Most of the experiments during the first cycle of this MERIT Award were performed on isolated, perfused organs. The rationale for using perfused tissues initially was that each could be studied in isolation in a NMR tube so that if 13C signals appeared from unanticipated products of a HP-substrate, we could be confident that such metabolites were generated in that tissue and did not appear as a result of in vivo circulation between organs. Building on those experiments, we are now ready to translate our most interesting probes to image metabolism in real time in vivo as quickly as possible. We will focus on four aims: 1) measure glucose production by hyperpolarized 13C imaging in isolated perfused mouse livers and animals in vivo. This technology has important implications in better understanding the tissue sources of glucose production in diabetic animals and humans;2) measure flux through the oxidative portion of the pentose phosphate pathways (PPPox) in vivo using HP-[1-13C]gluconolactone in injured tissues. Increased PPPox flux has been observed in times of cellular stress such as patients suffering from traumatic brain injury, ischemic heart disease, and cancer. Thus, given our discovery that HP-gluconolactone appears to be a selective probe of PPPox and there is currently no other simple way to measure PPPox in vivo, we believe this could lead to an important diagnostic tool for detecting damaged tissues by metabolic imaging;3) We now know that kinetic conversion of HP-acetoacetate to HP-betaHB appears to be slow in healthy perfused tissues, an unexpected finding. Given that chemical exchange between these two species should be fast on the time scale of a hyperpolarization experiment like that seen for conversion of HP-pyruvate to HP-lactate, we feel it is important to fully understand the limitations of this reaction in healthy tissues versus tissues bearing damaged mitochondrial. If conversion occurs more rapidly in damaged mitochondria, this may provide a quick, useful, imaging assay for assessing tissue viability in vivo. 4) Finally, we will develop a polarization method to simultaneously measure extracellular pH and tissue necrosis using a mixture of HP-[1,4- 13C]maleic acid and HP-[1,4-13C]fumarate in cirrhotic livers in vivo. It has been shown that HP-fumarate is converted to HP-malate only in necrotic tissues because the dicarboxylate, fumarate, cannot be transported into most healthy cells in vivo. Given our discovery that HP-[1,4-13C]maleic acid should provide a direct readout of tissue pH from its chemical shift, we will explore the combined use of HP-[1,4-13C]maleic and fumaric acids as imaging probes of cell necrosis and extracellular pH in various models of damaged tissues

Public Health Relevance

Hyperpolarized 13C probes combined with MRI offers the possibility of imaging metabolism as it occurs in vivo. This MERIT Award will continue its focus on developing a solid understanding of which metabolic pathways or reactions can be monitored quantitatively by imaging hyperpolarized materials and applying those that are quantitative to real-time metabolic imaging in vivo. At the end of this project, we will have developed at least three new metabolic probes for translation to imaging human disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37HL034557-25
Application #
8437731
Study Section
Special Emphasis Panel (NSS)
Program Officer
Schwartz, Lisa
Project Start
1988-07-01
Project End
2018-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
25
Fiscal Year
2013
Total Cost
$397,500
Indirect Cost
$147,500
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Marco-Rius, Irene; Cao, Peng; von Morze, Cornelius et al. (2016) Multiband spectral-spatial RF excitation for hyperpolarized [2-(13) C]dihydroxyacetone (13) C-MR metabolism studies. Magn Reson Med :
Ren, Jimin; Sherry, A Dean; Malloy, Craig R (2016) Band inversion amplifies (31) P-(31) P nuclear overhauser effects: Relaxation mechanism and dynamic behavior of ATP in the human brain by (31) P MRS at 7 T. Magn Reson Med :
Bastiaansen, Jessica A M; Merritt, Matthew E; Comment, Arnaud (2016) Measuring changes in substrate utilization in the myocardium in response to fasting using hyperpolarized [1-(13)C]butyrate and [1-(13)C]pyruvate. Sci Rep 6:25573
Jin, Eunsook S; Moreno, Karlos X; Wang, Jian-Xiong et al. (2016) Metabolism of hyperpolarized [1-(13)C]pyruvate through alternate pathways in rat liver. NMR Biomed 29:466-74
Jin, Eunsook S; Sherry, A Dean; Malloy, Craig R (2016) An Oral Load of [13C3]Glycerol and Blood NMR Analysis Detect Fatty Acid Esterification, Pentose Phosphate Pathway, and Glycerol Metabolism through the Tricarboxylic Acid Cycle in Human Liver. J Biol Chem 291:19031-41
Ren, Jimin; Sherry, A Dean; Malloy, Craig R (2016) Efficient (31) P band inversion transfer approach for measuring creatine kinase activity, ATP synthesis, and molecular dynamics in the human brain at 7 T. Magn Reson Med :
Wang, Jian-Xiong; Merritt, Matthew E; Sherry, Dean et al. (2016) A general chemical shift decomposition method for hyperpolarized (13) C metabolite magnetic resonance imaging. Magn Reson Chem 54:665-73
Marin-Valencia, Isaac; Hooshyar, M Ali; Pichumani, Kumar et al. (2015) The ratio of acetate-to-glucose oxidation in astrocytes from a single 13C NMR spectrum of cerebral cortex. J Neurochem 132:99-109
Khemtong, Chalermchai; Carpenter, Nicholas R; Lumata, Lloyd L et al. (2015) Hyperpolarized 13C NMR detects rapid drug-induced changes in cardiac metabolism. Magn Reson Med 74:312-9
Burgess, Shawn C; Merritt, Mathew E; Jones, John G et al. (2015) Limitations of detection of anaplerosis and pyruvate cycling from metabolism of [1-(13)C] acetate. Nat Med 21:108-9

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