Systems Pharmacology of the NGF Signaling Through p75 and TrkA Receptors

The nerve growth factor (NGF) pathway has been shown to play a key role in pain treatment. Recently, a systems pharmacology model has been proposed that can aid in the identification and validation of drug targets in the NGF pathway. However, this model did not include the role of the p75 receptor, which modulates the signaling of NGF through the tropomyosin receptor kinase A (TrkA). The precise mechanism of the interaction between these two receptors has not been completely elucidated, and we therefore adopted a systems pharmacology modeling approach to gain understanding of the effect of p75 on the dynamics of NGF signal transduction. Specifically, models were developed for the so-called heterodimer and for the ligand-passing hypotheses. We used the model to compare the effect of inhibition of NGF and TrkA and its implication for drug discovery and development for pain treatment.