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

Active Cooperative Agreement Awarded Last action

Award ID
U01DA058399
Recipient
Awarding agency
Obligated
$5,393,959

Award facts

Assistance listing
93.279 Drug Use and Addiction Research Programs
Completion date 66% complete
Place of performance
La Jolla, CA 92037, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
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.

Transactions

Action Obligated Date
Amendment $1,348,437
Amendment $1,348,437
Amendment $1,348,437
Original award $1,348,648

Subawards

Subrecipient Amount Awarded
Singulomics Corp Award revised to reflect Year 03 Funding $63,323
Singulomics Corp award has been revised to reflect Year 03 funding $50,000
Singulomics Corp Single nucleus gene expression in moderate and compulsive opioid self-administration in a rodent model of HIV $300,000

Quick answers

Who received award U01DA058399?

U01DA058399 was awarded to Scripps Research Institute by National Institute on Drug Abuse (National Institutes of Health) on September 1, 2023.

How much is award U01DA058399 worth?

$5,393,959 has been obligated on U01DA058399.

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