This project is concerned with elucidating energy metabolism, especially the formation, transfer, and use of high-energy phosphate (creatine and adeninenucleotides) in heart and skeletal muscle. We will further develop existing computer models of this metabolism, and methods for their analysis and construction. Microcomputers and collaboration between modelers and experimenters who re using the models on their own laboratory microcomputers will be emphasized, with the objective of making the models and techniques generally available to interested experimenters. We will use data from both nuclear magnetic resonance (NMR) and conventional chemical analyses, combining apparently divergent information (including viewpoints and definitions) from both sources, and deal with current inadequacies of methods of interpreting NMR experiments. Initially we will emphasize creatine kinase and the creatine kinase shuttle with phosphorus-31 NMR, by modeling and designing experiments. We will also improve methods of calculating exchange by enzymes and apply them to saturation-transfer measurements. We will examine control of the glycolytic pathway, with which we are experienced, emphasizing regulation by adenine nucleotides and magnesium ion. We will construct or adapt simple models of oxidative phosphorylation, the principal energy source of normal heart. We will complete, update, extend to other experimental conditions (e.g., blood-perfused heart, observable with in situ NMR), and validate as far as possible a nearly completed unified model of cardiac energy metabolism, now representing 13 experimental preparations or conditions and about 1500 data points from rat and dog hearts. We will also determine its control properties by sensitivity analysis, and then devise means of simplifying it or subsetting it for particular conditions or purposes. A parallel muscle model, with nearly the same enzyme subunits in different amounts, will be used to investigate the same metabolism in muscle. We will extend or construct data bases containing data needed for this work. We will update, document, distribute, and maintain the required computer programs and (as far as is now possible) the models used.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL015622-12
Application #
3334994
Study Section
(SSS)
Project Start
1978-01-01
Project End
1990-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
12
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Achs, M J; Garfinkel, L; Garfinkel, D (1991) A computer model of pancreatic islet glycolysis. J Theor Biol 150:109-35
Garfinkel, L; Cohen, D M; Soo, V W et al. (1989) An artificial-intelligence technique for qualitatively deriving enzyme kinetic mechanisms from initial-velocity measurements and its application to hexokinase. Biochem J 264:175-84
Garfinkel, D (1989) Constraint matching as a means of designing biochemical experiments in multi-enzyme systems. J Theor Biol 137:221-34
Garfinkel, D; Garfinkel, L (1988) Magnesium and regulation of carbohydrate metabolism at the molecular level. Magnesium 7:249-61
Garfinkel, L; Altschuld, R A; Garfinkel, D (1986) Magnesium in cardiac energy metabolism. J Mol Cell Cardiol 18:1003-13
Garfinkel, L; Garfinkel, D (1985) Magnesium regulation of the glycolytic pathway and the enzymes involved. Magnesium 4:60-72
Dennis, S C; Kohn, M C; Slegowski, M B et al. (1985) Monocarboxylate-uptake kinetics in perfused rat heart. Adv Myocardiol 6:259-72
Garfinkel, D (1985) Computer-based modeling of biological systems which are inherently complex: problems, strategies, and methods. Biomed Biochim Acta 44:823-9
Dennis, S C; Kohn, M C; Anderson, G J et al. (1985) Kinetic analysis of monocarboxylate uptake into perfused rat hearts. J Mol Cell Cardiol 17:987-95