Computer Modeling of Myosin Binding Protein C and its Effect on Cardiac Contraction

I am delighted to collaborate with Julian Stelzer, PhD (Case Western Reserve University) and Stuart Campbell (Yale University) on this R01 application titled “Elucidating the physiological roles and therapeutic potential of cardiac myosin binding protein C through in silico modeling”. The main goal of this project is to use mathematical modeling to predict the optimal way of modulating myosin-binding protein-C to rescue contractile function in different pathological states. This will require (1) developing a new spatially-explicit computer model of sarcomere-level contraction that accounts for the complex regulatory effects of MyBP-C, (2) refining the model using multi-scaled experimental data, and (3) testing the predictions of the model using experiments with mice afflicted with diverse types of cardiac dysfunction. My laboratory will contribute to project stages 1 and 2 above. We will extend our spatially-explicit 3D model of muscle contraction (FiberSim) to include the regulatory effects produced by myosin binding protein-C interacting with actin and myosin with phosphorylation-dependent kinetics. We will also work with Drs. Stelzer and Stuart Campbell to fit simulations to experimental data and to perform sensitivity analyses to determine the impact of different kinetic mechanisms. Finally, we will link the FiberSim model to a lumped parameter circulation system so that we can predict how sarcomere-level modifications will impact whole-body cardiovascular function (for example, cardiac output, systemic blood pressure). All of the source code will be published online under a GPL license that allows for unrestricted download and reuse.