The importance of understanding abnormal metabolism in common diseases such as cancer, diabetes and heart disease has long been appreciated. Because of constraints in technology, however, much of this research has been conducted in isolated systems where clinical relevance may be uncertain. The multidisciplinary group within this Resource has pioneered new concepts involving the stable isotope C and magnetic resonance methods for probing metabolic pathways, but translation of this technology to human subjects is limited by poor sensitivity. Technical progress within this Resource in dynamic nuclear polarization and high field magnetic resonance over the last three years now provides the foundation for major advances towards new ways of studying metabolism in patients. With this goal in mind, three closely interrelated Technology Research and Development projects are proposed in this renewal application. Project 1 will focus on the rational design, synthesis and characterization of ^^C-labeled molecules with long Tis that probe key aspects of tissue biochemistry such as glucose transport, citric acid cycle flux, redox and pH. Development of PARACEST agents for detecting metabolites will continue. Factors that limited detection of paramagnetic CEST agents in vivo will be circumvented using imaging methods optimized for short T2 tissues. Project 2 will implement hyperpolarization methods in vivo for the study of metabolism in rodent models at 4.7 T. This ambitious effort will include new approaches to combining conventional ^^C NMR isotopomer analysis with hyperpolarization technology, and advanced pulse sequences will be developed to image, for the first time, hyperpolarized protonated carbons. Project 3 will continue development of 7T spectroscopy in skeletal muscle and brain, methods for interpreting ^^C NMR spectra from the brain using multiplet information, and implementation of hyperpolarized ^^C in vivo. Comprehensive models with minimal prior assumptions will be developed to analyze citric acid cycle kinetics in glia and neurons based on enrichment and multiplet date in ^^C spectra acquired from the brain in vivo. The Center will retain its exclusive focus on metabolism, and it will continue to emphasize training of young scientists and clinicians, and dissemination ofthe technology.
Metabolism is abnormal in patients with cancer, diabetes, heart disease and many other high-impact diseases. Standard methods to measure metabolism in vivo, typically requiring radioactive tracers, do not provide sufficient information to fully understand these abnormalities. New methods, not requiring radioactivity, can be developed that provide images of metabolic pathways in patients.
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