The prevalence of insulin resistance and related metabolic disorders continues to rise. Although many of the fluxes in critical pathways involving glucose and fat metabolism have been described in isolated systems, there is considerable uncertainty regarding the relevance of these measurements to human subjects with disease, where cellular organization, substrate availability and many other factors are not duplicated by simple systems. A further difficulty is that in practical clinical situations, direct measurements of key physiological variables are largely inaccessible. Our multidisciplinary group, over the past 12 years of NCRR support, has pioneered and demonstrated new tools involving stable isotopes and new concepts in MR contrast agents. A limitation of the tracer-based work is sensitivity. However, three recent exciting developments will begin to overcome this issue: in vivo high-field MR spectroscopy, NMR spectroscopy of mass-limited samples with microcapillary probes, and ultra-high sensitivity 13C NMR spectroscopy by hyperpolarization. In parallel, new concepts in metabolically responsive contrast agents were pioneered in Dallas. Somewhat unexpectedly, this work with lanthanide-based contrast agents has converged beautifully with our tracer-based studies of metabolism. The theoretical foundations of these methods are well-understood within our group, and we are uniquely positioned to capitalize on these advances. We are also fortunate that UT Southwestern recently invested in extensive new laboratory facilities, and will provide a 3T and 7T MR systems for research with human subjects. We propose three technology development projects which focus exclusively on metabolism. Core 1 will continue development of 2H and 13C NMR methods to measure fluxes in intact animals and patients by simultaneous administration of multiple enriched compounds in a single study. Core 2 describes the chemistry of new classes of lanthanide - based contrast agents which will sensitize the bulk water signal to allow MR imaging of pH, [glucose], and other key physiological data. Core 3 focuses on the integration of the new contrast agent mechanisms with stable isotope studies, and the extension of these methods to in vivo and human applications. The Center also will continue to emphasize training of young scientists and clinicians, and dissemination of the technology.
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