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Mitochondrial oxidative phosphorylation in substance use disorder and HIV

Award Number: R01DA065090
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2026
PERIOD OF PERFORMANCE END DATE: 12/31/2030

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Mitochondrial oxidative phosphorylation in substance use disorder and HIV - Project Summary This proposal aims to address the intertwined epidemics of HIV-associated neurocognitive disorders (HAND) and opioid use disorder (OUD) in the context of fentanyl addiction by investigating dysregulated oxidative phosphorylation and testing NAD+ treatment as a novel therapeutic strategy. Individuals living with HIV are at increased risk for opioid and fentanyl addiction, which exacerbate neuroinflammation and contribute to HAND. Our preliminary single nuclei transcriptomics analyses of human HIV subjects—with and without OUD—reveal significant dysregulation of oxidative phosphorylation pathways in glial cells, a finding that is further supported by data from rodent models of extended oxycodone self-administration. Building on these insights, we hypothesize that chronic NAD+ treatment may restore mitochondrial function, reduce oxidative stress, and preserve blood–brain barrier integrity, thereby mitigating HAND and opioid-induced neurotoxicity. To test this, Aim 1 will establish a MastBBB-HIV-Fentanyl 3D human assembloid model composed of iPSC-derived neurons, astrocytes, microglia, and blood–brain barrier cells (endothelial cells and pericytes) to model HIV/HAND under fentanyl exposure. We will employ single-cell transcriptomics to elucidate the molecular pathways modified by NAD+ treatment, along with functional assays to assess mitochondrial function, glial activation, neuronal damage, dendritic spine morphology, and BBB integrity. Aim 2 will develop an integrated HIV-Tg rat model of extended fentanyl self-administration, with single-nucleus transcriptomics of the nucleus accumbens conducted at four stages—naïve, intoxication, withdrawal, and abstinence—to evaluate NAD+’s efficacy in reducing withdrawal severity and cognitive deficits. A comprehensive battery of behavioral tests will correlate molecular changes with functional outcomes, and candidate genes common to both the human and rat models will be validated via cell-type-specific CRISPR knockdown and overexpression using AAV vectors. Collectively, these integrated studies aim to define the neurobiological mechanisms underlying HAND and opioid addiction while advancing NAD+ as a promising therapeutic target.


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: 2026 ( Subtotal = $1,387,755 )
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Drug Use and Addiction Research Programs	001	1	3/18/2026	NEW	$2,096
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	1	2/27/2026	NEW	$1,385,659
														Subtotal = $1,387,755

Grand Total All Awards = $1,387,755

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Mitochondrial oxidative phosphorylation in substance use disorder and HIV

Award Number: R01DA065090

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2026

PERIOD OF PERFORMANCE END DATE: 12/31/2030

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