Human Biology Core, Project 10 of 10

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One of the principal TORS goals is integration of new metabolic, genetic, and molecular cell biological data, collected using multiple technologies in mouse models and human subjects, into a mechanistic understanding of key aspects of obesity and type II diabetes. To advance this goal, we have formed a public-private research partnership between the four TORS teams and an NIH-supported software and kinetic modeling company, Integrative Bioinformatics Inc (IBI). IBI's software product, ProcessDB, is a tool for managing the development of large scale quantitative mechanistic models and testing these simultaneously against multiple experimental protocols using diverse measurement technologies. Dr. Phair, a former professor of biomedical engineering and physiology at the Johns Hopkins School of Medicine, and his colleagues at IBI have many years of experience with these techniques at levels of biological organization from whole human subjects to cultured cells. They have published in many relevant areas including lipid and lipoprotein metabolism, endocrinology/nutrition, and molecular cell biology. To reach the long term goal of an integrated mechanistic model of key aspects of the physiology and pathophysiology of obesity, the modeling effort will draw from and contribute to each of the TORS subprojects. Initially, however, we plan to focus on integration of information from two TORS teams: Parks and Malloy (Burgess, Browning). To our knowledge, this will be the first integration of metabolic information from well-established NMR and G.C/MS techniques in the same human subjects and patients. Leveraging the unique strengths of both stable isotope methods is unprecedented. In years 02-05 we plan to expand these inter-team projects to include: 1) Selection of informative human subjects (Cohen/Hobbs) from the Dallas Heart Study to be analyzed using the GC/MS (Parks) and NMR (Malloy) technologies, and fitted to our developing integrated model using constraints from known genetic defects in these individuals. 2) Development of a parallel metabolic model for relevant aspects of mouse physiology and pathophysiology. This parallel development will facilitate translation of basic research in the mouse model to testable hypotheses in human subjects and patients. 3) Completion of a model of skeletal muscle metabolism including mitochondrial function (Malloy), that can be combined with the hepatic model to produce an integrated model of two major organs/tissues involved in the metabolic response to feeding and insulin. By putting the ProcessDB software on each Pi's desktop, all TORS groups will have constant access to the developing integrated models and will be able to propose modifications and additions to be tested. They can also add to the ProcessDB database new experimental protocols and data. ProcessDB will thus serve as a focused mechanistic "knowledge environment" for the TORS program, along the same lines as the signal transduction knowledge environment (STKE) developed by AAAS/Science. (http://stke.sciencemag.org/).