Within the physiological modeling community, computational modeling of the heart has emerged as arguably the most advanced exemplar of integrated cell-to-organ simulation. As such, the heart represents a highly promising candidate for demonstrating the potential of a systems biology approach for integrating across spatial and temporal scales of resolution in order to increase understanding of function and disease processes [129]. In order for cardiac modeling to be applied appropriately in the context of the VPR project, however, there are key challenges to be addressed. Many existing components of cardiac models have been combined largely unchanged from existing frameworks. This model reuse paradigm, while crucial to the development of hierarchical multi-scale models, has lead to the majority of current cardiac models being parameterized from measurements collected across a range of species, temperatures and other experimental conditions. What is now required is the development of canonical species and condition-specific cardiac models that robustly integrate multiple data sources and functional understanding to quantitatively characterize in silico the full spectrum of experimentally observed cardiac phenotypes. This, in turn, will reduce cases where failure of a model to recapitulate experimental observations represents inappropriate structure or parameter choices, and will increase the likelihood that failure of model prediction identifies genuine gaps in understanding and leads to new insights. Through the dissemination of such cardiac models and open source tools for solving them, our goal is to develop a rat cardiac modeling framework and species-specific models for (i) experimental design, testing and hypothesis generation for experimental driven research; (ii) integration with the other organ and system models through Project 5; and (iii) providing a foundation for quantifying genotype-phenotype relationships through Projects 5 and 6. In addition to these goals, which link this project with the broader goals of the Center, Project 3 will investigate the hypothesis that different regional alterations in structure, hemodynamics, metabolism, and myocyte excitation-contraction coupling mechanisms give rise to differences in regional ventricular function between a model of acquired hypertrophic disease (Strain A in Figure 1.4), a genetic model of hypertrophy (Strain F) and two associated hypertension rescue strains (Strains D and E).
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