From channelopathies to hypertension: A multi-mode modeling approach for exploration of heterogeneous systems spanning many scales and involving multiple organ systems

Despite the development of ever more sophisticated models at many scales, from the level of gene regulation or intra-cellular signal transduction or cellular metabolism, through models of tissue function, epithelial transport, or even whole organ physiology, there is presently, to our knowledge, no comprehensive, organism-level modeling environment that allows exploration of the whole chain of regulatory influences brought into play by a local perturbation such as a defect in a cell membrane ion transport protein. To fill this need, we are developing a comprehensive, modular, interactive modeling environment centered on overall regulation of blood pressure and body fluids. We rely on state-of-the-art multi-scale, multi-mode simulation methods. The core model will give succinct input-output (reduced-dimension) descriptions of all relevant organ systems and regulatory processes, and it will be modular, multi-resolution, and extensible, in the sense that detailed sub-modules of any process(es) can be "plugged-in" to the basic model in order to explore, e.g., system-level implications of local perturbations. The goal is to keep the basic core model compact enough to insure fast execution time (in view of eventual use in the clinic) and yet to allow elaborate detailed modules of target tissues or organs in order to focus on the problem area while maintaining the system-level regulatory compensations. We will present the core model, inspired by Guyton's classic 1972 model of overall regulation of blood pressure, and several aspects of the renal, cardiac, and lung modules to be included in the initial development