:a Systems Approach for PHysiological Integration of Renal, cardiac and respiratory function – SAPHIR

1-Scientific background and objectives : - 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 (i.e., open for inspection, modification, & extension) 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. - Objectives : To fill this need, we will develop a comprehensive, modular, interactive modeling environment centered on overall regulation of blood pressure and body fluids. We will use state-of-the-art multi-scale simulation methods, and we will design a user-friendly graphical user interface (GUI). The basic 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, eg. 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. - - 2-Description of the project, methodology : - Development of this modeling environment will proceed progressively in several stages in order to provide practical tools even in the early phases of the project. The basic system variables of the core model, chosen to reflect the needs of the initial target problems, will be blood pressure (both short- and long-term regulation), concentrations of (at least) NaCl, glucose, lactate, urea, PO2, PCO2, HCO3-, NH3/NH4+, and pH, and the volumes of the various fluid compartments. The essential regulatory variables will be autonomic tone and the levels of the hormones vasopressin, aldosterone, angiotensin. The core model will include basic descriptions of the heart, vasculature, intra- and extracellular spaces, lungs, kidneys, muscles (one option will be explicit red blood cells ). Rather than starting from scratch, we will build from two legacy models that treated overall regulation of blood pressure (Guyton et al. 1972) and fluid regulation (Ikeda et al. 1979). - The resulting modeling resource will be developed as an Open Source project and will be made available to the general community as part of the IUPS Physiome effort. We will also take full advantage of the high-performance computing (HPC) facilities of the FAME2 project (Pole de Compétitivité System@tic) not only for calculation-intensive model computations (when necessary) but also to provide a datawarehouse of relevant experimental measurements of parameter values, datasets of physiological data for model validation and benchmarking, etc. - Furthermore, at each stage, we will focus the development on specific problems of physiopathology. In addition to the basic core model (with scaled variants for human, rat, and mouse), we will develop modular extensions addressing specific problems stemming from our own specialties in renal physiology, hypertension, lung physiopathology, and cardiac/cardiovascular physiology. - In parallel to the model development, we will build a datawarehouse for the vast collection of heterogeneous experimental data necessary not only for evaluation of the many parameter values but also for experimental and clinical validation of the simulation results. This will involve ontology development and implementation of grid computing systems mediation software. - - 3-Expected results : - This modular, comprehensive systems modeling