Tuesday, December 3, 2024
12/3/2024
Project Summary/Abstract The goal of our Maximizing Investigators’ Research Award (MIRA) is to develop and apply olfactory-based (OR)-based sensors, and, more generally, G-protein coupled receptor (GPCR)-based sensors for biomedical applications. In Focus Area 1, we elucidate the role of ectopically expressed olfactory receptors (exORs), identifying endogenous ligands for exORs, and assessing exORs as therapeutic targets. Our 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 should enable an assessment of exORs as therapeutic targets, and open the door to new, first-in-class therapeutics. In Focus Area 2, we unravel how GPCR signaling pathways talk to one another and the consequences this crosstalk has for cellular processes and organismal behavior. Our long-term goal is to enable combinatorial control of up to 17 different GPCR signaling pathways, providing access to cellular phenotypes that may teach us 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. The objective of this Equipment Supplement to the parent MIRA is to purchase a benchtop fluorescence activated cell sorter (FACS) with capability to sort up to three colors with a speed of 100,000 events/sec and ability to deposit into 96-well plates. The requested equipment will support the objectives of the parent MIRA. With respect to Focus Area 1, the increased availability of a FACS will facilitate the acquisition of large olfactory receptor (OR)- ligand datasets to train machine learning algorithms for ectopically expressed OR deorphanization. With respect to Focus Area 2, the cell sorter will accelerate the engineering of GPCRs to bind human orthogonal ligands for use as chemogenetic tools to probe GPCR signaling crosstalk.
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