# Gene Regulation in the Opioid Dependent Human Brain (Project 2)

> **NIH NIH P50** · RESEARCH TRIANGLE INSTITUTE · 2024 · $544,428

## Abstract

PROJECT SUMMARY/ABSTRACT
 The ongoing opioid epidemic is one of the most important public health crises of our time with overdose
fatalities quadrupling since 1999 and surpassing those of gun homicides in recent years. Given the individual
and societal burden of opioid dependence, it is necessary to characterize the biological pathways to
dependence that can be targeted for treatment and intervention. The work proposed in Project 2 combines
multi-omics resources to examine specific hypotheses regarding the functional brain architecture of opioid
addiction (OA). Guided by existing theory implicating the prefrontal cortex (PFC), nucleus accumbens (NAc),
and amygdala in the cycle of substance abuse, we propose to generate and combine existing data at
multiple omics levels in each brain region using postmortem human tissue collected from opioid overdose
cases and matched controls. The measurement approaches we use are genome-wide, in each of the
three brain regions and in each biological domain: single nucleotide polymorphism (SNP), epigenome (DNA
methylation and histone acetylation), and transcript (via RNA-seq) in our combined sample (N=641) with
follow-up single-cell validation/replication.
 We will accomplish these goals across three aims. In Aim 1, in the existing combined sample, we will fill
out the brain regions not currently assessed in specific brain/regions or biological domains and perform
analyses to detect region-specific and general (across-brain regions) methylation, histone acetylation, and
gene expression differences between cases and controls. In addition, we will perform analyses aimed at
integrating across those biological domains. In Aim 2, we will perform single-cell follow-up of Aim 1 findings
to pinpoint all cell types within the PFC, NAc, and amygdala that drive the differences identified in Aim 1, with
validation by RNA-seq in fluorescence activated cell sorting (FACS) separated cells and RNA-FISH. In Aim
3, we will genotype samples where needed and perform genetic association mapping—histone modification,
DNA methylation, and gene expression QTL mapping—to identify genetic variants that account for the
regulatory differences observed between cases and controls in Aim 1. These QTL approaches will allow us
to identify regulatory differences with a genetic basis, versus those somatically acquired as a consequence
of chronic opiate use, exposure, or other environmental factors.
 Our overall goal is to create a framework in which we can map, in brain, the OA functional relevance of
genomic sets (genes, pathways, features) and generate results that can be leveraged in Project 1 and the
Synergy Core through mapOA, and in Project 3 through selected genes, targeted for functional validation in
vivo in the dlPFC and NAc using genetic engineering, viral vector injection, and pharmacology approaches in
mice. Through this synergy we will distinguish between predisposing and exposure consequent
dysregulation and move toward mechanistic ...

## Key facts

- **NIH application ID:** 10888293
- **Project number:** 5P50DA054071-03
- **Recipient organization:** RESEARCH TRIANGLE INSTITUTE
- **Principal Investigator:** Peter Christopher Scacheri
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $544,428
- **Award type:** 5
- **Project period:** 2022-09-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10888293

## Citation

> US National Institutes of Health, RePORTER application 10888293, Gene Regulation in the Opioid Dependent Human Brain (Project 2) (5P50DA054071-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10888293. Licensed CC0.

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