WP4 Vertical model integration
Drug chemical structure should be linked to intracellular molecular pathways via protein-ligand binding profiles and protein-protein interactions, to cellular biochemical biomarkers and phenotypes via metabolic pathways, to organphenotypes, and eventually to clinical phenotypes and systemic biomarkers. This calls for vertically integrating modeling exercises described previously. At the cellular level, genome scale metabolic network reconstructions comprise thousands of biochemical reactions and are an important tool of bottom-up systems biology. Notably, genome scalemodels may be used as a template for contextualization of different ‘omics data. A genome-scale model of hepatic metabolism has been previously established. In a complementary approach, dynamic models of intracellular signaling allow amechanistic description of in intracellular information flow following extracellular perturbations. The RWTH partner has already successfully established and applied amulti-scale model to address drug-induced liver injury. In particular, the multi-scalemodel was used to describe mitochondrial dysfunction following a paracetamol overdose. Analogously, intracellular signaling cascades have been integrated into PBPK models at the whole-body scale, thus providing a mechanistic platform for model-based analysis of inflammation.
WP4 deals with the vertical integration of models and across different levels of biological organization. Physiology-based pharmacokinetic modelling will be used as a highly flexible platform to simulate drug concentration profiles in the heart or in the liver. Thereby, quantitative estimates of cellular exposure will be obtained which are in turn used as input for molecular pathway modelling (WP2). Vice versa, results from computational chemistry (WP1) can be used in the physiological models at organ scale to quantify specific model parameters. Experimental data from the project partners will be continuously used for model validation and refinement. Notably, this involves both in vitro data from cellular or tissue cultures as well as real patient data. A key goal will be the integration of intracellular models into standardized PBPK models thereby enabling a mechanistic correlation of events at the cellular scale and the organism level.
Reference for banner picture: Krauss et al., PLOS Comp. Biol., 2012