Summary/Abstract: National Center for In Vivo Metabolism (EB015908) This application proposes to renew a Biomedical Technology Research Centers (BTRC) focused on the use of stable isotopes to probe metabolism in human patients. The BTRC is motivated by the strong current interest in disruptions of intermediary metabolism in high impact conditions such as nonalcoholic fatty liver disease, cancer, congestive heart failure, diabetes and others. Although we have considerable knowledge from animal and cell models about metabolic pathways, little of this information can be used for clinical research and direct patient care because the information yield from traditional metabolic studies such as PET is so poor. Stable isotopes with detection of metabolic products by NMR are attractive because of the inherently rich information content of these exams which is far superior to alternatives. The poor inherent sensitivity of NMR is the critical obstacle to clinical translation. One solution is analysis of tissue biopsies and blood samples in high resolution analytical systems, an approach pioneered in this BTRC. Another solution is imaging and spectroscopy of hyperpolarized nuclei. There are a number of major opportunities to help translation of this technology to the clinic, including better 15N and 13C probes, improved software for simulation and data analysis, improved integration of NMR and mass spectrometry data, implementation of hyperpolarization exams in human patients, and validation of hyperpolarization results. We propose coordinated development of technologies focused on in vivo exams. Three technology research and development projects are planned, all driven by specific needs of our collaborative users. In TR&D 1, we will develop new probes tailored for 15N and 13C hyperpolarization and provide the infrastructure to understand the biological value of these probes. In TR&D 2, we will develop integrated methods for combining data from mass spectrometry and NMR spectroscopy exams, with the purpose of probing metabolism in small, biopsy- sized tissue samples. TR&D 3 will focus on in vivo applications of 13C NMR and creation of an infrastructure for hyperpolarization studies in human patients. The capacity to investigate imaging and spectroscopy of hyperpolarized nuclei is limited to a small handful of centers in the nation. The ability to integrate conventional analytical NMR and mass spectrometry methods with hyperpolarization exams is even less accessible. This program will leverage extraordinary institutional support for space, equipment and personnel in a combined basic research and clinical environment. This diverse user group, including the physicians, share one commonality in having a long track record of metabolic studies using conventional NMR and mass spectrometry for examining metabolism. The Center will retain its exclusive focus on metabolism and continue efforts in training young scientists.