Despite extensive knowledge of metabolic pathways, understanding the basic metabolic mechanisms of prominent diseases is limited by the ability to grasp the regulation of complex metabolic systems. Genetic gain/loss of function approaches have provided a wealth of information about how metabolism can be regulated, but have not been very successful at identifying the cause of complex disease. Ideally, top-down approaches would be used to examine the function of metabolism using quantitative approaches, then to guide gain/loss of function studies. The scientific community is moving quickly to stable isotopes because of high information yield, convenience, and the capacity to translate methods between human subjects, rodent models and cell preparations. To accomplish this goal, it is essential to extend earlier concepts using computational methods, and to integrate mass spectrometry (MS) with nuclear magnetic resonance (NMR). However, in order for the approaches to be embraced by the molecular physiologist/geneticist or clinical scientist interested in disease physiology, they must be flexible, reliable and easy-to-use methods relevant in a wide range of conditions. In this TR&D project we will perform cell, rodent and computational studies to develop translation methods to address these needs. First, we will integrate tracer flux approaches and metabolomics to identify target enzymes in the regulation of metabolism or its dysregulation during disease. Secondly, we will leverage the specificity of NMR isotopomer analysis and the sensitivity of mass isotopomer analysis to measure flux with high confidence on milligram scale samples. Finally, we will develop and distribute a free, open source software platform that simulates NMR and MS data based on flux/tracer input and calculates flux from experimental data in a single, easy to use graphical interface complete. Accomplishing these aims will provide the scientific community with new tools that will guide tactical studies in pharmacology, genetics and clinical science.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Biotechnology Resource Grants (P41)
Project #
5P41EB015908-30
Application #
9403261
Study Section
Special Emphasis Panel (ZEB1)
Project Start
Project End
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
30
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Type
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Jin, Eunsook S; Browning, Jeffrey D; Murphy, Rebecca E et al. (2018) Fatty liver disrupts glycerol metabolism in gluconeogenic and lipogenic pathways in humans. J Lipid Res 59:1685-1694
Makarewich, Catherine A; Baskin, Kedryn K; Munir, Amir Z et al. (2018) MOXI Is a Mitochondrial Micropeptide That Enhances Fatty Acid ?-Oxidation. Cell Rep 23:3701-3709
Lux, Jacques; Sherry, A Dean (2018) Advances in gadolinium-based MRI contrast agent designs for monitoring biological processes in vivo. Curr Opin Chem Biol 45:121-130
Kaushik, Akash K; DeBerardinis, Ralph J (2018) Applications of metabolomics to study cancer metabolism. Biochim Biophys Acta Rev Cancer 1870:2-14
Chiu, Tsuicheng D; Arai, Tatsuya J; Campbell Iii, James et al. (2018) MR-CBCT image-guided system for radiotherapy of orthotopic rat prostate tumors. PLoS One 13:e0198065
Xie, Fang; Cai, Huawei; Peng, Fangyu (2018) Anti-prostate cancer activity of 8-hydroxyquinoline-2-carboxaldehyde-thiosemicarbazide copper complexes in vivo by bioluminescence imaging. J Biol Inorg Chem :
Imakura, Yuki; Nonaka, Hiroshi; Takakusagi, Yoichi et al. (2018) Rational Design of [13 C,D14 ]Tert-butylbenzene as a Scaffold Structure for Designing Long-lived Hyperpolarized 13 C Probes. Chem Asian J 13:280-283
Kikuchi, Kazufumi; Ishimatsu, Keisuke; Zhang, Shanrong et al. (2018) Presaturation Power Adjusted Pulsed CEST: A Method to Increase Independence of Target CEST Signals. Contrast Media Mol Imaging 2018:3141789
Garda, Zoltán; Molnár, Enik?; Kálmán, Ferenc K et al. (2018) Effect of the Nature of Donor Atoms on the Thermodynamic, Kinetic and Relaxation Properties of Mn(II) Complexes Formed With Some Trisubstituted 12-Membered Macrocyclic Ligands. Front Chem 6:232
Zhou, Heling; Arias-Ramos, Nuria; López-Larrubia, Pilar et al. (2018) Oxygenation Imaging by Nuclear Magnetic Resonance Methods. Methods Mol Biol 1718:297-313

Showing the most recent 10 out of 149 publications