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Janelle Tobias Abstract– Frank Lab

The endocannabinoid system (ECS) is a network consisting of cannabinoid receptors, lipophilic ligands, and the enzymes which metabolized these ligands. While this system is infamous for inducing the psychoactive effects of marijuana, the ECS plays a major physiological role in metabolism. In particular, the ECS can impact glucose stimulated insulin secretion (GSIS) from pancreatic β-cells, which secrete insulin to regulate blood glucose levels. The ECS is challenging to study in β-cells because they express multiple cannabinoid receptor isoforms, which can respond promiscuously to ECS ligands. Thus, my project aims to develop a novel tool set, termed Optically-Cleavable Targeted (OCT-) ligands, which will enable probing of the ECS in β-cells with improved spatiotemporal resolution. OCT-ligands merged the spatial targeting of genetically-encoded SNAP-tags with the temporal precision of photopharmacology. The generic structure of these ligands contains 4 key aspects: a ligand of interest, photocage, linker, and biorthogonal handle. I have synthesized OCT-ligands to target cannabinoid receptors, and will evaluate these ligands in model β-cell lines using live-cell confocal microscopy. However, this approach can be applied to study other proteins of interest in other cell types, contingent on the feasibility of expressing protein-tags (such as SNAP-, HALO-, CLIP-tags) and the chemical synthesis of the desired ligand.