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Molecular effects of cannabinoids on the Blood Brain Barrier in HIV-infected brain

Award Number: R01DA059344
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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Molecular effects of cannabinoids on the Blood Brain Barrier in HIV-infected brain - Molecular effects of cannabinoids on the Blood Brain Barrier in HIV-infected brain Infection with the human immunodeficiency virus (HIV) causes significant disease morbidity in the brain, largely due to HIV-associated blood-brain barrier (BBB) disruption, inflammation, and persistence of HIV-infected CNS target cells such as microglia and macrophages, in spite of antiretroviral therapies (ART). Cannabis is a commonly used drug by people with HIV (PWH). Recently, we made the important observation that the impact of cannabis on BBB integrity markers is context-dependent, with signs of BBB disruption in non-HIV subjects, but paradoxically improving BBB integrity in PWH. This observation makes it a high priority to understand the mechanistic basis of this dichotamous influence of cannabis on the BBB. Cannabis and HIV interact in multifactorial ways that are still poorly understood. Importantly, HIV brain target cells microglia/macrophages express the cannabinoid receptor 2 (CB2R), while endothelial cells of the blood brain barrier (BBB) express both CB1R and CB2R and other cannabinoid receptors such as GPR55. It is also unknown how cannabis influences HIV-associated brain inflammation or the active/latent status of HIV in infected microglia. By protecting vascular integrity, it follows that cannabis will not only affect the select transport of substrates into the CNS, it will also directly influence the infiltration of inflammatory cells and the passage of ART or other treatments to the brain. The goal of this application is to test the hypothesis that cannabinoids positively impact BBB integrity in the HIV-infected brain environment, leading to reduced inflammatory cell infiltration and ultimately protection from HIV-associated neurocognitive disorders. Our analysis of two human brain microvascular endothelial cell (HBMEC) lines (hCMEC/D3 and HBMEC/ci18) with opposing vascular integrity responses to cannabinoids in the context of HIV suggest a molecular mechanism that can explain the context-dependent effects of cannabis in human BBB properties. Based on this preliminary data, our hypothesis posits that beneficial effects of cannabinoids in the context of HIV occur via CB2R, while cannabinoid signaling via GPR55 may be damaging. In the proposed studies we will model the human BBB in vitro using multicellular systems containing the two HBMEC lines in parallel, along with pericytes, astrocytes and microglia, to replicate HIV-induced vascular phenotypes characterized by loss of tight junction proteins and increased permeability to fluorescent labelled- dextran. Implications to infection in the brain will be validated in vivo using the EcoHIV mouse model, which develops BBB disorders. Successful completion of these experiments will define the molecular mechanisms that underlie the dichotomous influence of cannabis on the BBB in the context of HIV, forming the basis of new approaches aimed at optimizing BBB integrity.


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 = $808,747 )
2025	2025	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3525 JOHN HOPKINS CT STE 200	SAN DIEGO	CA	92121	SAN DIEGO	USA	Drug Use and Addiction Research Programs	002	2	8/7/2025	NON-COMPETING CONTINUATION	$189,846
2025	2025	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3525 JOHN HOPKINS CT STE 200	SAN DIEGO	CA	92121	SAN DIEGO	USA	Drug Use and Addiction Research Programs	001	2	6/30/2025	NON-COMPETING CONTINUATION	$618,901
2025	2024	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3525 JOHN HOPKINS CT STE 200	SAN DIEGO	CA	92121	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	1	6/23/2025	NEW	$0
														Subtotal = $808,747

Issue Date FY: 2024 ( Subtotal = $779,613 )
2024	2024	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3525 JOHN HOPKINS CT STE 200	SAN DIEGO	CA	92121	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	1	8/9/2024	NEW	$779,613
														Subtotal = $779,613

Grand Total All Awards = $1,588,360

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Molecular effects of cannabinoids on the Blood Brain Barrier in HIV-infected brain

Award Number: R01DA059344

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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