Biochemical imaging using hyperpolarized (HP) nuclei now offers the possibility of extending the inherent power of 13C NMR to rapidly image intermediary metabolism in human patients. The recent installation of a clinical polarizer in this BTRC provides the opportunity to test and validate this technology as it moves towards clinical research applications. The overall intent is to develop a good understanding of how to interpret 13C NMR spectra and images from the liver after injection of HP-[1-13C]pyruvate and other substrates. A general theme in this TR&D project is to perform conventional 2H and 13C isotopomer analysis and hyperpolarization exams in the same tissue. With this approach, standard tracer methods are used to efficiently validate and interpret the HP data.
Aim 1 will focus on the utility of HP [1-13C]pyruvate for monitoring TCA cycle flux and pathways related to gluconeogenesis in a rat model. Pharmacological and nutritional interventions will be used to selectively manipulate specific aspects of liver metabolism. The sensitivity of HP data to these interventions will be tested, and critically compared to results from simultaneous 2H and 13C NMR isotopomer analysis.
In Aim 2 we will investigate novel probes such as HP-[2-13C]dihydroxyacetone for imaging phosphoenol pyruvate (PEP). 13C labeled mono-esters of TCA cycle intermediates, developed in TR&D 1, will also be evaluated in vivo. With our collaborators, we have already determined that detection of HP-[1-13C]lactate, HP-[1- 13C]alanine and HP-[13C]bicarbonate from the liver is feasible in the pig. Consequently Aim 3 will test the effects of nutritional state on gluconeogenic pathways and TCA cycle flux, using conventional methods, and at the same time perform HP spectroscopy and imaging after injection of HP-[1-13C]pyruvate. Parallel experiments in the same animals with an identical protocol will be performed with [U-13C]pyruvate, not hyperpolarized, to measure the fraction of exogenous pyruvate entering the malate, lactate, alanine and acetyl- CoA pools. These methods will be extended to human subjects in Aim 4 where we will monitor metabolism of HP-[1-13C]pyruvate in the liver and evaluate the impact of simple alterations in nutritional state. The primary goal is to implement hyperpolarization exams in the human liver and to critically evaluate the metabolic information resulting from these exams.
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