PROJECT SUMMARY: A major factor plaguing drug development is that there is no preclinical drug screenthat can accurately predict unintended drug induced cardiac arrhythmias. The current approaches rely onsubstitute markers such as QT interval prolongation on the ECG. Unfortunately, QT prolongation is neitherspecific nor sensitive to indicate likelihood of arrhythmias. There is an urgent need to identify a new approachthat can predict actual proarrhythmia rather than surrogate indicators. Mathematical modeling and simulationconstitutes one of the most promising methodologies to reveal fundamental biological principles andmechanisms, model effects of interactions between system components and predict emergent drug effects.Thus, we propose the development of a novel multiscale approach based on drug-channel structuralinteractions and kinetics intended to predict drug induced cardiotoxicity in the context of: 1) preclinical drugscreening, 2) drug rehabilitation, and 3) prediction of the intersection of drug effects and coexistent risk factors.Our underlying hypothesis is that the fundamental mode of drug interaction derived from each drug?s uniquestructure activity relationship determines the resultant effects on cardiac electrical activity in cells and tissue.By capturing these complex drug channel interactions in a model, we expect to be able to predict drug safetyor electro-toxicity in the heart. We have brought together an expert team to assemble and test a new multiscalemodel framework that connects detailed mathematical models to predict atomic scale interactions of drugs onthe promiscuous hERG potassium channel to functional scale predictions at the level of the channel, cell andtissue. Predictions from the atomic structure simulations will be used to inform the kinetic parameters ofmodels that capture the complex dynamical interactions of drugs and ion channels. The computationalcomponents will then be studied in predictive models at the channel, cell and tissue scales to exposefundamental mechanisms and complex interactions underlying emergent behaviors. Experiments inmammalian cells and tissues will be undertaken to validate model predictions. Drug properties will beperturbed in models to rehabilitate dangerous drugs and reduce their potential toxicity. The multiscale modelfor prediction of cardiopharmacology that we will develop in this application will be applied to projectsdemonstrating its usefulness for efficacy or toxicity of drug treatments in the complex physiological system ofthe heart.
|Effective start/end date||7/5/16 → 6/30/20|
- National Institutes of Health: $739,652.00