Working with Craig Malloy, novel methods using the stable isotopes 13C and 2H as tracers and high resolution NMR techniques have been developed that allow measurement of multiple fluxes in vivo in animals and human subjects. 13C isotopomer NMR methods were initially developed in isolated, perfused hearts (JBC, 263, 6964-71, 1988; AJP, 259, H987-95, 1990) and used to measure substrate selection, anaplerosis, and TCA cycle flux (Biochemistry, 31, 4833-37, 1992; AJP, 274, H591-99, 1998), and to examine the influence of altered Ca2+ and redox state on metabolic fluxes in vivo (AJP, 287, H889-95, 2004). Methods were later developed to measure metabolic fluxes in live anesthetized animals and in human subjects (AJP, 275, E843-52, 1998; AJP, 281, E848-56, 2001). With the addition of two human MR systems to the Advanced Imaging Research Center in 2006, our goal over the next few years is to translate these methods to clinical studies of the influence of excess fatty acids on glucose and triglyceride storage and metabolism in skeletal muscle and liver in humans. 13C isotopomer methods have also been used to reveal that pyruvate cycling is an active metabolic process in the ?O-cell and that flux through this pathway correlates with glucose stimulated insulin secretion (PNAS, 99, 2708-13, 2002). Such studies may lead to new drugs to reverse the negative impact of accumulation of long chain fatty acids in ?O-cells on their ability of secrete insulin (JBC, 279, 27263-71, 2004). My second long-standing research interest is the development of new molecular imaging agents that respond to physiology or metabolism and report that information by MRI. We have been involved with development of gadolinium complexes as non-specific extracellular MRI contrast agents since the early 1980!|s and are now heavily involved with the next generation smart agents that respond to physiological parameters such as pH (Angew. Chem. Int. Ed., 38, 3192-94, 1999) or for imaging the tissue distribution of the important metabolite, glucose (JACS, 125, 15288-89, 2003). A new class of MR contrast agents was also recently discovered by our group that can be activated by specific radio-frequency pulses, called PARACEST agents (JACS, 123, 1517-18, 2001; Accts. Chem. Res., 36, 783-90, 2003). This discovery has generated considerable enthusiasm in the MRI community because this new class of agents offers the potential to image a much broader spectrum of physiological/biochemical parameters including cell redox, enzyme activity, and tissue hypoxia.
RESEARCH INTERESTS
MRS studies of intermediary metabolism in intact tissues
Macrocylic ligand systems for monitoring intracellular cations by NMR
Gadolinium-based MRI contrast agents.
PARACEST imaging agents
Molecular imaging
RECENT PUBLICATIONS
E. Vinogradov, H He, A Lubag, JA Balschi, AD Sherry & RE Lenkinski, "MRI detection of Paramagnetic Chemical Exchange Effects in mice kidneys in vivo" Magn. Reson. Med., 58:650-655, 2007
JW Joseph, ML Odegaard, SM Ronnebaum, SC Burgess, J Muehlbauer, AD Sherry & CB Newgard, "Normal Flux through ATP-Citrate Lyase or Fatty Acid Synthase Is Not Required for Glucose-stimulated Insulin Secretion" J. Biol. Chem., 282:31592-31600, 2007
A Pasha, G Tircso, ET Benyo, E Brucher & AD Sherry, "Synthesis and characterization of DOTA-(amide)4 derivatives: equilibrium and kinetic behavior of their lanthanide(III) complexes" Eur. J. Inorg. Chem., 4340-4349, 2007
M Merritt, C Harrison, C Storey, FMH Jeffrey, AD Sherry & CR Malloy, "Hyperpolarized 13C Allows a Direct Measure of Flux through a Single Enzyme-Catalyzed Step by NMR" Proc. Natl. Acad. Sci., USA, 104:19773-19777, 2007
ME Merritt, C Harrison, Z Kovacs, P Kshirsagar, CR Malloy & AD Sherry, "Hyperpolarized 89Y offers the potential of direct imaging of metal ions in biological systems by magnetic resonance" J. Amer. Chem. Soc., 129:12942-12943, 2007
SIGNIFICANT PUBLICATIONS
PCM van Zijl, CK Jones, J Ren, CR Malloy & AD Sherry, "MRI Detection of Glycogen In Vivo Using Chemical Exchange Saturation Transfer Imaging (glycoCEST)" Proc. Natl. Acad Sci, USA, 104:4359-4364, 2007
SC Burgess, T He, Z Yan, J Lindner, AD Sherry, CR Malloy, JD Browning & MA Magnuson, "Cytosolic phosphoenolpyruvate carboxykinase does not solely control the rate of hepatic gluconeogenesis in the intact mouse liver" Cell Metabolism, 5:313-320, 2007
FK Kalman, M Woods, P Jurek, M Spiller, P Caravan, G Tircso, R Kiraly, E Brucher & AD Sherry, "Potentiometric and Relaxometric Properties of Gadolinium-based MRI Contrast Agent for Sensing Tissue pH" Inorg Chem, 46:5260-5270, 2007
NM Rofsky, AD Sherry and RE Lenkinski, "Nephrogenic Systemic Fibrosis: A Chemical and Rational Perspective" Radiology, 247:608-612, 2008
SM Ronnebaum, JW Joseph, O Ilkayeva, SC Burgess, D Lu, TC Becker, AD Sherry & CB Newgard, "Chronic Suppression of Acetyl CoA Carboxylase 1 in beta-Cells Impairs Insulin Secretion via Inhibition of Glucose Rather Than Lipid Metabolism" J. Biol. Chem., 283:14248-14256, 2008
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