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. The ability to measure 13C enrichments and isotopomer patterns in certain target molecules such as glutamate can be paired with mathematical modeling to estimate flux in intact systems. MR provides a unique tool for making these measurements since it can easily measure the presence of a variety of isotopomers by observing the j-coupled multiplets present in 13C spectra. Progress has been made with both in vivo and ex vivo spectroscopy methods, as well as in vitro analysis of extracts from organs or blood. With this in mind, it seems appropriate that the Resource turn its attention to the new field of hyperpolarization for MR sensitivity enhancement. Hyperpolarization of 13C is one of the most promising new modalities for metabolic imaging. The combination of 13C isotopomer analysis with this new physical technique is both logical and pertinent, and serves the goals of multiple driving projects. We believe that the increased sensitivity available through hyperpolarization will allow the in vivo use of isotopically labeled compounds for assessing metabolism in clinically reasonable time periods. Extending this technology to the clinic depends upon development of new experimental MR methods as well as adaptation of the metabolic models already produced by the Resource to the unique constraints imposed by the HP technology itself. The goal of in vivo measurement of flux using hyperpolarized stable isotopes demands the advancement of 5 aims:
Aim 1 is to develop a new set of tracer molecules for assessing glucose metabolism. Within this Aim, the pentose phosphate pathway will be probed with a gluconolactone glucose analogue and the utility of other glucose agents, synthesized in TR&D 1, will be assessed.
Aim 2 is to develop new methods for measuring absolute flux using hyperpolarization. We will take advantage of our expertise with 13C NMR isotopomer analysis and prelabel tissues that will allow us to simultaneously measure relative fluxes from tissue extracts and index this information to results from hyperpolarization experiments. By judicious selection of the labeling pattern of available substrates, molecules that produce [1-13C] and [1,2-13C]acetyl-CoA can be generated. Mathematical models for analysis of observed kinetics will be developed and validated against standard physiological measurements such as oxygen consumption. Finally, we will integrate pre-labeling and kinetic analysis from hyperpolarization studies to obtain complete pictures of metabolic networks from 13C data exclusively.
Aim 3 presents a major challenge: detect hyperpolarized 13C signals through protons. INEPT parameters will be optimized to detect [1-13C] lactate and alanine in isolated tissues and the detection threshold will be determined in the perfused rat heart and mouse liver.
Aim 4 is to adapt current chemical shift imaging (CSI) technologies to the detection of hyperpolarized nuclei at 4.7 T. In this Aim, CSI protocols will be implemented and schemes that explore polarization transfer imaging will be evaluated.
Aim 5 is to transfer hyperpolarized BC technology to a 3 T scanner. This will require a number of steps and milestones including: 1) Implement acquisition-weighted double spin-echo EPSI for rapid 13C CSI, 2) Implement FLOPSY-EPSI for transferring polarization from glutamate C5 to C4 and C3. 3) Develop low-SAR adiabatic decoupling with WURST RF pulses 4) Develop SENSE-EPSI, keyhole-EPSI, and compressed EPSI. This TR&D project interacts extensively with the other TR&D projects as well as with multiple Driving Biomedical Projects. The intent is to develop in the Research Resource a suite of technologies for assessing in vivo metabolism in periods that are clinically relevant.
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