Supported for the last four years by NIH grant P50-GM094503, our National Center for Systems Biology is focused on the systems biology of cardiovascular disease—understanding how disease phenotypes apparent at the whole-organism scale emerge from molecular, cellular, tissue, organ, and organ-system interactions. The overarching aims of our center are to make leading contributions in basic and translational science in cardiovascular systems biology, effectively disseminate associated resources to the scientific community, and to train the next generation of scientists in this area.
With the scientific focus on complex cardiovascular disease (disorders of blood pressure regulation and hypertensive heart disease) the Virtual Physiological Rat Project has developed detailed multi-scale models of components of the cardiovascular system responsible for processes ranging from beat-to-beat cardiovascular dynamics to long-term regulation of blood volume. Using this multi-scale systems approach the VPR Project has brought together otherwise disparate bodies of knowledge and fields of study. For example, as described in Project 1, computer models informed by experimental animal models and clinical data have been used to make predictions concerning the relationship between arterial stiffening, autonomic function, renal function, and long-term pressure regulation that have survived independent testing by independent laboratories. Project 3 describes how, by integrating the biochemistry of energy metabolism and the dynamics of myofilament mechanics in a physio-chemically consistent framework, we are beginning to understand how energetic state and mechanical function are coupled, how the coupling dysfunctions in heart disease, and how to design therapies to restore mechanical/energetic balance. In Project 2 computer models representing biochemical, electrical and mechanical systems of the heart and circulatory system, developed and identified based on rodent experimental models, are being applied in patient-specific modeling to guide diagnostics and therapies. Furthermore, VPR models are being applied to translate from cell and molecular-level screens of drug candidates to predict effects of drugs on whole-body function. These efforts, which have revealed novel insight into recent failures in clinical trials of drugs, have crystallized around a scientific project on quantitative systems pharmacology (Project 4).