R01DA056602

Multiomic Profiling of Cell Types Mediating Opioid Use Disorder in Rats - Project Summary

The misuse and abuse of prescription pain relievers, such as oxycodone, contributed to the unprecedented opioid epidemic in the United States. The opioid crisis has devastating consequences on public health, including a surge in opioid misuse and related overdoses. Research is urgently needed to develop better treatments for opiate addiction.

Despite substantial knowledge of the pharmacokinetic and behavioral effects of oxycodone in various animal models, only a small number of candidate genes and neuroanatomical systems affected by opioids have been studied. Recent technological advances in the field of single-cell genomics are promising avenues for the unbiased discovery and characterization of brain cell types that respond to opioids.

In response to this RFA, we leverage an innovative multi-omics methodology (single-cell multiome ATAC + gene expression) to map the transcriptome and epigenome from the same cell across thousands of cells in brain regions relevant to the effects of opioid exposure. To this aim, we will use a rat model of extended access to oxycodone intravenous self-administration that recapitulates several neuroadaptations also observed in humans with opioid use disorders (OUD).

This approach provides an exceptional opportunity to systematically explore the cellular diversity of the opioid system and, at the same time, the causative mechanisms that regulate cellular states based on the associations between epigenetic changes and the expression of target genes in individual cells. We will integrate this innovative multi-omics methodology with rigorous computational approaches to explore the cellular organization of the opioid system in multiple brain regions and different stages of OUD progression (initial exposure, escalation of use, acute withdrawal, prolonged abstinence, and cue-induced relapse).

We have provided strong preliminary data that support the feasibility of our proposed plan for the following aims. In Aim 1, we will collect brain tissues at different stages of the extended access to oxycodone intravenous self-administration (IVSA) protocol, and we will generate single-cell genomics data from both male and female rats that are exposed to either saline or oxycodone.

In Aim 2, we will integrate these transcriptomic and epigenomic datasets to identify changes in cellular states, genes, and upstream regulators that are associated with different stages of oxycodone use. This approach will facilitate the identification of linkages between cis-regulatory elements and target genes.

In Aim 3, we will validate key cell type-specific findings by RNA-FISH and identify the top 3 target genes for functional validation. To this aim, we will use a viral-mediated CRISPR-Cas9 system to modulate addictive behaviors in rat models of oxycodone self-administration.

The results of this study will enable future studies that may identify new targets for the treatment and prevention of OUD.

San Diego University Of California

TO SUPPORT BASIC, CLINICAL, TRANSLATIONAL, AND IMPLEMENTATION RESEARCH IN THE FIELD OF SUBSTANCE USE. TO DEVELOP NEW KNOWLEDGE AND APPROACHES FOR THE PREVENTION, DIAGNOSIS, AND TREATMENT OF DRUG USE, MISUSE, AND ADDICTION, DRUG OVERDOSE, AND RELATED HEALTH OUTCOME, INCLUDING HIV/AIDS. TO SUPPORT RESEARCH TRAINING AND RESEARCH SCIENTIST DEVELOPMENT. TO SUPPORT DISSEMINATION OF RESEARCH FINDINGS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) LEGISLATION IS INTENDED TO EXPAND AND IMPROVE THE SBIR PROGRAMS TO EMPHASIZE AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF TECHNOLOGY DEVELOPED THROUGH FEDERAL SBIR RESEARCH AND DEVELOPMENT; INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT; AND FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN THE SBIR PROGRAM. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) LEGISTLATION IS INTENDED TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS; FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS; INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT; AND FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.279 - Drug Abuse and Addiction Research Programs

National Institute on Drug Abuse (NIDA) [HHS - NIH]

La Jolla, California 920930648 United States

Single Zip Code

Large Scale Mapping and/or Molecular Profiling of Ensembles and/or Cell-Types Mediating Opioid Action in the Rodent Brain (R01 - Clinical Trial Not Allowed) (RFA-DA-22-011)

Amendment Since initial award the total obligations have increased 449% from $554,504 to $3,046,001.