This FOA will support high-throughput screening approaches to identify novel receptors, signal transducers, or small molecules that modulate Substance Use Disorder (SUD)-relevant signal transduction pathways (dopamine, opioid, cannabinoid, nicotinic, or other appropriately justified pathway). Applicants may also propose secondary screens and/or validation of high value identified targets.
Many years of research have identified key receptors and signal transduction pathways relevant to addictive substances including nicotinic, opioid, cannabinoid, and dopamine pathways. However, there is much we do not know about the modulation of these signal transduction pathways as illustrated by three recent examples. First, researchers have used a genetically encoded biosensor to show that opioid receptors respond differently to peptides or non-peptide opioids depending on the subcellular location of the opioid receptor. High-throughput small molecule screening of cells expressing this biosensor might be used to identify compounds with different analgesic efficacy or altered addiction liability. Second, the atypical chemokine receptor ACKR3/CXCR7 was identified to be a broad-spectrum scavenger for opioid peptides, suggesting the possibility of other undiscovered receptors or signal transduction molecules that might interact with opioid or other SUD-relevant pathways. Third, nematode genetic screens have been used to identify a conserved orphan receptor GPR139 with anti-opioid activity. Deletion of GPR139 led to altered morphine-induced behavioral responses in mice. These examples strongly suggest there is more to be learned about the components involved in opioid receptor signaling and function.
In parallel, a variety of high-throughput screening approaches have been developed or improved to facilitate the identification of novel targets or small molecules. These include high throughput mutant screening in genetically tractable organisms as well as screening of FDA-approved and other small molecules using novel cell-based biosensor approaches. In addition, CRISPR inactivation (CRISPRi) or CRISPR activation (CRISPRa) screens can be used to turn individual genes off or on in mammalian cells or other simple systems to identify genes with specific phenotypes.
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