Multiplexed Screens of Olfactory Receptor Binding

Animal olfaction is extremely sensitive and precise mechanism for chemical detection with the ability to distinguish very dilute compounds from complex mixtures.  This sense is mediated by molecules binding to one or more olfactory receptors (ORs), which are a subtype of G protein-coupled receptors (GPCRs) that mediate signal transduction by stimulating cyclic AMP (cAMP) production.  Current methods for monitoring OR activation are either qualitative or rely on luminescent reporters not practical for screening thousands of receptors against thousands of ligands.  Advancements in next generation sequencing and genome editing techniques allow us to develop a novel platform to measure multiplexed responses from a library of engineered human cells each clonally expressing unique ORs on the genome using landing pad integration.  Receptor activation is linked to a cAMP responsive reporter expressing a barcode that identifies each OR and measure quantitatively using RNAseq. Apart from chemical sensing, the system enables us to pursue a variety of applications such as: deciphering functional differences in ORs among populations, screening drugs that interact with G protein coupled receptors, and engineering receptors with novel specificities.