DART2.0: comprehensive cell type-specific behavioral neuropharmacology

This project is a collaboration with Dr. Michael Tadross at Duke University. Dr. Tadross has pioneered the development of DART (drugs acutely restricted by tethering) technology, a two-component system in which drugs home to a defined cell type. The technology works by genetically programming a subset of cells to express HaloTag, an enzyme borrowed from bacteria, to attract a drug molecule attached via a long flexible linker to the HaloTag ligand. DART provides a unique combination of features: cell type specificity arises from expression of HaloTag on a genetically defined cell type; receptor specificity is inherited from the drug payload; and acute onset upon drug delivery (critical to avoid compensatory confounds) is similar to that of traditional pharmacology. In addition, the method functions in behaving animals and does not require mutation or overexpression of the targeted native receptor. Thus, DART is the first and only method to date that enables the behavioral effects of clinically relevant drugs to be deconstructed with cellular specificity. On this project, Northwestern University will design and synthesized a number of new DART tools for validation and use in studying new neurobiology. Northwestern will synthesize drug payloads and attach them at specific drug sites via optimized linkers to HaloTag ligand.