This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This TR&D project represents a substantially new direction for stable isotope work in the Resource. New methods and applications for 13C and 2H tracers have been developed in the Resource and applied widely. Until now the prospect of in vivo studies was limited, for the most part, to examination of blood or urine from humans, and tissue biopsies from experimental animals. Over the last 4 years UT Southwestern and this Resource have invested heavily in two technologies, the 7T and dynamic nuclear polarization, that enables translation to in vivo spectroscopy and imaging. The goal of this project is to further develop these enabling technologies to support current clinical research and to lay the foundation for human studies in the near future.
Aim 1 is designed to investigate the utility of multiplet 13C NMR spectroscopy for analysis of citric acid cycle and glutamatergic fluxes in the brain. Integrated mathematical tools for analysis of large networks of metabolic processes occurring in more than one compartment will be developed. The focus will be the mammalian brain. The high information content of 13C NMR spectra provided by spin-coupled multiplets has not previously been used for analysis of kinetics in multiple compartments. A set of differential equations describing all 13C isotopomers of all relevant intermediates in glia and neurons has been developed. Consequently, any combination of 13C fractional enrichment or 13C multiplets, measured as a function of time, can be fit to derive fluxes. The advantage of this approach is fewer prior assumptions about the metabolic system and improved precision in the estimate of metabolic variables. Two models are under development that are suitable for analysis of brain spectra, one to analyze spectra collected over time (kinetic analysis), and a second for the analysis of a single spectrum at metabolic steady state. The software will be made available to the scientific community.
Aim 2 will further develop MR spectroscopy at 7T for studies of brain and skeletal muscle metabolism. This project is designed to develop and refine spectroscopy at 7T for analysis of metabolism and detection of biomarkers in human skeletal muscle and brain. The major technical goal is installation of 2-channel parallel transmit capabilities for improved 1H spectroscopy and chemical shift imaging of the brain. 1H MR spectra from patients with brain malignancies will be correlated with 13C data obtained by biopsy. Broad band 1 H decoupling for 13C NMR spectroscopy of skeletal muscle will be refined, and a package of spectroscopy studies including 31p, 13C and 1H spectroscopy will be provided to clinical investigators in skeletal muscle metabolism.
Aim 3 examines the interaction of ischemia and substrates in the 13C NMR spectrum of the heart. After exposure of the myocardium to [1-13C]pyruvate, the ratio 13C bicarbonate/[1-13C]lactate is sensitive to ischemia and to changes in the concentration competing physiological substrates such as long chain fatty acids and ketones. We will test whether 13C-enriched water soluble short chain fatty acids can be used to probe flux in the citric acid cycle of the heart independent of competing substrates. Isolated rat hearts will be supplied with physiological mixtures of long chain fatty acids and other substrates. Competition of a short chain fatty acid with physiological substrates for entry into the acetyl-CoA pool will be examined by 13C NMR isotopomer analysiS over a range of conditions. The optimal fatty acid will be tested in isolated mouse hearts and rat hearts as a suitable probe for the citric acid cycle after hyperpolarization of 13C in carbon 1, and detection of glutamate enriched in C5. Finally, the optimal molecule will be tested for 13C imaging in vivo against competing substrates.
Aim 4 will investigate the feasibility of imaging anaplerosis with hyperpolarized 13C. Reaction pathways feeding carbon into the citric acid cycle for biosynthetic purposes are termed """"""""anaplerotic sequences"""""""". These reactions playa central role in key synthetic processes yet there is no general method for specifically imaging these pathways. Hyperpolarized [U-13C]acetic acid and hyperpolarized [U-13C]pyruvic acid will be used to label carbons 4 and 5 of glutamate in the isolated heart. Since the effects of anaplerosis on the 13C spectrum of glutamate are due to changes in 13C enrichment in carbons 3, 2 and 1 of glutamate, flip-flop spectroscopy (FLOPSY-8) will probe 13C multiplets in protonated carbons of glutamate and measure in a few seconds the activity of anaplerotic reactions. The method will be validated with conventional isotopomer methods.
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