Integrating Cellular Metabolism into a Multiscale Whole-Body Model
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Cellular metabolism continuously processes an enormous range of external compounds into endogenous metabolites and is as such a key element in human physiology. The multifaceted physiological role of the metabolic network fulfilling the catalytic conversions can only be fully understood from a whole-body perspective where the causal interplay of the metabolic states of individual cells, the surrounding tissue and the whole organism are simultaneously considered. We here present an approach relying on dynamic flux balance analysis that allows the integration of metabolic networks at the cellular scale into standardized physiologically-based pharmacokinetic models at the whole-body level. To evaluate our approach we integrated a genome-scale network reconstruction of a human hepatocyte into the liver tissue of a physiologically-based pharmacokinetic model of a human adult. The resulting multiscale model was used to investigate hyperuricemia therapy, ammonia detoxification and paracetamol-induced toxication at a systems level. The specific models simultaneously integrate multiple layers of biological organization and offer mechanistic insights into pathology and medication. The approach presented may in future support a mechanistic understanding in diagnostics and drug development.
Projects: E4: Vertical integration across biological scales, E: Model integration
PLoS Comput Biol
PLoS Comput Biol 8(10) : e1002750
25th Oct 2012
Markus Krauss, Stephan Schaller, Steffen Borchers, Rolf Findeisen, Jörg Lippert, Lars Kuepfer
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- Created: 29th Oct 2012 at 12:17
- Last updated: 24th Oct 2013 at 16:15
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