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/).

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Linked Center Core Grant (PL1)
Project #
5PL1DK081183-05
Application #
8106124
Study Section
Special Emphasis Panel (ZRR1-SRC (99))
Program Officer
Laughlin, Maren R
Project Start
2007-09-30
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$351,158
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Type
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Browning, Jeffrey D; Burgess, Shawn C (2012) Use of (2)H(2)O for estimating rates of gluconeogenesis: determination and correction of error due to transaldolase exchange. Am J Physiol Endocrinol Metab 303:E1304-12
Browning, Jeffrey D; Baxter, Jeannie; Satapati, Santhosh et al. (2012) The effect of short-term fasting on liver and skeletal muscle lipid, glucose, and energy metabolism in healthy women and men. J Lipid Res 53:577-86
Ramos-Roman, Maria A; Sweetman, Lawrence; Valdez, Maressa J et al. (2012) Postprandial changes in plasma acylcarnitine concentrations as markers of fatty acid flux in overweight and obesity. Metabolism 61:202-12
Livingston, Edward H (2012) Pitfalls in using BMI as a selection criterion for bariatric surgery. Curr Opin Endocrinol Diabetes Obes 19:347-51
Browning, Jeffrey D; Baker, Jonathan A; Rogers, Thomas et al. (2011) Short-term weight loss and hepatic triglyceride reduction: evidence of a metabolic advantage with dietary carbohydrate restriction. Am J Clin Nutr 93:1048-52
Sunny, Nishanth E; Parks, Elizabeth J; Browning, Jeffrey D et al. (2011) Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease. Cell Metab 14:804-10
Browning, Jeffrey D; Horton, Jay D (2010) Fasting reduces plasma proprotein convertase, subtilisin/kexin type 9 and cholesterol biosynthesis in humans. J Lipid Res 51:3359-63
Livingston, Edward H; Cao, Jing (2010) Procedure volume as a predictor of surgical outcomes. JAMA 304:95-7

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