National Centers for Systems Biology

Virtual Physiological Rat (University of Michigan)

The Virtual Physiological Rat Project

Principal Investigator: Daniel Beard, Ph.D., University of Michigan

Other Key Investigators: James Bassingthwaighte (University of Washington-Seattle); Allen Cowley (Medical College of Wisconsin); Edmund Crampin (University of Auckland, New Zealand); Ranjan Dash (Medical College of Wisconsin); Melinda Dwinell (Medical College of Wisconsin); Aron Geurts (Medical College of Wisconsin); Peter Hunter (University of Auckland, New Zealand); Timothy Kamp (University of Wisconsin-Madison); Mette Olufsen (North Carolina State University); Nicolas Smith (Kings College London); Andrew McCulloch (University of California-San Diego); Stig Omholt (Norwegian University)

Overview: Despite a depth of knowledge of basic cardiovascular physiology and a host of physiological and genomic data from animal models of disease, we lack even a rudimentary understanding of how multiple genes and environmental factors interact to determine cardiovascular phenotype. This is a fundamental question-perhaps the fundamental question-in basic biomedical research.

The Virtual Physiological Rat Project tackles this question by integrating computational modeling of genetic and physiological systems in rat and experimental studies on genetically defined strains of rat that capture distinct cardiovascular phenotypes. Validated models will be developed to account for genetic variation and physiological response to environment (e.g., diet). In addition, new strains of genetically engineered rat will be developed with the ultimate goal of using computer models to predict the physiological characteristics of not yet realized genetic combinations, derive those combinations in the lab, and then test the predictions. By systematically and iteratively using multiscale computational models to analyze data, generate hypotheses, design experiments, and predict phenotypes in novel strains, we will attain the capability to predict and understand the emergence of complex traits.

Our initial efforts will focus on integrating simulations of the mechanics of the circulation, cardiac electrophysiology and mechanics, metabolism of specific cell and tissue types, and renal function. These models will be used as the vehicle to analyze experimental data from a number genetically defined strains showing cardiovascular phenotypes relevant to human disease. Differences in model parameterizations between the different strains provide unique clues to reveal differences in molecular function in response to physiological and environmental perturbations. These differences will be further investigated with targeted physiological studies and through site-directed mutagenesis and selective breeding to test model predictions.