A Mathematical Model of the Synthetic Notch Receptor

Alexander Diefes

Duke University

"A Mathematical Model of the Synthetic Notch Receptor"

Synthetic receptors are engineered proteins with potential applications to studying cell-cell interactions and cancer cell therapy. One promising research direction is engineering the Notch receptor, a transmembrane protein that can detect extracellular signals such as antigens or other ligands, and convert them to intracellular signals to activate expression of certain genes. Both the intracellular and extracellular domains can be engineered and replaced with alternative domains, creating the family of modified Notch receptors known as synthetic Notch (synNotch). SynNotch has the potential to improve chimeric antigen receptor (CAR) T-cell therapy by tuning binding affinity to a specific cancer antigen and minimizing off-target effects. We propose an ordinary differential equation model of synNotch receptor activity that has predictive value of how custom cell response behaviors can be programmed. The mathematical model couples activation dynamics on a fast timescale, characteristic of receptor-ligand interactions, and of slower downstream gene expression dynamics. Local and global sensitivity analyses indicate model parameters that yield the greatest variability in downstream results, indicating their potential to be engineered for different functions. Specifically, we find that ligand association and ligand-dependent activation have the greatest potential for modulating transcription factor release.

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