Funding Opportunity Number: PAR-24-267
Award Amount: Up to $125,000
Deadline: March 3, 2025, July 28, 2025
Background
Given the profound individual and societal impact of drug addiction, elucidating the neurobiological mechanisms of addiction is necessary to inform the development of future preventative, diagnostic, and therapeutic strategies. New addiction therapeutics in particular could have a major impact on this health crisis.
While a variety of targets for potential addiction therapeutics have been discovered over the years, development of small molecule modulators for many of these targets has proven to be difficult due to potency, selectivity, efficacy, off-target side effects, toxicity, or other challenges. Thus, identification of new targets for future addiction therapeutics is critical. The National Institute on Drug Abuse (NIDA) supports significant target discovery efforts in the genomic realm through three major and partially overlapping areas of investment: 1. animal and human transcriptomic and/or epigenomic studies at the tissue or single cell level, 2. human addiction genetics, and 3. animal addiction genetics. With respect to transcriptomic or epigenomic studies, many transcripts or enhancers have been found to be regulated by specific drug exposure paradigms. Similarly human and animal studies have identified genetic and epigenetic variants relevant to substance use disorders (SUDs).
Once candidate genes or variants are in hand, rapid validation by orthogonal methods can be used to confirm their putative roles in addiction-relevant phenotypes. Approaches including CRISPR inhibition (CRISPRi), CRISPR activation (CRISPRa), epigenome editing, induced pluripotent stem cell (iPS) systems, and related technologies enable high-throughput functional testing and prioritization of candidate SUD genes and variants.
Genes or variants with addiction-relevant phenotypes that have been validated orthogonally require further characterization to identify the causal mechanisms involved. These studies usually entail the creation of conditional gene knock-out or knock-in animals for characterization of resultant behavioral, molecular, neurobiological, or other phenotypes. Rapidly evolving genome editing technologies can significantly decrease the time and effort it takes to generate knock-out, knock-down, or knock-in animals and can even be applied to species that have previously been more challenging to manipulate genetically (e.g. rat, primate).
Research Objectives. The purpose of this initiative is to support projects that propose to either:
- Orthogonally validate a set of candidate addiction-relevant genes, variants, or transcripts to identify those most likely to be involved in specific addiction-relevant processes, or
- Functionally characterize the mechanistic role (e.g. behavioral, molecular, and/or neurobiological) of one or more orthogonally-validated addiction-relevant genes, genetic or epigenetic variants, or transcripts in living organisms or in human organoid systems.
For more information, please see the opportunity website.