Olfactory receptor-based sensors for biomedical applications

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Project Summary/Abstract Olfactory receptors (ORs) are one of the largest family of chemical detecting cell-surface receptors in humans. ORs are expressed beyond the olfactory tissue, with 55 ORs highly expressed ectopically (exORs) in 18 different tissues, where they drive tissue-specific processes including sperm chemotaxis and muscle regeneration. The majority of exORs, however, have no known ligands; they are orphans, which limits the ability to understand their role in human health, including 1) elucidation of exOR downstream pathways in the endogenous tissue, 2) the identification of exOR endogenous ligands, and ultimately 3) an assessment of exORs as potential therapeutic targets. During the MIRA renewal period, the goal is to leverage the OR-based sensor technology to generate large sets of high-quality experimental exOR-ligand data to train machine learning models to predict ligands for the 36 currently orphaned exORs. Such an algorithm would vastly accelerate exOR deorphanization, and may prove to be general, enabling the deorphanization of all 302 orphan ORs. The long- term goal is to use the identified ligands that activate the exORs to tease out their role in human health, including identifying the endogenous exOR ligands in the tissues in which they are overexpressed, and determining the downstream processes in which they are involved. This understanding will enable an assessment of exORs as therapeutic targets, and open the door to new, first-in-class therapeutics. Olfactory receptors belong to the class of cell surface proteins called G-protein coupled receptors (GPCRs). Non-sensory GPCRs are involved in a myriad of biological process, from cell migration to immunity, making them important therapeutic targets. GPCRs signal combinatorially, with ~100s of GPCRs expressed in mammalian cells signaling via a total of 17 G-protein subtypes—resulting in extensive crosstalk between GPCR signaling pathways, often with important therapeutic implications. A gap in knowledge exists in understanding the extent of GPCR signaling pathway crosstalk and its effect on cellular processes and animal behavior. Dissecting GPCR signaling pathway crosstalk will enable 1) the identification of GPCR signaling pathways leading to therapeutically desired outcomes, vis a vis pathways leading to side effects, towards the development of more precise and safer therapeutics, and 2) a more nuanced understanding of GPCR signaling that will be crucial for the engineering of next-generation therapeutic cells. During the MIRA renewal period the goal is to develop a chemogenetic toolset to combinatorially activate/deactivate multiple (≥ 3) GPCR signaling pathways while leaving the rest of the cell intact in order to fully dissect the effects of GPCR signaling crosstalk and its biomedical implications. The long-term goal is to ultimately enable combinatorial control of up to 17 different GPCR signaling pathways, providing access to cellular phenotypes that may explain how combinatorial GPCR activation can be leveraged for the development of new therapies and the GPCR-based circuit architecture could inspire the development of next-generation sense and response therapeutic cells.