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The role of cannabinoids in the regulation of the blood brain barrier in the context of NeuroHIV and anti-retroviral therapy

Award Number: R01DA052970
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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The role of cannabinoids in the regulation of the blood brain barrier in the context of NeuroHIV and anti-retroviral therapy - PROJECT SUMARY/ABSTRACT Despite antiretroviral therapy (ART), neurocognitive complications continue to be highly prevalent in people living with HIV (PLWH). One explanation could be the constant compromise of the blood brain barrier (BBB) driven by chronic inflammatory responses. The introduction of medicinal marijuana into HIV treatment practice appear to be beneficial for several virus associated complications (ranging from chronic pain to appetite stimulation). Yet, the effects and mechanisms of cannabis on HIV associated chronic inflammation, the endocannabinoid system, immune modulation and neurologic disorders are minimally understood. As indicated in the RFA, preclinical models can provide a rigorous in-depth analysis of the molecular and cellular mechanisms at the intersection between phytocannabinoids, HIV and ART. To this end, we propose a comprehensive evaluation of the two most used cannabinoid compounds (THC, CBD) on BBB function, immune-endothelial interactions and neuroinflammation. We will utilize state of the art chip microfluidics models of the neurovascular unit (NVU) and animal models for HIV (w/ w/o ART). Previously, we discovered that the brain endothelium upregulate CB2 in HIV infected human brain tissue. We have also found that modulation of CB2 affects indices of HIV pathology (in-vivo) and regulates the BBB. Our preliminary studies identify the diverse effects that phytocannabinoids can have on the different properties of the BBB. Specifically, cannabinoids (THC, CBD) alone can enhance the physical barrier, partially reduce endothelial activation and augment efflux transporter activity. Although some of these effects may appear beneficial, the presence of HIV and ART changes how the function of the BBB is regulated by cannabinoid substances. For example, the augmented transporter activity by THC has important considerations for altering ART-CNS penetrability. Thus, we hypothesize that phytocannabinoids differentially modulates BBB function that are both beneficial and deleterious in NeuroHIV. In Aim 1, using our latest tissue-engineered microfluidic NVU model, we will perform analyses of the kinetic changes in BBB permeability, transporter status and immune-endothelial interaction. Then, in Aim 2, we will compare outcomes between widely used routes of cannabinoid administration (oral vs. inhaled) in vivo using two relevant models of HIV infection (‘humanized’ mice and a model of aseptic meningitis/encephalitis). Experiments will evaluate changes in the BBB in the context of ART and cannabinoid exposure. Finally, we propose to identify novel crosstalk mechanisms that bridge cannabinoid receptor signaling to signals that control BBB maintenance (Aim 3). It’s clear that cannabinoids exert unknown cell specific effects that contribute to the tumultuous interpretation of how these compounds impact NeuroHIV. Using innovative preclinical tools, our studies will contribute significantly towards understanding the consequences of cannabinoid use on the BBB in the modern era of NeuroHIV.


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 = $571,118 )
2025	2025	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	001	5	4/7/2025	NON-COMPETING CONTINUATION	$57,112
2025	2025	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	000	5	12/5/2024	NON-COMPETING CONTINUATION	$514,006
														Subtotal = $571,118

Issue Date FY: 2024 ( Subtotal = $604,910 )
2024	2024	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	000	4	1/17/2024	NON-COMPETING CONTINUATION	$544,419
2024	2024	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	001	4	4/25/2024	NON-COMPETING CONTINUATION	$60,491
														Subtotal = $604,910

Issue Date FY: 2023 ( Subtotal = $604,910 )
2023	2023	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	000	3	1/12/2023	NON-COMPETING CONTINUATION	$604,910
														Subtotal = $604,910

Issue Date FY: 2022 ( Subtotal = $611,409 )
2022	2022	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	000	2	12/8/2021	NON-COMPETING CONTINUATION	$550,267
2022	2022	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	001	2	3/29/2022	NON-COMPETING CONTINUATION	$61,142
														Subtotal = $611,409

Issue Date FY: 2021 ( Subtotal = $599,712 )
2021	2021	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	000	1	3/23/2021	NEW	$599,712
														Subtotal = $599,712

Grand Total All Awards = $2,992,059

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The role of cannabinoids in the regulation of the blood brain barrier in the context of NeuroHIV and anti-retroviral therapy

Award Number: R01DA052970

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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