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

Award Number: U01DA056004
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Summary The abuse of stimulants such as methamphetamine (METH) exacerbates the deleterious effects of HIV infection. Here, we will carry out single nucleus RNA-Seq with the goal of identifying cell types and cell states that are pivotal in the effects of HIV and chronic methamphetamine (METH) self-administration on key brain regions relevant to the effects of persistent HIV infection and METH use disorder in HIV transgenic (Tg) rats, which harbor a non-replicating HIV-1 transgene and express chronic low-levels of multiple HIV-1 proteins. The occasional but limited use of a drug is clinically distinct from escalated drug use, which is characterized by the emergence of chronic compulsive drug-seeking and taking. Thus, we will use an established, state-of-the-art paradigm of voluntary intravenous drug self-administration under long access (LgA) conditions that leads to escalated (compulsive) METH intake in comparison to self-administration under short access (ShA) conditions, which leads to a moderate and stable pattern of METH intake. The paradigm of escalated drug intake under LgA conditions is highly relevant to the human substance use disorder (SUD) as 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 METH in this paradigm display increased compulsivity, neuroinflammation, and neural injury. The project will address the following vexing question about persistent HIV infection in the CNS: what are the cell types and cell states that drive neuroinflammation, neurodegeneration, and compulsive METH abuse in the setting of HIV that can reveal the pathogenic mechanisms behind neuroHIV disease progression, virus expression and persistence? The overarching hypothesis behind the present project is that the exploration of the gene regulatory network at the single cell level will elucidate key mechanisms that underlie the effects of HIV and METH abuse and their detrimental interactions on neuroHIV disease progression, virus expression, and virus persistence and will indicate novel therapeutic targets for neuroinflammation, neurodegeneration, and compulsivity to take METH. To test this hypothesis, we will use a validated systems biology strategy for the reconstruction and interrogation of genome-wide gene regulatory networks to identify the gene network dysregulations associated with the effects of HIV, compulsive METH use, and their interactions at single cell resolution gene profiling by single nucleus RNA-Seq. 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 is expected to identify novel mechanistic hypotheses that may lead to transformative new therapeutic concepts for substance use disorder (SUD) in the HIV setting, and will establish key resources for the neuroHIV field to be made publicly available through the SCORCH data coordination center.


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 = $588,372 )
2025	2025	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	4	12/20/2024	NON-COMPETING CONTINUATION	$588,372
														Subtotal = $588,372

Issue Date FY: 2024 ( Subtotal = $1,342,901 )
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	001	3	2/2/2024	NON-COMPETING CONTINUATION	$0
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	002	3	4/29/2024	NON-COMPETING CONTINUATION	$134,289
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	3	12/1/2023	NON-COMPETING CONTINUATION	$1,208,612
														Subtotal = $1,342,901

Issue Date FY: 2023 ( Subtotal = $1,318,918 )
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	2	12/1/2022	NON-COMPETING CONTINUATION	$1,187,028
2023	2023	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	001	2	1/18/2023	NON-COMPETING CONTINUATION	$131,890
														Subtotal = $1,318,918

Issue Date FY: 2022 ( Subtotal = $1,338,293 )
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	001	1	4/25/2022	NEW	$0
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	1	3/15/2022	NEW	$1,338,293
														Subtotal = $1,338,293

Grand Total All Awards = $4,588,484

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

Award Number: U01DA056004

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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