U01DA058399

Single nucleus gene expression in moderate and compulsive opioid self-administration in a rodent model of HIV - Summary

The abuse of opioid drugs is associated with treatment non-compliance, greater risk of viral transmission, and more rapid clinical progression of HIV disease.

The overarching hypothesis behind the present project is that the analysis of molecular profiles of neuronal and glia cells at the single cell level in drug abuse-relevant brain regions by single nucleus RNA-Seq (snRNA-Seq) will reveal key genes that are dysregulated by the interaction of HIV with opioid abuse, resulting in neurodegeneration and cognitive impairment.

To test the present hypothesis, we propose to use validated systems biology strategies for the reconstruction and interrogation of a genome-scale integrated gene regulatory network in conjunction with snRNA-Seq from HIV transgenic (TG) rats, which harbor a non-replicating HIV-1 transgene expressing chronic low-levels of multiple HIV-1 proteins in disease-relevant cell types, and wild-type rats.

The occasional but limited use of a drug is clinically distinct from dependent drug use, which is characterized by the emergence of dependence and a negative emotional state when access to the drug is prevented that drives negative reinforcement, a powerful source of motivation for drug seeking.

Therefore, we will use a state-of-the-art paradigm of voluntary intravenous opioid self-administration under short access (SHA) conditions, which is characterized by a non-dependent, "recreational" pattern of drug use, and long access (LGA) conditions, which leads to dependent drug intake.

Escalated drug intake under LGA conditions is highly relevant to human substance use disorder (SUD) as it has been suggested that it models all 7 of the criteria for drug addiction in the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV and 7 of the 11 criteria in the DSM-V.

We showed that HIV TG rats self-administering oxycodone in this LGA paradigm of escalated self-administration display increased neural injury and cognitive impairment.

The project will address the following vexing question about opioid abuse in the setting of HIV infection: What are the cell types and cell states that drive neuroinflammation, neurodegeneration, virus expression, and escalated (dependent) opioid self-administration and cognitive impairment in the setting of HIV?

Overall, this collaborative interdisciplinary proposal integrating single cell level transcriptomics, state-of-the-art behavior methods in HIV TG and wild-type rats, and computational strategies for the deconvolution of the gene regulatory network at the single cell level will elucidate key mechanisms that underlie the effects of HIV and opioid abuse and their detrimental interactions on neuroHIV progression, virus expression and persistence.

The results will indicate transformative new mechanistic hypotheses that may lead to novel therapeutic concepts for opioid use disorder (OUD) in the setting of HIV and will establish key resources for the neuroHIV field to be made publicly available through the SCORCH Data Coordination Center and other public repositories.

Scripps Research Institute

TO SUPPORT BASIC AND CLINICAL NEUROSCIENCE, BIOMEDICAL, BEHAVIORAL AND SOCIAL SCIENCE, EPIDEMIOLOGIC, HEALTH SERVICES AND HEALTH DISPARITY RESEARCH. TO DEVELOP NEW KNOWLEDGE AND APPROACHES RELATED TO THE PREVENTION, DIAGNOSIS, TREATMENT, ETIOLOGY, AND CONSEQUENCES OF DRUG ABUSE AND ADDICTION, 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 LEGISLATION INTENDS THAT THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM 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, TO 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 920371000 United States

Single Zip Code

Single Cell Opioid Responses in the Context of HIV (SCORCH) Program Expansion: CNS Data Generation for Chronic Opioid, Methamphetamine, Cocaine and/or Cannabinoid Exposures (U01 - Clinical Trial Not Allowed) (RFA-DA-23-004)

Amendment Since initial award the total obligations have increased 200% from $1,348,648 to $4,045,522.