We present the current state of the development of the SAPHIR project (a Systems Approach for PHysiological Integration of Renal, cardiac and respiratory function). The aim is to provide an open-source multi-resolution modelling environment that will permit, at a practical level, a plug-and-play construction of integrated systems models using lumped-parameter components at the organ/tissue level while also allowing focus on cellular-or molecular-level detailed sub-models embedded in the larger core model. Thus, an in silico exploration of gene-to-organ-to-organism scenarios will be possible, while keeping computation time manageable. As a first prototype implementation in this environment, we describe a core model of human physiology targeting the short-and long-term regulation of blood pressure, body fluids and homeostasis of the major solutes. In tandem with the development of the core models, the project involves database implementation and ontology development.

Reactive oxygen species (ROS) are involved in the pathophysiology of several diseases (e.g. Alzheimer or atherosclerosis) and also in the aging process. The main source of ROS in aerobic organisms is the electron transport chain (ETC) in the inner mitochondrial membrane. Superoxide is produced at complexes I and III of the ETC, starting a complex network of ROS reactions. To achieve a deeper mechanistic understanding of how ROS are generated by complex III, we developed a mathematical model that successfully describes experimental data of complex III activity in various rat tissues, the production of ROS with and without antimycin and ROS generation depending on different values of the membrane potential ∆Ψ. The model also reinforces the idea of ubiquinone acting as a redox mediator between heme bL and oxygen, as proposed earlier.

(1) model BP, PRA and [Ang II] are within reported ranges, and respond physiologically to sodium intake; (2) short-term Ang II infusion induces reported rise in BP and PRA. The modeled circulating RAS, in interaction with an integrated CVR, exhibits a realistic response to BP control maneuvers. This construction will allow for modelling hypertensive and CVR patients, including salt-sensitivity, polymorphisms, and pharmacotherapeutics.