Michael T. Cooling

The Physiome Model Repository 2

MOTIVATION The Physiome Model Repository 2 (PMR2) software was created as part of the IUPS Physiome Project (Hunter and Borg, 2003), and today it serves as the foundation for the CellML model repository. Key advantages brought to the end user by PMR2 include: facilities for model exchange, enhanced collaboration and a detailed change history for each model. AVAILABILITY PMR2 is available under an open source license at http://www.cellml.org/tools/pmr/; a fully functional instance of this software can be accessed at http://models.physiomeproject.org/.

Sensitivity of NFAT Cycling to Cytosolic Calcium Concentration: Implications for Hypertrophic Signals in Cardiac Myocytes

The nuclear factor of activated T-cell (NFAT) transcription factors play an important role in many biological processes, including pathological cardiac hypertrophy. Stimulated by calcium signals, NFAT is translocated to the nucleus where it can regulate hypertrophic genes (excitation-transcription coupling). In excitable cells, such as myocytes, calcium is a key second messenger for multiple signaling events, including excitation-contraction coupling. Whether the calcium signals due to excitation-contraction and excitation-transcription coupling coincide or how they can be differentiated is currently unclear. Here we construct a mathematical model of NFAT cycling fitted to skeletal myocyte and baby hamster kidney cell data. The model replicates key behavior with respect to sensitivity to calcineurin overexpression and to calcium oscillations. Finally, we measure the sensitivity of the system to a simulated hypertrophic calcium signal, against a background excitation-contraction coupling calcium oscillation. We find that NFAT cycling is sensitive to excitation-transcription coupling even when both calcium signals are in the same cellular compartment, thus showing that separation of the signals may not be necessary in vitro.

A Reappraisal of How to Build Modular, Reusable Models of Biological Systems

61Department of Bioengineering, University of Washington, Seattle, Washington, United States of America, 2Auckland Bioengineering Institute, University of Auckland,Auckland, New Zealand, 3Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America, 4Department of Molecular andIntegrative Physiology, University of Michigan, Ann Arbor, Michigan, United States of America, 5Department of Physiology and Biophysics, University of Washington,Seattle, Washington, United States of America, 6Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, Washington, UnitedStates of America

Multiscale Modeling of Intracranial Aneurysms: Cell Signaling, Hemodynamics, and Remodeling

The genesis, growth, and rupture of intracranial aneurysms (IAs) involve physics at the molecular, cellular, blood vessel, and organ levels that occur over time scales ranging from seconds to years. Comprehensive mathematical modeling of IAs, therefore, requires the description and integration of events across length and time scales that span many orders of magnitude. In this letter, we outline a strategy for mulstiscale modeling of IAs that involves the construction of individual models at each relevant scale and their subsequent combination into an integrative model that captures the overall complexity of IA development. An example of the approach is provided using three models operating at different length and time scales: 1) shear stress induced nitric oxide production; 2) smooth muscle cell apoptosis; and 3) fluid-structure-growth modeling. A computational framework for combining them is presented. We conclude with a discussion of the advantages and challenges of the approach.

Computational models of the primary cilium and endothelial mechanotransmission

In endothelial cells (ECs), the mechanotransduction of fluid shear stress is partially dependent on the transmission of force from the fluid into the cell (mechanotransmission). The role of the primary cilium in EC mechanotransmission is not yet known. To motivate a framework towards quantifying cilia contribution to EC mechanotransmission, we have reviewed mechanical models of both (1) the primary cilium (three-dimensional and lower-dimensional) and (2) whole ECs (finite element, non-finite element, and tensegrity). Both the primary cilia and whole EC models typically incorporate fluid-induced wall shear stress and spatial geometry based on experimentally acquired images of cells. This paper presents future modelling directions as well as the major goals towards integrating primary cilium models into a multi-component EC mechanical model. Finally, we outline how an integrated cilium-EC model can be used to better understand mechanotransduction in the endothelium.

Modular modelling with Physiome standards

The complexity of computational models is increasing, supported by research in modelling tools and frameworks. But relatively little thought has gone into design principles for complex models. We propose a set of design principles for complex model construction with the Physiome standard modelling protocol CellML. By following the principles, models are generated that are extensible and are themselves suitable for reuse in larger models of increasing complexity. We illustrate these principles with examples including an architectural prototype linking, for the first time, electrophysiology, thermodynamically compliant metabolism, signal transduction, gene regulation and synthetic biology. The design principles complement other Physiome research projects, facilitating the application of virtual experiment protocols and model analysis techniques to assist the modelling community in creating libraries of composable, characterised and simulatable quantitative descriptions of physiology.

The CellML Metadata Framework 2.0 Specification.

The CellML Metadata Framework 2.0 is a modular framework that describes how semantic annotations should be made about mathematical models encoded in the CellML (www.cellml.org) format, and their elements. In addition to the Core specification, there are several satellite specifications, each designed to cater for model annotation in a different context. Basic Model Information, Citation, License and Biological Annotation specifications are presented.

Mechanical Models of Endothelial Mechanotransmission Based on a Population of Cells

Computational cell mechanics models are dependent on cell morphology. Most studies of cell mechanics use an idealized geometry or a cell-specific approach. These approaches do not consider the effect of morphological variation in cell populations. In this chapter we analyze shape variation within a population of endothelial cells, and the effect this variation has on stress estimates from finite-element modeling. We developed shape descriptors to quantify variation in the nucleus and overall cell shape in a population of human microvascular endothelial cells (n = 15). From these descriptors, we generate statistically representative spatial models that more accurately reflect the cell shape of the entire population. We also generate models with non-typical morphology that are less likely to be found in the cell population. Both of these model types were subject to finite-element analysis, and compared to illustrate how morphological variation effects stress estimates.

A Primer on Modular Mass-Action Modelling with CellML

CellML is a model exchange format designed to greatly facilitate the communication of models. Here we provide a primer on modelling mass-action kinetics with CellML and discuss some of the language features for structuring models. We illustrate these with examples of simple reactions, from which we build a basic biochemical system. We explore some best practices for structuring the models to greatly aid model reusability, as well as communication, and provide information on interacting with the CellML research community. CellML source code for the models in this chapter can be found online at the CellML model Repository (Lloyd et al. 2008), at http://models.cellml.org/workspace/modularmassactionprimer.

A global sensitivity tool for cardiac cell modeling: Application to ionic current balance and hypertrophic signaling

Cardiovascular diseases are the major cause of death in the developed countries. Identifying key cellular processes involved in generation of the electrical signal and in regulation of signal transduction pathways is essential for unraveling the underlying mechanisms of heart rhythm behavior. Computational cardiac models provide important insights into cardiovascular function and disease. Sensitivity analysis presents a key tool for exploring the large parameter space of such models, in order to determine the key factors determining and controlling the underlying physiological processes. We developed a new global sensitivity analysis tool which implements the Morris method, a global sensitivity screening algorithm, onto a Nimrod platform, which is a distributed resources software toolkit. The newly developed tool has been validated using the model of IP3-calcineurin signal transduction pathway model which has 30 parameters. The key driving factors of the IP3 transient behaviour have been calculated and confirmed to agree with previously published data. We next demonstrated the use of this method as an assessment tool for characterizing the structure of cardiac ionic models. In three latest human ventricular myocyte models, we examined the contribution of transmembrane currents to the shape of the electrical signal (i.e. on the action potential duration). The resulting profiles of the ionic current balance demonstrated the highly nonlinear nature of cardiac ionic models and identified key players in different models. Such profiling suggests new avenues for development of methodologies to predict drug action effects in cardiac cells.