# Transcriptional Regulation In Human Opioid Use Disorders

> **NIH NIH P01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $240,463

## Abstract

PROJECT SUMMARY/ABSTRACT – PROJECT 4
 The objective of Project 4 is to characterize the transcriptional and epigenetic mechanisms of opioid use
disorder (OUD) with a focus on dorsal striatum (DS) and nucleus accumbens (NAc), two key brain reward
regions. In all prior molecular studies of the human OUD brain, we analyzed isolated neurons vs. non-neuronal
cells, which displayed major differences in opioid action. We are now advancing this effort by performing
multiomic analyses at the single-cell level, using single nucleus RNAseq (snRNAseq) and snATACseq. Since
genetic tags are not possible in humans, such single-cell approaches offer the only available means of
studying individual cell populations (e.g., D1 vs. D2 medium spiny neurons) in the human brain. We are
performing equivalent single-cell studies on DS and NAc of rats that self-administer (SA) an opioid drug across
multiple phases of drug intake including relapse. These temporal assessments are instrumental in guiding
analysis of human tissue. Our proposed experiments incorporate not only heroin, which our group has studied
extensively, but also fentanyl given its current dominance in OUDs and the virtual complete lack of information
about neurobiological aspects of fentanyl use in humans. Overlaying the human and rat snRNAseq and
snATACseq data with sequencing datasets on bulk DS and NAc or on sorted neurons from these regions, as
well as with sequencing datasets available from the PPG’s work on mouse SA models, provides insight into the
most important mechanisms underlying abnormal gene expression associated with OUDs. With this approach,
our research has identified PRC2 (polycomb repressive complex 2) as one of the strongest-implicated
mediators of molecular pathology in DS and NAc across the three species. Based on these deductions, we are
now examining the causal role of PRC2 in opioid-induced behavioral and transcriptional abnormalities by use
of viral and genetic mouse tools already validated in PPG laboratories. We are also studying PRC2’s role in
opioid-induced regulation of the dendritic morphology of striatal D1 and D2 neurons. Given the prominent
development of PRC2 inhibitors for the treatment of specific cancers, characterization of PRC2 contributions to
OUDs offers a translational opportunity to advance novel therapies for drug addiction.

## Key facts

- **NIH application ID:** 10934813
- **Project number:** 2P01DA047233-06A1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** YASMIN L. HURD
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $240,463
- **Award type:** 2
- **Project period:** 2019-02-15 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10934813

## Citation

> US National Institutes of Health, RePORTER application 10934813, Transcriptional Regulation In Human Opioid Use Disorders (2P01DA047233-06A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10934813. Licensed CC0.

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