# Decoding the grammar of transcriptional enhancers regulating different stages of opioid use disorder

> **NIH NIH U01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $705,490

## Abstract

Project Summary
The United States is facing an unprecedented opioid epidemic caused by the misuse and abuse of both
prescription pain relievers and illegal opioids. This issue has devastating consequences for public health,
including a significant increase in overdoses related fatalities, in neonatal withdrawal syndrome and spread of
infectious diseases such as HIV and hepatitis. Numerous studies indicate that opioid use disorder (OUD) has a
strong genetic component. However, the genes networks implicated in opioid addiction remain poorly
understood. The primary goal of this proposal is to study the transcriptional regulatory mechanisms that
underlie the development of distinct stages of oxycodone abuse disorder. We will leverage the power of
quantitative epigenomic methods that will provide a comprehensive map of regulatory elements, transcription
factors and downstream target genes that are dysregulated in specific stages along the OUD trajectories. Our
major innovation is the use of capped small (cs)RNA-seq, a method that we developed to quantify newly
initiated transcripts with high sensitivity and high spatial resolution directly from total RNA. This approach
enables the unbiased annotation of Transcriptional Start Sites (TSS) of both activated genes and transcribed
regulatory elements at single nucleotide resolution. Compared with other epigenomic profiling, csRNA-seq is
highly sensitive to changes in transcription, and it can capture the dynamic regulation of both stable genes and
unstable transcripts, such as enhancer RNA. To study regulatory changes in distinct stages of OUD, we will
use a rat model of oxycodone self-administration under extended access conditions. This model recapitulates
several aspects of the human addiction-like behaviors, including tolerance, dependence, and motivation. Thus,
it enhances the translational relevance of our results. This proposal will use two inbred strains that exhibit large
differences in their motivation to seek oxycodone during abstinence while having similar pharmacokinetic for
oxycodone and similar exposure to oxycodone. Using transcriptional initiation profiling, in combination with
other sensitive profiling techniques, we will investigate the transcriptional regulatory networks underlying
different stages of the OUD, including initial exposure, escalation of use, acute and sustained abstinence.
Together, our proposed studies will have a broad impact in the field by defining regulatory networks that
underlie phenotypes associated with vulnerability to distinct stages along the OUD trajectory in rats, and it may
lead to novel therapeutic targets to treat OUD.

## Key facts

- **NIH application ID:** 10452698
- **Project number:** 5U01DA051972-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Christopher W Benner
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $705,490
- **Award type:** 5
- **Project period:** 2020-09-30 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10452698

## Citation

> US National Institutes of Health, RePORTER application 10452698, Decoding the grammar of transcriptional enhancers regulating different stages of opioid use disorder (5U01DA051972-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10452698. Licensed CC0.

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