This NIH S10 High-End Instrumentation grant application request funds to purchase a GE SPINlabTM dissolution DNP (dynamic nuclear polarization) instrument for the purpose of creating hyperpolarized (HP) 13C- and 15N- labeled metabolic substrates, thereby enabling high sensitivity magnetic resonance (MR) interrogation of metabolic pathways in vivo in small-animal models and bioreactors (cultured cell systems). The GE SPINlab is currently the only commercially available hyperpolarization device. In the ?open path? configuration, as specified herein, it is well-suited for preclinical research. The Washington University School of Medicine (Saint Louis) has a rich history of metabolic research in basic science and in medicine. As evidenced by descriptions herein of the currently funded metabolic research programs of the Major User Group, there is a pressing need for SPINlab-enabled HP MR spectroscopy-driven metabolic pathway analysis capabilities. Importantly, the SPINlab will be sited in a centralized preclinical PET/CT/MRI resource, in close proximity to a new, preclinical, simultaneous PET/MR scanner (to be acquired, recently funded, NGA issued). Upwards of four million dollars in institutional support have been committed to ensure the success of this new HP MR metabolic research program. The addition of SPINlab-enabled HP MR to our capabilities to synthesize and image the full armamentarium of PET radiotracers (metabolic, and non-metabolic), and to simultaneously measure both imaging readouts with PET/MR, has the potential to open entirely new avenues of scientific discovery not otherwise possible. For example, it will now be possible to cross-calibrate and cross-validate both imaging technologies. From a HP MR perspective, metabolic measurements using various 13C tracers can be compared with their PET 11C- radiotracer counterparts to determine the impact of non-tracer doses of substrate on cellular metabolism. Conversely, measurements of various components of metabolism by PET with compartmental modeling (e.g., oxidation and storage) can be referenced to the true metabolic fate of the exogenous substrate measured with HP MR. Most exciting is the potential use of the quantitative capabilities of PET to facilitate the HP MR quantification of substrate flux through metabolic pathways of interest. Such information will enable/enhance the accurate interpretation of HP MR derived measurements of disease effects and dose response. SPINlab-enabled HP MR is a promising and powerful technology for metabolic assessment and pathway analysis. Washington University presents a near ideal environment in which to initiate such a research program.
Magnetic resonance spectroscopy is a powerful tool for the study of metabolism in health and disease in living biological systems; however, it is challenged by poor signal detection sensitivity (low signal-to-noise). The GE SPINlabTM dynamic nuclear polarization unit requested in this grant application provides upwards of a hundred- thousand fold increase in signal strength, enabling a host of metabolic studies in living systems that would otherwise be impossible. The SPINlab unit will be deployed in concert with a preclinical, simultaneous positron emission tomography / magnetic resonance imaging scanner, thus further leveraging its powerful capabilities.