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

Award Number: U01DA058399
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $1,348,437 )
2025	2025	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	3	8/13/2025	NON-COMPETING CONTINUATION	$1,348,437
														Subtotal = $1,348,437

Issue Date FY: 2024 ( Subtotal = $1,348,437 )
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	2	8/26/2024	NON-COMPETING CONTINUATION	$1,348,437
														Subtotal = $1,348,437

Issue Date FY: 2023 ( Subtotal = $1,348,648 )
2023	2023	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	1	8/29/2023	NEW	$1,348,648
														Subtotal = $1,348,648

Grand Total All Awards = $4,045,522

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

Award Number: U01DA058399

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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