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

Active Cooperative Agreement Awarded Last action

Award ID
U01DA056004
Recipient
Awarding agency
Obligated
$20,042,113

Award facts

Assistance listing
93.279 Drug Use and Addiction Research Programs
Completion date 98% 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 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.

Transactions

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Show all 37

Subawards

Subrecipient Amount Awarded
Singulomics Corp This award has been revised to reflect Year 5 funding $89,009
Singulomics Corp This award has been revised to reflect Year 5 funding. $89,009
Singulomics Corp Award a cost reimbursable subaward. $40,000
Alma Mater Studiorum - Universita' DI Bologna Single nucleus gene expression in moderate and compulsive drug self-administration in a rodent model of hiv $100,000

Quick answers

Who received award U01DA056004?

U01DA056004 was awarded to Scripps Research Institute by National Institute on Drug Abuse (National Institutes of Health) on March 15, 2022.

How much is award U01DA056004 worth?

$20,042,113 has been obligated on U01DA056004.

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