Multi- and Large-Scale Systems Modeling and Analysis: Cellular Metabolic Dynamics in Tissue-Organ and Whole-Body Systems <P>

	Strategies and methods will be presented for developing and applying models of metabolic system dynamics that span several length and time scales.  A framework for this research has been developed in the Center for Modeling Integrated Metabolic Systems (MIMS).  Approaches will be described with bottom-up models of cellular metabolic pathways in tissue/organ systems and top-down  models linking the whole body responses to metabolic processes in tissue/organ subsystems.  Model validation will be illustrated by comparison of model simulated outputs with data from in vivo experiments with various input perturbations, e.g., exercise and ischemia.  The mathematical models for spatially lumped and distributed systems are based  on dynamic species mass transport equations in blood and tissue  with membrane transport and chemical reaction fluxes that are related to species concentrations. Depending on the objectives of the model, distinctions of cellular domains (e.g., cytosol and  mitochondria) and the specifics of  metabolic  pathways differ.  The model equations involve a large number of  parameters that must be estimated  based  on relatively sparse data. Using constrained optimization, we obtain parameter values that provide the best (least-squares) fit of model outputs to data.  These parameter values, however, are not unique.   Dynamic sensitivity analysis is applied to determine the relative importance of the parameters on system outputs.  Relating whole-body function to cellular metabolism and critical metabolic pathways for potential manipulation is an important challenge.