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 understandingof key aspects of obesity and type II diabetes. To advance this goal, we have formed a public-private researchpartnership 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 developmentof large scale quantitative mechanistic models and testing these simultaneously against multiple experimentalprotocols using diverse measurement technologies. Dr. Phair, a former professor of biomedical engineering andphysiology at the Johns Hopkins School of Medicine, and his colleagues at IBI have many years of experiencewith these techniques at levels of biological organization from whole human subjects to cultured cells. Theyhave published in many relevant areas including lipid and lipoprotein metabolism, endocrinology/nutrition, andmolecular cell biology. To reach the long term goal of an integrated mechanistic model of key aspects of thephysiology and pathophysiology of obesity, the modeling effort will draw from and contribute to each of theTORS 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 metabolicinformation 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 toexpand these inter-team projects to include: 1) Selection of informative human subjects (Cohen/Hobbs) from theDallas Heart Study to be analyzed using the GC/MS (Parks) and NMR (Malloy) technologies, and fitted to ourdeveloping integrated model using constraints from known genetic defects in these individuals. 2) Developmentof a parallel metabolic model for relevant aspects of mouse physiology and pathophysiology. This paralleldevelopment will facilitate translation of basic research in the mouse model to testable hypotheses in humansubjects 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 majororgans/tissues involved in the metabolic response to feeding and insulin. By putting the ProcessDB software oneach Pi's desktop, all TORS groups will have constant access to the developing integrated models and will beable to propose modifications and additions to be tested. They can also add to the ProcessDB database newexperimental 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/).
Showing the most recent 10 out of 14 publications
